The DOI matches its Crossref record; 295 of the 297 references it cites were found in a registry or an index; 2 of the 353 sources its claims cite were checked for support.
The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes
Open accessAbstract
The pathophysiology of type 2 diabetes mellitus (DM) is varied and complex.However, the association of DM with obesity and inactivity indicates an important, and potentially pathogenic, link between fuel and energy homeostasis and the emergence of metabolic disease.Given the central role for mitochondria in fuel utilization and energy production, disordered mitochondrial function at the cellular level can impact whole-body metabolic homeostasis.Thus, the hypothesis that defective or insufficient mitochondrial function might play a potentially pathogenic role in mediating risk of type 2 DM has emerged in recent years.Here, we summarize current literature on risk factors for diabetes pathogenesis, on the specific role(s) of mitochondria in tissues involved in its pathophysiology, and on evidence pointing to alterations in mitochondrial function in these tissues that could contribute to the development of DM.We also review literature on metabolic phenotypes of existing animal models of impaired mitochondrial function.We conclude that, whereas the association between impaired mitochondrial function and DM is strong, a causal pathogenic relationship remains uncertain.However, we hypothesize that genetically determined and/or inactivity-mediated alterations in mitochondrial oxidative activity may directly impact adaptive responses to overnutrition, causing an imbalance between oxidative activity and nutrient load.This imbalance may lead in turn to chronic accumulation of lipid oxidative metabolites that can mediate insulin resistance and secretory dysfunction.More refined experimental strategies that accurately mimic potential reductions in mitochondrial functional capacity in humans at risk for diabetes will be required to determine the potential pathogenic role in human insulin resistance and type 2 DM.(Endocrine Reviews 31: 364 -395, 2010) I. Type 2 Diabetes Pathogenesis A. Risk factors associated with type 2 diabetes II.General Overview of Mitochondrial Biology A. The dynamic morphology of mitochondria B. Mechanisms that control mitochondrial density and capacity III.Role of Mitochondria in Tissue-Specific Contexts A. Muscle B. Adipose tissue C. Liver D. Pancreatic -cells IV.Experimental Strategies to Explore the Relationship between Mitochondrial Function and DM A. PGC-1 ␣ and  overexpression B. PGC-1 knockout models C. Other mitochondrial function defects V. Conclusions I. Type 2 Diabetes Pathogenesis T ype 2 diabetes mellitus (DM) in the United States and around the world has reached epidemic proportions.At present, 17.9 million people in the United States have been diagnosed with diabetes, with an additional 5.7 million undiagnosed (1).Together, this encompasses 8% of the population, and thus, diabetes is a major public health issue.In addition, current data indicate that 57 million Americans suffer from prediabetes (defined as fasting blood glucose between 100 and 125 mg/dl) (1).Diabetes disproportionately affects specific ethnic populations, with risk increased 1.8-fold in African-Americans, 1.7fold in Mexican-Americans, and 2.2-fold in Native Amer-
Overview
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Written from the paper’s full text.
TL;DR
This review argues that impaired mitochondrial oxidative function is strongly associated with type 2 diabetes but that a causal pathogenic relationship remains uncertain. It hypothesizes that genetically determined and/or inactivity-mediated reductions in mitochondrial oxidative activity can create an imbalance between oxidative capacity and nutrient load, promoting lipid metabolite accumulation, insulin resistance, and secretory dysfunction.
Key findings
- In skeletal muscle, OXPHOS complex I activity was reduced by about 40% in type 2 DM and by 20% in obese individuals; these differences did not remain after normalization for mitochondrial mass, suggesting reduced mitochondrial mass is a major contributor.
- In offspring of type 2 diabetic subjects, 31P spectroscopy showed fasting mitochondrial OXPHOS rates reduced by 30%, TCA cycle flux reduced by 30%, and muscle mitochondrial density 38% lower; insulin-stimulated ATP synthesis was reduced by more than 90% in nonobese first-degree relatives.
- OXPHOS mRNA expression was reduced by 20–30% in humans with type 2 DM, and muscle PGC-1α and PGC-1β mRNA were reduced by nearly 50% in diabetes; however, oxidative dysfunction was not observed in all insulin-resistant individuals.
- Mouse models with PGC-1α or PGC-1β deficiency or other mitochondrial defects often showed normal or enhanced insulin sensitivity, leading the authors to conclude that absolute mitochondrial deficiency alone does not directly produce insulin resistance.
Methods
- Design: narrative review and critical synthesis of published literature on mitochondrial function in type 2 diabetes pathogenesis.
- Data/sample: human studies of muscle, adipose tissue, liver, and pancreatic β-cells, plus animal models including PGC-1α/β transgenic and knockout mice and other mitochondrial function defects.
- Main analysis: qualitative integration of evidence across tissues and experimental models, with summary tables of PGC-1 transgenic and knockout phenotypes; no systematic review, meta-analysis, or new primary data are reported.
Limitations
- Stated: current human data are insufficient to determine whether impaired oxidative capacity causes insulin resistance or results from it; animal data are limited by interspecies comparisons and difficulty recapitulating subtle human mitochondrial changes and gene–fuel-load interactions.
- Stated: serial liver biopsies in humans are unlikely to be performed, limiting longitudinal tests of the proposed hepatic hypothesis.
- Evident from the text: as a narrative review, it does not use a systematic search strategy or formal quality appraisal, and the cited human studies vary by population, obesity, fitness, ethnicity, and tissue, which the authors note may explain discordant findings.
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Claims the paper makes
195 Not checked yet · 80 Own interpretation · 4 No basis given · 2 Partly supported · 1 Own result · accuracy not yet measured
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In the paper
“Recent human data have highlighted the importance of disordered hepatic metabolism, including inappropriately increased hepatic glucose production, hyperlipidemia, and lipid accumulation, in both obesity and type 2 DM (207).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > C. Liver
What the sources say
- Partly supportedcites [207] Kotronen, 2008, Tissue specificity of insulin resistance in humans: fat in the liver rather than muscle is associated with features of the metabolic syndrome., Diabetologia sourceExperimental — accuracy not yet measured
The Introduction and Discussion link liver fat to impaired insulin suppression of hepatic glucose production and VLDL production, and to elevated triacylglycerols. However, the study examined 45 non-diabetic men (Participants and study design; Abstract). Its findings therefore do not establish the claimed pattern in people with type 2 diabetes. (LLM, conf=0.88)
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The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Subsequent recruitment of granules to the plasma membrane (second phase) appears to depend on mitochondrial metabolites produced by anaplerosis (238).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > D. Pancreatic -cells 1. Roles of mitochondria in -cells
What the sources say
- Partly supportedcites [238] Hasan, 2008, Impaired anaplerosis and insulin secretion in insulinoma cells caused by small interfering RNA-mediated suppression of pyruvate carboxylase., J Biol Chem sourceExperimental — accuracy not yet measured
The Conclusions report that downstream products of anaplerosis support insulin secretion in pyruvate-carboxylase knockdown insulinoma cells. The paper does not establish that those products specifically drive granule recruitment to the plasma membrane during the second phase of secretion. (LLM, conf=0.86)
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- Partly supported
In the paper
“Similarly, Boushel et al. (115) found modest reductions in ADP and succinate-stimulated oxygen consumption in permeabilized muscle fibers from obese individuals with type 2 DM.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 3. Evidence for reduced muscle mitochondrial oxidative function in DM
What the sources say
- Not checked yetcites [115] Boushel, 2007, Patients with type 2 diabetes have normal mitochondrial function in skeletal muscle., Diabetologia source
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This imbalance may lead in turn to chronic accumulation of lipid oxidative metabolites that can mediate insulin resistance and secretory dysfunction.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > Abstract
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In the paper
“Several longitudinal studies have indicated that insulin resistance, measured as reduced insulin-stimulated glucose disposal during the hyperinsulinemic euglycemic clamp or by iv glucose tolerance testing, is common in high-risk individuals years before the onset of type 2 DM (27)(28)(29).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > A. Risk factors associated with type 2 diabetes
What the sources say
- Not checked yetcites (27)(28)(29)
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Moreover, oxidative activity (e.g., citrate synthase, acyl CoA dehydrogenase) is a robust correlate of insulin sensitivity, even better than either im triglycerides or long-chain fatty acyl CoA (110).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 3. Evidence for reduced muscle mitochondrial oxidative function in DM
What the sources say
- Not checked yetcites [110] Bruce, 2003, Muscle oxidative capacity is a better predictor of insulin sensitivity than lipid status., J Clin Endocrinol Metab source
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Analysis of global gene expression patterns has also demonstrated a 20 -30% reduction in mRNA expression levels for multiple nuclear-encoded genes of the OXPHOS pathway in humans with type 2 DM (121-123).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 3. Evidence for reduced muscle mitochondrial oxidative function in DM
What the sources say
- Not checked yetcites [121] Mootha, 2003, PGC-1α-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes., Nat Genet source
- Not checked yetcites [122] Patti, 2003, Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes: potential role of PGC1 and NRF1., Proc Natl Acad Sci USA source
- Not checked yetcites [123] Sreekumar, 2002, Gene expression profile in skeletal muscle of type 2 diabetes and the effect of insulin treatment., Diabetes source
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Several conditions associated with susceptibility to insulin resistance, including obesity, lipid accumulation, and aging, have all been associated with reduced nuclearencoded OXPHOS gene expression.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 4. Factors affecting OXPHOS gene expression in muscle
What the sources say
- Not checked yetcites [127] Crunkhorn, 2007, Peroxisome proliferator activator receptor γ coactivator-1 expression is reduced in obesity: potential pathogenic role of saturated fatty acids and p38 mitogen-activated protein kinase activation., J Biol Chem source
- Not checked yetcites [128] Sparks, 2005, A high-fat diet coordinately downregulates genes required for mitochondrial oxidative phosphorylation in skeletal muscle., Diabetes source
- Not checked yetcites [129] Richardson, 2005, Lipid infusion decreases the expression of nuclear encoded mitochondrial genes and increases the expression of extracellular matrix genes in human skeletal muscle., J Biol Chem source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Reduced OXPHOS gene expression has been observed in response to genetic and nutritional obesity (127), short-term high-fat feeding (even in humans) (128), lipid infusion (129), and lipid loading of myotubes (127).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 4. Factors affecting OXPHOS gene expression in muscle
What the sources say
- Not checked yetcites [128] Sparks, 2005, A high-fat diet coordinately downregulates genes required for mitochondrial oxidative phosphorylation in skeletal muscle., Diabetes source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Interestingly, a recent study of Asian Indian subjects found no correlation between changes in OXPHOS gene expression and insulin resistance (125).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 3. Evidence for reduced muscle mitochondrial oxidative function in DM
What the sources say
- Not checked yetcites [125] Nair, 2008, Asian Indians have enhanced skeletal muscle mitochondrial capacity to produce ATP in association with severe insulin resistance., Diabetes source
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, defects in lipid oxidation in DM can be significant contributors to disordered oxidative metabolism even in the absence of detectable alterations in OXPHOS gene expression or function.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 3. Evidence for reduced muscle mitochondrial oxidative function in DM
plainconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“Reduced OXPHOS gene expression has been observed in response to genetic and nutritional obesity (127), short-term high-fat feeding (even in humans) (128), lipid infusion (129), and lipid loading of myotubes (127).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 4. Factors affecting OXPHOS gene expression in muscle
What the sources say
- Not checked yetcites [127] Crunkhorn, 2007, Peroxisome proliferator activator receptor γ coactivator-1 expression is reduced in obesity: potential pathogenic role of saturated fatty acids and p38 mitogen-activated protein kinase activation., J Biol Chem source
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, one possible mechanism by which impaired mitochondrial function might contribute to insulin resistance is via altered metabolism of fatty acids.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 2. Potential mechanisms by which impaired muscle mitochondrial oxidative function could result in insulin resistance
hedgedconditional- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Because these short-term experimental protocols (several hours in duration at most) would not be expected to alter mitochondrial density, DNA content, or number, these data strongly suggest that inability to appropriately modulate oxidative function in response to the prevailing energetic environment is a signature of insulin resistance and diabetes risk.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 3. Evidence for reduced muscle mitochondrial oxidative function in DM
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Importantly, similar reductions in OXPHOS gene expression have been observed in some, but not all, populations of insulin-resistant, but completely normoglycemic, individuals (122, 124).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 3. Evidence for reduced muscle mitochondrial oxidative function in DM
What the sources say
- Not checked yetcites [122] Patti, 2003, Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes: potential role of PGC1 and NRF1., Proc Natl Acad Sci USA source
- Not checked yetcites [124] Morino, 2005, Reduced mitochondrial density and increased IRS-1 serine phosphorylation in muscle of insulin-resistant offspring of type 2 diabetic parents., J Clin Invest source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“This possibility is consistent with electron microscopy demonstrating diminished mitochondrial size in obesity and diabetes (116), particularly in subsarcolemmal fractions (114).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 3. Evidence for reduced muscle mitochondrial oxidative function in DM
What the sources say
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“However, circulating triglycerides were significantly elevated in both nondiabetic and diabetic individuals of Asian Indian origin (125).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 3. Evidence for reduced muscle mitochondrial oxidative function in DM
What the sources say
- Not checked yetcites [125] Nair, 2008, Asian Indians have enhanced skeletal muscle mitochondrial capacity to produce ATP in association with severe insulin resistance., Diabetes source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“First, oxidative dysfunction is not observed in all insulin resistant individuals (125).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 4. Factors affecting OXPHOS gene expression in muscle
What the sources say
- Not checked yetcites [125] Nair, 2008, Asian Indians have enhanced skeletal muscle mitochondrial capacity to produce ATP in association with severe insulin resistance., Diabetes source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Similarly, in rats bred for low aerobic capacity over multiple generations, expression of several OXPHOS genes is markedly reduced, even in the absence of obesity (134).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 4. Factors affecting OXPHOS gene expression in muscle
What the sources say
- Not checked yetcites [134] Wisløff, 2005, Cardiovascular risk factors emerge after artificial selection for low aerobic capacity., Science source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Aging is also linked to impaired oxidative function (140) in parallel with reductions in OXPHOS gene expression, including COX7A1, NDUFB6, and ATP50 (136 -138).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 4. Factors affecting OXPHOS gene expression in muscle
What the sources say
- Not checked yetcites [140] Petersen, 2003, Mitochondrial dysfunction in the elderly: possible role in insulin resistance., Science source
- Not checked yetcites [136] Rönn, 2008, Age influences DNA methylation and gene expression of COX7A1 in human skeletal muscle., Diabetologia source
- Not checked yetcites [137] Ling, 2004, Multiple environmental and genetic factors influence skeletal muscle PGC-1α and PGC-1β gene expression in twins., J Clin Invest source
- Not checked yetcites [138] Rönn, 2009, Genetic variation in ATP5O is associated with skeletal muscle ATP50 mRNA expression and glucose uptake in young twins, PLoS ONE source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Genetic and epigenetic modifications may also contribute to reduced expression of OXPHOS genes in type 2 DM.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 4. Factors affecting OXPHOS gene expression in muscle
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“For example, expression of COX7A1, a complex IV gene down-regulated in type 2 DM, is heritable (50 -72% heritability, as assessed by analysis in monozygotic and dizygotic twins), indicating a strong genetic or shared familial environmental contribution (136).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 4. Factors affecting OXPHOS gene expression in muscle
What the sources say
- Not checked yetcites [136] Rönn, 2008, Age influences DNA methylation and gene expression of COX7A1 in human skeletal muscle., Diabetologia source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Reductions in OXPHOS gene expression in patients with established type 2 DM can be partially normalized by insulin treatment (123).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 4. Factors affecting OXPHOS gene expression in muscle
What the sources say
- Not checked yetcites [123] Sreekumar, 2002, Gene expression profile in skeletal muscle of type 2 diabetes and the effect of insulin treatment., Diabetes source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Similarly, relatively short-term reductions in serum fatty acids and intracellular fatty acyl CoA levels mediated by acipimox treatment in healthy humans are associated with reduced expression of nuclear-encoded mitochondrial oxidative genes-in parallel with enhanced insulin sensitivity (294).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 4. Factors affecting OXPHOS gene expression in muscle
What the sources say
- Not checked yetcites [294] Bajaj, 2007, Paradoxical changes in muscle gene expression in insulin-resistant subjects after sustained reduction in plasma free fatty acid concentration., Diabetes source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“In humans, maximal oxygen uptake is robustly correlated with OXPHOS gene expression (133).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 4. Factors affecting OXPHOS gene expression in muscle
What the sources say
- Not checked yetcites [133] Parikh, 2008, Molecular correlates for maximal oxygen uptake and type 1 fibers, Am J Physiol Endocrinol Metab source
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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In the paper
“Reduced OXPHOS gene expression has been observed in response to genetic and nutritional obesity (127), short-term high-fat feeding (even in humans) (128), lipid infusion (129), and lipid loading of myotubes (127).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 4. Factors affecting OXPHOS gene expression in muscle
What the sources say
- Not checked yetcites [127] Crunkhorn, 2007, Peroxisome proliferator activator receptor γ coactivator-1 expression is reduced in obesity: potential pathogenic role of saturated fatty acids and p38 mitogen-activated protein kinase activation., J Biol Chem source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“Similar patterns are observed for the complex I gene NDUFB6 (137) and the ATP synthase component ATP5O (138).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 4. Factors affecting OXPHOS gene expression in muscle
What the sources say
- Not checked yetcites [137] Ling, 2004, Multiple environmental and genetic factors influence skeletal muscle PGC-1α and PGC-1β gene expression in twins., J Clin Invest source
- Not checked yetcites [138] Rönn, 2009, Genetic variation in ATP5O is associated with skeletal muscle ATP50 mRNA expression and glucose uptake in young twins, PLoS ONE source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Similarly, withdrawal of insulin in individuals with type 1 diabetes reduces muscle OXPHOS gene expression and ATP production rates (142).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 4. Factors affecting OXPHOS gene expression in muscle
What the sources say
- Not checked yetcites [142] Karakelides, 2007, Effect of insulin deprivation on muscle mitochondrial ATP production and gene transcript levels in type 1 diabetic subjects., Diabetes source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Reduced OXPHOS gene expression has been observed in response to genetic and nutritional obesity (127), short-term high-fat feeding (even in humans) (128), lipid infusion (129), and lipid loading of myotubes (127).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 4. Factors affecting OXPHOS gene expression in muscle
What the sources say
- Not checked yetcites [129] Richardson, 2005, Lipid infusion decreases the expression of nuclear encoded mitochondrial genes and increases the expression of extracellular matrix genes in human skeletal muscle., J Biol Chem source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“Interestingly, epigenetic mechanisms may also contribute to these patterns because reduced expression parallels increased DNA methylation of both the COX7A1 promoter (136) and NDUFB6 (137, 139).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 4. Factors affecting OXPHOS gene expression in muscle
What the sources say
- Not checked yetcites [136] Rönn, 2008, Age influences DNA methylation and gene expression of COX7A1 in human skeletal muscle., Diabetologia source
- Not checked yetcites [137] Ling, 2004, Multiple environmental and genetic factors influence skeletal muscle PGC-1α and PGC-1β gene expression in twins., J Clin Invest source
- Not checked yetcites [139] Ling, 2009, Epigenetics: a molecular link between environmental factors and type 2 diabetes., Diabetes source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“However, several lines of evidence suggest that this may not be a causal relationship in all situations.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 4. Factors affecting OXPHOS gene expression in muscle
hedged- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Mediators of mitochondrial biogenesis, including ERR␣, may contribute to the strong heritability of OXPHOS components.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 4. Factors affecting OXPHOS gene expression in muscle
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“However, these responses are not observed in all studies of high-fat feeding; in fact, some studies demonstrate that high-fat feeding is associated with increased numbers of mitochondrial protein and DNA content, potentially mediated by chronic fatty acid activation of PPAR nuclear receptors (130 -132).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 4. Factors affecting OXPHOS gene expression in muscle
What the sources say
- Not checked yetcites [130] Garcia-Roves, 2007, Raising plasma fatty acid concentration induces increased biogenesis of mitochondria in skeletal muscle., Proc Natl Acad Sci USA source
- Not checked yetcites [131] Hancock, 2008, High-fat diets cause insulin resistance despite an increase in muscle mitochondria., Proc Natl Acad Sci USA source
- Not checked yetcites [132] Sreekumar, 2002, Effects of caloric restriction on mitochondrial function and gene transcripts in rat muscle, Am J Physiol Endocrinol Metab source
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In the paper
“Reduced physical fitness is associated with reduced muscle OXPHOS gene expression.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 4. Factors affecting OXPHOS gene expression in muscle
What the sources say
- Not checked yetcites [133] Parikh, 2008, Molecular correlates for maximal oxygen uptake and type 1 fibers, Am J Physiol Endocrinol Metab source
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In the paper
“In summary, insulin resistance has been associated with alterations in skeletal muscle mitochondrial oxidative function and its transcriptional regulatory pathways.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 4. Factors affecting OXPHOS gene expression in muscle
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In the paper
“For example, saturated fatty acids reduce PGC-1␣ promoter transcriptional activity and expression in cultured myotubes, in parallel with reduced OXPHOS expression and O 2 consumption (127).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 4. Factors affecting OXPHOS gene expression in muscle
What the sources say
- Not checked yetcites [127] Crunkhorn, 2007, Peroxisome proliferator activator receptor γ coactivator-1 expression is reduced in obesity: potential pathogenic role of saturated fatty acids and p38 mitogen-activated protein kinase activation., J Biol Chem source
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In the paper
“Such depots appear to be less active as a function of aging and/or obesity (151, 164 -167).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 2. Potential mechanisms by which impaired adipose tissue mitochondrial oxidative capacity could result in insulin resistance
What the sources say
- Not checked yetcites [151] Cypess, 2009, Identification and importance of brown adipose tissue in adult humans., N Engl J Med source
- Not checked yetcites [164] Saito, 2009, High incidence of metabolically active brown adipose tissue in healthy adult humans: effects of cold exposure and adiposity., Diabetes source
- Not checked yetcites [165] Lichtenbelt, 2009, Cold-activated brown adipose tissue in healthy men., N Engl J Med source
- Not checked yetcites [166] Virtanen, 2009, Functional brown adipose tissue in healthy adults., N Engl J Med source
- Not checked yetcites [167] Zingaretti, 2009, The presence of UCP1 demonstrates that metabolically active adipose tissue in the neck of adult humans truly represents brown adipose tissue., FASEB J source
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In the paper
“These results suggest that, in the absence of mechanisms to ensure continuously elevated fuel oxidation, such as those present in brown fat, uncoupling of white adipose tissue mitochondria may decrease ATP levels and impair anabolic flux (183).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 2. Potential mechanisms by which impaired adipose tissue mitochondrial oxidative capacity could result in insulin resistance
What the sources say
- Not checked yetcites [183] Rossmeisl, 2004, Role of energy charge and AMP-activated protein kinase in adipocytes in the control of body fat stores, Int J Obes Relat Metab Disord source
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In the paper
“However, UCP1 expression in adipocytes driven by the aP2 promoter failed to significantly raise resting metabolic rate (185).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 2. Potential mechanisms by which impaired adipose tissue mitochondrial oxidative capacity could result in insulin resistance
What the sources say
- Not checked yetcites [185] Stefl, 1998, Brown fat is essential for cold-induced thermogenesis but not for obesity resistance in aP2-Ucp mice, Am J Physiol
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In the paper
“Interestingly, a recent compendium of mitochondrial proteins from 14 different mouse tissues indicates that white adipocyte mitochondria contain a more diverse protein repertoire than mitochondria from heart, skeletal muscle, or brain (31).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 1. Roles of mitochondria in adipose tissue
What the sources say
- Not checked yetcites [31] Pagliarini, 2008, A mitochondrial protein compendium elucidates complex I disease biology., Cell source
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In the paper
“Moreover, in cultured adipocytes, ectopic expression of UCP1 impairs fatty acid synthesis (186, 187).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 2. Potential mechanisms by which impaired adipose tissue mitochondrial oxidative capacity could result in insulin resistance
What the sources say
- Not checked yetcites [186] Rossmeisl, 2000, Decreased fatty acid synthesis due to mitochondrial uncoupling in adipose tissue, FASEB J source
- Not checked yetcites [187] Si, 2007, Effects of forced uncoupling protein 1 expression in 3T3–L1 cells on mitochondrial function and lipid metabolism., J Lipid Res source
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In the paper
“In addition to effects on fuel utilization, decreased mitochondrial capacity in adipocytes may also alter adipocyte insulin sensitivity and/or function due to the high energetic requirements for fatty acid storage, adipokine secretion (160), insulin signaling (161), and glucose uptake.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 2. Potential mechanisms by which impaired adipose tissue mitochondrial oxidative capacity could result in insulin resistance
What the sources say
- Not checked yetcites [160] Koh, 2007, Essential role of mitochondrial function in adiponectin synthesis in adipocytes., Diabetes source
- Not checked yetcites [161] Shi, 2008, Paradoxical effect of mitochondrial respiratory chain impairment on insulin signaling and glucose transport in adipose cells., J Biol Chem source
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In the paper
“Gain-of-function studies in mice where ectopic expression of UCPs mitigate diet-induced obesity support the notion that uncoupling could be sufficient (183, 184).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 2. Potential mechanisms by which impaired adipose tissue mitochondrial oxidative capacity could result in insulin resistance
What the sources say
- Not checked yetcites [183] Rossmeisl, 2004, Role of energy charge and AMP-activated protein kinase in adipocytes in the control of body fat stores, Int J Obes Relat Metab Disord source
- Not checked yetcites [184] Harper, 2001, Mitochondrial uncoupling as a target for drug development for the treatment of obesity., Obes Rev source
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In the paper
“In this tissue, electron transport is greatly accelerated due to tissue-specific expression of the mitochondrial UCP1.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 1. Roles of mitochondria in adipose tissue
What the sources say
- Not checked yetcites [150] Cannon, 1985, The biochemistry of an inefficient tissue: brown adipose tissue., Essays Biochem
- Not checked yetcites [153] Bouillaud, 1985, Molecular approach to thermogenesis in brown adipose tissue: cDNA cloning of the mitochondrial uncoupling protein., Proc Natl Acad Sci USA source
- Not checked yetcites [154] Jacobsson, 1985, Mitochondrial uncoupling protein from mouse brown fat. Molecular cloning, genetic mapping, and mRNA expression., J Biol Chem source
- Not checked yetcites [155] Ricquier, 1997, The mitochondrial uncoupling protein: structural and genetic studies., Prog Nucleic Acid Res Mol Biol source
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In the paper
“Second, oxidative activity is determined by the need to generate energy to meet cellular demands, e.g., contraction and ion transport; thus oxidative capacity is not likely to be limiting in the resting state in muscle (3).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 4. Factors affecting OXPHOS gene expression in muscle
What the sources say
- Not checked yetcites [3] Holloszy, 2009, Skeletal muscle “mitochondrial deficiency” does not mediate insulin resistance., Am J Clin Nutr source
hedged- Asserted: passes — The authors put it forward as true.
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In the paper
“Thus, white adipocyte mitochondria appear to be equipped for a broader array of functions compared with mitochondria in tissues that must sustain rapid bursts of energy-requiring processes.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 1. Roles of mitochondria in adipose tissue
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“UCP1-mediated uncoupling alone, however, cannot fully account for the large thermogenic capacity of brown adipocytes in the absence of mechanisms that ensure continuous substrate delivery to the ETC.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 1. Roles of mitochondria in adipose tissue
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“This apparent paradoxical result (high insulin sensitivity despite deficiency in lipid storage), appears to be due to the increased mitochondrial density and activity in white adipocytes, which are brown-like in their increased capacity to oxidize large quantities of fatty acids.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 4. Factors affecting mitochondrial OXPHOS expression and function in adipose tissue
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In the paper
“For example, mice with adipose tissue-specific ablation of the insulin receptor (FIRKO mice) display high levels of mitochondrial genes involved in fatty acid oxidation and OXPHOS over the lifespan of the animals (201).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 3. Evidence for reduced adipose tissue mitochondrial capacity in DM
What the sources say
- Not checked yetcites [201] Katic, 2007, Mitochondrial gene expression and increased oxidative metabolism: role in increased lifespan of fat-specific insulin receptor knock-out mice., Aging Cell source
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In the paper
“The genetic program leading to brown adipose tissue development, and potentially to the high abundance of mitochondria, is initiated by the zinc-finger protein PRDM16 (202)(203)(204).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 4. Factors affecting mitochondrial OXPHOS expression and function in adipose tissue
What the sources say
- Not checked yetcites [202] Seale, 2007, Transcriptional control of brown fat determination by PRDM16., Cell Metab source
- Not checked yetcites [203] Seale, 2008, PRDM16 controls a brown fat/skeletal muscle switch., Nature source
- Not checked yetcites [204] Timmons, 2007, Myogenic gene expression signature establishes that brown and white adipocytes originate from distinct cell lineages., Proc Natl Acad Sci USA source
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In the paper
“Administration of thiazolidinediones induces changes in mitochondrial content and remodeling in white adipocytes concomitantly with an improvement in insulin sensitivity (170, 173, 177, 190, 194 -198).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 3. Evidence for reduced adipose tissue mitochondrial capacity in DM
What the sources say
- Not checked yetcites [170] Bogacka, 2005, Pioglitazone induces mitochondrial biogenesis in human subcutaneous adipose tissue in vivo., Diabetes source
- Not checked yetcites [173] Orci, 2004, Rapid transformation of white adipocytes into fat-oxidizing machines., Proc Natl Acad Sci USA source
- Not checked yetcites [177] Wilson-Fritch, 2004, Mitochondrial remodeling in adipose tissue associated with obesity and treatment with rosiglitazone., J Clin Invest source
- Not checked yetcites [190] Rong, 2007, Adipose mitochondrial biogenesis is suppressed in db/db and high-fat diet-fed mice and improved by rosiglitazone., Diabetes source
- Not checked yetcites [194] Boden, 2005, Thiazolidinediones upregulate fatty acid uptake and oxidation in adipose tissue of diabetic patients., Diabetes source
- Not checked yetcites [195] Bogacka, 2005, Structural and functional consequences of mitochondrial biogenesis in human adipocytes in vitro., J Clin Endocrinol Metab source
- Not checked yetcites [196] Digby, 1998, Thiazolidinedione exposure increases the expression of uncoupling protein 1 in cultured human preadipocytes., Diabetes source
- Not checked yetcites [197] Goetzman, 2009, The regulation of acyl-CoA dehydrogenases in adipose tissue by rosiglitazone., Obesity (Silver Spring) source
- Not checked yetcites [198] Laplante, 2006, Mechanisms of the depot specificity of peroxisome proliferator-activated receptor γ action on adipose tissue metabolism., Diabetes source
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In the paper
“In parallel, expression of nuclear-encoded OXPHOS genes is down-regulated in visceral adipose tissue of humans with type 2 DM (193).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 3. Evidence for reduced adipose tissue mitochondrial capacity in DM
What the sources say
- Not checked yetcites [193] Dahlman, 2006, Downregulation of electron transport chain genes in visceral adipose tissue in type 2 diabetes independent of obesity and possibly involving tumor necrosis factor-α., Diabetes source
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In the paper
“Similarly, patterns of gene expression are distinct in liver (32).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 1. Role of mitochondria in liver
What the sources say
- Not checked yetcites [32] Mootha, 2003, Integrated analysis of protein composition, tissue diversity, and gene regulation in mouse mitochondria., Cell source
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In the paper
“Nitric oxide production by the endothelial nitric oxide synthase has also been linked to enhanced adipose tissue mitochondrial biogenesis and prevention of high-fat dietinduced obesity (200).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 4. Factors affecting mitochondrial OXPHOS expression and function in adipose tissue
What the sources say
- Not checked yetcites [200] Tedesco, 2008, Cannabinoid type 1 receptor blockade promotes mitochondrial biogenesis through endothelial nitric oxide synthase expression in white adipocytes., Diabetes source
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In the paper
“Interestingly, in cultured adipocytes, impairment of respiratory chain function through depletion of Tfam during adipocyte differentiation results in impaired insulinstimulated glucose transport (161); data in animal models are necessary to determine the physiological relevance of this finding.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 2. Potential mechanisms by which impaired adipose tissue mitochondrial oxidative capacity could result in insulin resistance
What the sources say
- Not checked yetcites [161] Shi, 2008, Paradoxical effect of mitochondrial respiratory chain impairment on insulin signaling and glucose transport in adipose cells., J Biol Chem source
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In the paper
“Hepatic lipid accumulation may result when adipose lipid storage capacity is exceeded, as in obesity or adipocyte dysfunction (e.g., lipodystrophy) (213).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 2. Potential mechanisms by which impaired hepatic mitochondrial function could influence hepatic insulin sensitivity
What the sources say
- Not checked yetcites [213] Agarwal, 2006, Genetic disorders of adipose tissue development, differentiation, and death., Annu Rev Genomics Hum Genet source
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In the paper
“Thus, increased ROS related to increased fatty acid oxidation and/or hyperglycemia might contribute to up-regulation of OXPHOS gene expression in coexisting obesity and type 2 DM.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 3. Evidence for impaired liver mitochondrial function in diabetes and NASH
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In the paper
“Up-regulation of PGC-1 in this context may contribute to increased gluconeogenesis and hyperlipidemia, in part via coactivation of sterol regulatory element binding transcription factor 1, as observed in high-fat diet-fed mice (223).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 3. Evidence for impaired liver mitochondrial function in diabetes and NASH
What the sources say
- Not checked yetcites [223] Lin, 2003, PGC-1β in the regulation of hepatic glucose and energy metabolism., J Biol Chem source
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In the paper
“Recent application of 31 P NMR to the liver in humans demonstrates that rates of ATP synthesis are 3-fold higher in liver than in muscle (212).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 1. Role of mitochondria in liver
What the sources say
- Not checked yetcites [212] Schmid, 2008, Quantitative ATP synthesis in human liver measured by localized 31P spectroscopy using the magnetization transfer experiment., NMR Biomed source
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In the paper
“In summary, available data indicate that hepatic lipid accumulation and insulin resistance are intimately linked with mitochondrial oxidative dysfunction.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 3. Evidence for impaired liver mitochondrial function in diabetes and NASH
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“In contrast, studies in Japanese individuals with established DM and modest obesity (BMI 27 kg/m 2 ) observed a modestly increased expression of multiple genes within all complexes of OXPHOS complexes, in parallel with BMI and insulin resistance (measured by homeostasis model assessment of insulin resistance, HOMA-IR) (231).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 3. Evidence for impaired liver mitochondrial function in diabetes and NASH
What the sources say
- Not checked yetcites [231] Takamura, 2008, Obesity upregulates genes involved in oxidative phosphorylation in livers of diabetic patients., Obesity (Silver Spring) source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“However, more broadly, these data indicate that hepatic insulin resistance can cause mitochondrial dysfunction, at least in mice.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 2. Potential mechanisms by which impaired hepatic mitochondrial function could influence hepatic insulin sensitivity
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“Conversely, modest weight loss (about 8 kg) normalizes intrahepatic lipid in subjects with type 2 DM, in parallel with normalization of hepatic insulin sensitivity, even in the absence of changes in intramyocellular lipid accumulation or circulating adipocytokines (215).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 2. Potential mechanisms by which impaired hepatic mitochondrial function could influence hepatic insulin sensitivity
What the sources say
- Not checked yetcites [215] Petersen, 2005, Reversal of nonalcoholic hepatic steatosis, hepatic insulin resistance, and hyperglycemia by moderate weight reduction in patients with type 2 diabetes., Diabetes source
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In the paper
“These data indicate that normal insulin signaling, which inhibits Foxo1, is required for maintenance of normal mitochondrial function in this model.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 2. Potential mechanisms by which impaired hepatic mitochondrial function could influence hepatic insulin sensitivity
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“These effects in the liver appear to be mediated via reduced expression of the insulin receptor (221).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 2. Potential mechanisms by which impaired hepatic mitochondrial function could influence hepatic insulin sensitivity
What the sources say
- Not checked yetcites [221] Ruddock, 2008, Saturated fatty acids inhibit hepatic insulin action by modulating insulin receptor expression and post-receptor signalling., J Biochem source
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In the paper
“Interestingly, hepatic lipid accumulation is also a robust predictor of not only hepatic, but also muscle and adipose insulin sensitivity [better than intraabdominal fat, body mass index (BMI), or other obesity measures] (217, 218).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 2. Potential mechanisms by which impaired hepatic mitochondrial function could influence hepatic insulin sensitivity
What the sources say
- Not checked yetcites [217] Hwang, 2007, Increased intrahepatic triglyceride is associated with peripheral insulin resistance: in vivo MR imaging and spectroscopy studies, Am J Physiol Endocrinol Metab source
- Not checked yetcites [218] Korenblat, 2008, Liver, muscle, and adipose tissue insulin action is directly related to intrahepatic triglyceride content in obese subjects., Gastroenterology source
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Mitochondrial dysfunction was reversed by deletion of Foxo1.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 2. Potential mechanisms by which impaired hepatic mitochondrial function could influence hepatic insulin sensitivity
What the sources say
- Not checked yetcites [229] Cheng, 2009, Foxo1 integrates insulin signaling with mitochondrial function in the liver., Nat Med source
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In the paper
“Moreover, NASH is characterized by prominent abnormalities in mitochondrial ultrastructure, with increased size, loss of cristae, and paracrystalline inclusion bodies similar to those observed in some mitochondrial myopathies (235).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 3. Evidence for impaired liver mitochondrial function in diabetes and NASH
What the sources say
- Not checked yetcites [235] Sanyal, 2001, Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities., Gastroenterology source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Similarly, circulating -hydroxybutyrate levels are increased in NASH (235).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 3. Evidence for impaired liver mitochondrial function in diabetes and NASH
What the sources say
- Not checked yetcites [235] Sanyal, 2001, Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities., Gastroenterology source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“At a cellular level, incubation of hepatocytes with saturated long-chain fatty acids induces insulin resistance by reducing insulin-stimulated tyrosine phosphorylation of the insulin receptor and its downstream substrates (220, 221).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 2. Potential mechanisms by which impaired hepatic mitochondrial function could influence hepatic insulin sensitivity
What the sources say
- Not checked yetcites [220] Nakamura, 2009, Palmitate induces insulin resistance in H4IIEC3 hepatocytes through reactive oxygen species produced by mitochondria., J Biol Chem source
- Not checked yetcites [221] Ruddock, 2008, Saturated fatty acids inhibit hepatic insulin action by modulating insulin receptor expression and post-receptor signalling., J Biochem source
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Together, these data suggest excessive, but incomplete, fatty acid oxidation, potentially limited by reduced availability of NADϩ and FAD.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 3. Evidence for impaired liver mitochondrial function in diabetes and NASH
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“Similar patterns were observed in obese subjects with established type 2 DM.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 3. Evidence for impaired liver mitochondrial function in diabetes and NASH
What the sources say
- Not checked yetcites [232] Pihlajamäki, 2009, Thyroid hormone-related regulation of gene expression in human fatty liver., J Clin Endocrinol Metab source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“These data suggest that mitochondrial diabetes is more likely to result from a gradual deterioration of -cell function, rather than from an acute functional impairment due to insufficient ATP production (246).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 2. Evidence for reduced -cell mitochondrial capacity in DM
What the sources say
- Not checked yetcites [246] Maassen, 2004, Mitochondrial diabetes: molecular mechanisms and clinical presentation, Diabetes source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In a mixed background, UCP2 knockout improves glycemic control in ob/ob mice (258), whereas in a pure C57BL6/J background, UCP2 knockout accelerates -cell failure and diabetes (259).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 3. Factors affecting mitochondrial function in -cells
What the sources say
- Not checked yetcites [259] Pi, 2009, Persistent oxidative stress due to absence of uncoupling protein 2 associated with impaired pancreatic β-cell function., Endocrinology source
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“It is likely that decreased ATP production due to unbalanced activation of UCPs by direct actions of fatty acids and their derivatives, in addition to excessive ROS, could underlie the accumulation of -cell damage that precedes type 2 DM (Fig. 4).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 3. Factors affecting mitochondrial function in -cells
hedgedconditional- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“Of these, the best studied is the 3243AϾG mutation in the mtDNA-encoded tRNALeu, UUR gene, which is associated with maternally inherited diabetes and deafness (MIDD) (243,244).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 2. Evidence for reduced -cell mitochondrial capacity in DM
What the sources say
- Not checked yetcites [243] Kadowaki, 1994, A subtype of diabetes mellitus associated with a mutation of mitochondrial DNA., N Engl J Med source
- Not checked yetcites [244] Maassen, 2006, New insights in the molecular pathogenesis of the maternally inherited diabetes and deafness syndrome., Endocrinol Metab Clin North Am source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Moreover, Tfam has recently been shown to be directly downstream of PDX1, a key transcription factor for -cell development (242).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 2. Evidence for reduced -cell mitochondrial capacity in DM
What the sources say
- Not checked yetcites [242] Gauthier, 2009, PDX1 deficiency causes mitochondrial dysfunction and defective insulin secretion through TFAM suppression., Cell Metab source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, uncoupling occurs to an excessive degree, compromising ATP synthesis enough to impair insulin secretion and -cell fitness.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > FIG. 4.
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This delicate balance in which UCP2 is desirable for -cell protection, but undesirable for glycemic control, probably underlies the discrepancy in results between two reports on the phenotype of UCP2 knockout mice.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 3. Factors affecting mitochondrial function in -cells
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“PGC-1␣ and related coactivators are critical for the regulation of mitochondrial oxidative capacity, as demonstrated by the approximately 2-fold increases in mtDNA and oxygen consumption and a 50% increase in mitochondrial density in myotubes overexpressing PGC-1␣ (56).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > A. PGC-1 ␣ and  overexpression
What the sources say
- Not checked yetcites [56] Wu, 1999, Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1., Cell source
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Another example is mutation 14577 TϾC, a missense substitution in the NADH dehydrogenase 6 gene (245).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 2. Evidence for reduced -cell mitochondrial capacity in DM
What the sources say
- Not checked yetcites [245] Tawata, 2000, A new mitochondrial DNA mutation at 14577 T/C is probably a major pathogenic mutation for maternally inherited type 2 diabetes., Diabetes source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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In the paper
“Thus, the activation of UCP2 protects the -cell from the deleterious effects of excess ROS (257) by dissipating the proton gradient and decreasing ROS production in a controlled negative feedback manner (Fig. 4).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 3. Factors affecting mitochondrial function in -cells
What the sources say
- Not checked yetcites [257] Brand, 2005, The efficiency and plasticity of mitochondrial energy transduction., Biochem Soc Trans source
plaindirect- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“Higher levels of overexpression of PGC-1␣ achieved through actin promoter-driven expression in transgenic animals display a strikingly different phenotype (263,264).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > A. PGC-1 ␣ and  overexpression
What the sources say
- Not checked yetcites [263] Miura, 2003, Overexpression of peroxisome proliferator-activated receptor γ coactivator-1α down-regulates GLUT4 mRNA in skeletal muscles., J Biol Chem source
- Not checked yetcites [264] Miura, 2006, Overexpression of peroxisome proliferator-activated receptor γ co-activator-1α leads to muscle atrophy with depletion of ATP., Am J Pathol source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In a mixed background, UCP2 knockout improves glycemic control in ob/ob mice (258), whereas in a pure C57BL6/J background, UCP2 knockout accelerates -cell failure and diabetes (259).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 3. Factors affecting mitochondrial function in -cells
What the sources say
- Not checked yetcites [258] Zhang, 2001, Uncoupling protein-2 negatively regulates insulin secretion and is a major link between obesity, β-cell dysfunction, and type 2 diabetes., Cell source
plaindirect- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“Thus, high-level expression of PGC-1 may actually cause accumulation of lipids and/or incomplete oxidation products, leading to reduced insulin sensitivity, as observed in PGC-1␣ transgenic mice (267-269).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > A. PGC-1 ␣ and  overexpression
What the sources say
- Not checked yetcites [267] Calvo, 2008, Muscle-specific expression of PPARγ coactivator-1α improves exercise performance and increases peak oxygen uptake., J Appl Physiol source
- Not checked yetcites [268] Lin, 2002, Transcriptional co-activator PGC-1 α drives the formation of slow-twitch muscle fibers., Nature source
- Not checked yetcites [269] Sandri, 2006, PGC-1α protects skeletal muscle from atrophy by suppressing FoxO3 action and atrophy-specific gene transcription., Proc Natl Acad Sci USA source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“Moreover, high-level expression of PGC-1␣ can induce not only increases in lipid oxidation genes but also parallel increases in expression of genes promoting lipid uptake and synthesis (270).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > A. PGC-1 ␣ and  overexpression
What the sources say
- Not checked yetcites [270] Choi, 2008, Paradoxical effects of increased expression of PGC-1α on muscle mitochondrial function and insulin-stimulated muscle glucose metabolism., Proc Natl Acad Sci USA source
plaindirect- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“When PGC-1␣ overexpression is restricted to skeletal muscle but overexpressed throughout development by the use of the creatine kinase gene promoter, very large increases in mitochondrial mass, OXPHOS, and fatty acid oxidation genes are observed (267-269).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > A. PGC-1 ␣ and  overexpression
What the sources say
- Not checked yetcites [267] Calvo, 2008, Muscle-specific expression of PPARγ coactivator-1α improves exercise performance and increases peak oxygen uptake., J Appl Physiol source
- Not checked yetcites [268] Lin, 2002, Transcriptional co-activator PGC-1 α drives the formation of slow-twitch muscle fibers., Nature source
- Not checked yetcites [269] Sandri, 2006, PGC-1α protects skeletal muscle from atrophy by suppressing FoxO3 action and atrophy-specific gene transcription., Proc Natl Acad Sci USA source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The net balance of these effects, and thus the net accumulation of pathogenic lipid species, is likely to be determined by the metabolic and hormonal milieu.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > A. PGC-1 ␣ and  overexpression
hedgedconditional- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, whole-body and inducible skeletal muscle-or cardiac-specific overexpression of PGC-1␣ can produce deleterious effects on muscle structure and function.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > A. PGC-1 ␣ and  overexpression
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Mice displayed enhanced endurance and oxidative work (271).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > A. PGC-1 ␣ and  overexpression
What the sources say
- Not checked yetcites [271] Arany, 2007, The transcriptional coactivator PGC-1β drives the formation of oxidative type IIX fibers in skeletal muscle., Cell Metab source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In addition, PGC-1␣ and PGC-1 coactivate different nuclear receptors (272).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > A. PGC-1 ␣ and  overexpression
What the sources say
- Not checked yetcites [272] Kamei, 2003, PPARγ coactivator 1β/ERR ligand 1 is an ERR protein ligand, whose expression induces a high-energy expenditure and antagonizes obesity., Proc Natl Acad Sci USA source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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In the paper
“Although PGC-1-mediated gene expression and function appear to overlap considerably with that of PGC-1␣, PGC-1 has distinct expression profiles in skeletal muscle, being expressed in parallel with myosin IIx rather than type I fibers (271).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > A. PGC-1 ␣ and  overexpression
What the sources say
- Not checked yetcites [271] Arany, 2007, The transcriptional coactivator PGC-1β drives the formation of oxidative type IIX fibers in skeletal muscle., Cell Metab source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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In the paper
“Insulin resistance was paralleled by accumulation of triglycerides and long-chain acyl CoA (270).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > A. PGC-1 ␣ and  overexpression
What the sources say
- Not checked yetcites [270] Choi, 2008, Paradoxical effects of increased expression of PGC-1α on muscle mitochondrial function and insulin-stimulated muscle glucose metabolism., Proc Natl Acad Sci USA source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These results also suggest that inappropriate, nonphysiological regulation of PGC-1␣ expression may prevent appropriate modulation of oxidative metabolism with feeding/fasting, or exercise/recovery-the hallmarks of impaired metabolic flexibility observed in human insulin resistance.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > A. PGC-1 ␣ and  overexpression
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“Although the physiological effects of the related gene ERR␥ remain unclear, it interacts with PGC-1 to regulate expression of ERR␣ (278), and polymorphisms at this locus were found to be associated with increased glucose area under the curve in a genetic analysis of Old Order Amish subjects (279).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > C. Other mitochondrial function defects
What the sources say
- Not checked yetcites [279] Rampersaud, 2007, Identification of novel candidate genes for type 2 diabetes from a genome-wide association scan in the Old Order Amish: evidence for replication from diabetes-related quantitative traits and from independent populations., Diabetes source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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None of the sources cited for this claim have been checked yet.
In the paper
“Interestingly, muscle is significantly more insulin sensitive in both whole-body and muscle-specific PGC-1␣ null mice.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > B. PGC-1 knockout models
What the sources say
- Not checked yetcites [63] Handschin, 2007, Skeletal muscle fiber-type switching, exercise intolerance, and myopathy in PGC-1α muscle-specific knock-out animals., J Biol Chem source
- Not checked yetcites [64] Handschin, 2007, Abnormal glucose homeostasis in skeletal muscle-specific PGC-1α knockout mice reveals skeletal muscle-pancreatic β-cell crosstalk., J Clin Invest source
- Not checked yetcites [68] Arany, 2005, Transcriptional coactivator PGC-1 α controls the energy state and contractile function of cardiac muscle., Cell Metab source
- Not checked yetcites [69] Lin, 2004, Defects in adaptive energy metabolism with CNS-linked hyperactivity in PGC-1α null mice., Cell source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
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None of the sources cited for this claim have been checked yet.
In the paper
“Many of these phenotypes are recapitulated in a muscle-specific PGC-1␣ knockout line (63, 64) (Table 2).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > B. PGC-1 knockout models
What the sources say
- Not checked yetcites [63] Handschin, 2007, Skeletal muscle fiber-type switching, exercise intolerance, and myopathy in PGC-1α muscle-specific knock-out animals., J Biol Chem source
- Not checked yetcites [64] Handschin, 2007, Abnormal glucose homeostasis in skeletal muscle-specific PGC-1α knockout mice reveals skeletal muscle-pancreatic β-cell crosstalk., J Clin Invest source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Activation of AMP kinase in this setting of reduced ATP production may also contribute to enhanced insulin sensitivity (274).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > B. PGC-1 knockout models
What the sources say
- Not checked yetcites [274] Pospisilik, 2007, Targeted deletion of AIF decreases mitochondrial oxidative phosphorylation and protects from obesity and diabetes., Cell source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“It is possible that the compensatory mechanisms elicited by the complete lack of PGC-1␣, which result in a leaner phenotype, have a paradoxical insulin-sensitizing effect.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > B. PGC-1 knockout models
hedgedconditional- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“Insulin sensitivity in these animals is reported to be normal.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > B. PGC-1 knockout models
What the sources say
- Not checked yetcites [59] Sonoda, 2007, PGC-1β controls mitochondrial metabolism to modulate circadian activity, adaptive thermogenesis, and hepatic steatosis., Proc Natl Acad Sci USA source
- Not checked yetcites [62] Lai, 2008, Transcriptional coactivators PGC-1α and PGC-lβ control overlapping programs required for perinatal maturation of the heart., Genes Dev source
- Not checked yetcites [65] Vianna, 2006, Hypomorphic mutation of PGC-1β causes mitochondrial dysfunction and liver insulin resistance., Cell Metab source
- Not checked yetcites [66] Lelliott, 2006, Ablation of PGC-1β results in defective mitochondrial activity, thermogenesis, hepatic function, and cardiac performance, PLoS Biol source
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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None of the sources cited for this claim have been checked yet.
In the paper
“PGC-1 family members interact with the family of estrogen-related nuclear receptors, or ERRs, to transactivate transcription of oxidative genes (275) and mitofusins (276).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > C. Other mitochondrial function defects
What the sources say
- Not checked yetcites [275] Mootha, 2004, ERRα and Gabpa/b specify PGC-1α-dependent oxidative phosphorylation gene expression that is altered in diabetic muscle., Proc Natl Acad Sci USA source
- Not checked yetcites [276] Soriano, 2006, Evidence for a mitochondrial regulatory pathway defined by peroxisome proliferator-activated receptor-γ coactivator-1 α, estrogen-related receptor-α, and mitofusin 2., Diabetes source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“The existence of compensation for PGC-1 deficiency by PGC-1␣ and vice versa is evidenced by the phenotype of double PGC-1␣ and PGC-1 muscle-specific knockout mice (62).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > B. PGC-1 knockout models
What the sources say
- Not checked yetcites [62] Lai, 2008, Transcriptional coactivators PGC-1α and PGC-lβ control overlapping programs required for perinatal maturation of the heart., Genes Dev source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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None of the sources cited for this claim have been checked yet.
In the paper
“This apparently paradoxical finding-where decreased oxidative function is not paralleled by insulin resistance-may be explained by the leanness and hyperactivity noted in one of the whole-body knockout lines (68, 69).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > B. PGC-1 knockout models
What the sources say
- Not checked yetcites [68] Arany, 2005, Transcriptional coactivator PGC-1 α controls the energy state and contractile function of cardiac muscle., Cell Metab source
- Not checked yetcites [69] Lin, 2004, Defects in adaptive energy metabolism with CNS-linked hyperactivity in PGC-1α null mice., Cell source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“For example, decreased metabolic efficiency (61), defined as decreased ATP produced per unit of oxidized fuel and/or oxygen, may lead to enhanced whole-body fuel utilization and thus a leaner, more insulin-sensitive phenotype.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > B. PGC-1 knockout models
What the sources say
- Not checked yetcites [61] Lehman, 2008, The transcriptional coactivator PGC-1α is essential for maximal and efficient cardiac mitochondrial fatty acid oxidation and lipid homeostasis, Am J Physiol Heart Circ Physiol source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“In the muscle-specific knockout lines, reduction in food intake, body weight, and adiposity (despite decreased physical activity) may also contribute to insulin sensitivity (63, 64).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > B. PGC-1 knockout models
What the sources say
- Not checked yetcites [63] Handschin, 2007, Skeletal muscle fiber-type switching, exercise intolerance, and myopathy in PGC-1α muscle-specific knock-out animals., J Biol Chem source
- Not checked yetcites [64] Handschin, 2007, Abnormal glucose homeostasis in skeletal muscle-specific PGC-1α knockout mice reveals skeletal muscle-pancreatic β-cell crosstalk., J Clin Invest source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These data raise the possibility that reduced expression of PGC1 family genes and impaired oxidative function may play a more important, and potentially pathogenic role in liver than in muscle.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > B. PGC-1 knockout models
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In each of these tissues, mitochondrial oxidative activity must be appropriate to fully oxidize nutrient loads, particularly fatty acids.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > V. Conclusions
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“More importantly, resolution of oxidative stress can reverse insulin resistance.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > V. Conclusions
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Moreover, experimental induction of insulin resistance and/or components of the insulin-resistant/diabetes milieu may contribute to reductions in mitochondrial oxidative capacity, further fueling a vicious cycle of diabetes risk (Fig. 6).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > V. Conclusions
hedgedconditional- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, these data indicate that primary defects in mtDNA, even when produced experimentally by ablation of nuclear-encoded genes, do not produce overt metabolic phenotypes.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > C. Other mitochondrial function defects
hedged- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Mitochondrial function in tissues involved in the pathogenesis of DM (liver, muscle, adipose tissue, and pancreatic -cells) is critical for multiple aspects of cellular metabolism.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > V. Conclusions
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“1 200 -300%”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > V. Conclusions
What the sources say
- Not checked yetcites [262] Liang, 2009, Whole body overexpression of PGC-1α has opposite effects on hepatic and muscle insulin sensitivity, Am J Physiol Endocrinol Metab source
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Balance is achieved when oxidative activity equals or exceeds fuel loads.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > V. Conclusions
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“POLG-null mice die during embryogenesis with severe mtDNA depletion (283), whereas knock-in mutant mice have accelerated aging potentially linked to impaired repair of mtDNA mutations (284).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > C. Other mitochondrial function defects
What the sources say
- Not checked yetcites [284] Trifunovic, 2004, Premature ageing in mice expressing defective mitochondrial DNA polymerase., Nature source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These observations are consistent with those in humans harboring mutations in mtDNA, where mitochondrial diabetes typically manifests as a gradual deterioration of pancreatic -cell function (see Section III.D).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > C. Other mitochondrial function defects
plaincorrelational- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These data also suggest that defects in resolution of oxidative stress may be another mechanism conferring increased risk for both mitochondrial dysfunction and insulin resistance.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > V. Conclusions
hedgedconditional- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, in these experimental models in which mitochondrial oxidative capacity is severely restricted, insulin action is enhanced.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > C. Other mitochondrial function defects
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“POLG-null mice die during embryogenesis with severe mtDNA depletion (283), whereas knock-in mutant mice have accelerated aging potentially linked to impaired repair of mtDNA mutations (284).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > C. Other mitochondrial function defects
What the sources say
- Not checked yetcites [283] Hance, 2005, Mitochondrial DNA polymerase γ is essential for mammalian embryogenesis., Hum Mol Genet source
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The sufficiency to fully oxidize fatty acids resides in the balance between: 1) net mitochondrial oxidative activity, in turn determined by the need to generate energy to meet cellular demands, e.g., contraction and ion transport; and 2) fuel availability (determined by food intake, adiposity, and adipose storage capacity) (Fig. 5A).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > V. Conclusions
plaindirect- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“For example, a high-fat, high-sucrose diet in the diabetes-prone C57BL6 mouse causes mitochondrial alterations in parallel with enhanced ROS production and impaired insulin sensitivity.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > V. Conclusions
What the sources say
- Not checked yetcites [286] Stump, 2003, Effect of insulin on human skeletal muscle mitochondrial ATP production, protein synthesis, and mRNA transcripts., Proc Natl Acad Sci USA source
- Not checked yetcites [287] Anderson, 2009, Substrate-specific derangements in mitochondrial metabolism and redox balance in the atrium of the type 2 diabetic human heart., J Am Coll Cardiol source
- Not checked yetcites [288] Bonnard, 2008, Mitochondrial dysfunction results from oxidative stress in the skeletal muscle of diet-induced insulin-resistant mice., J Clin Invest
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Secondly, chronic imbalance in energy metabolism due to overnutrition, obesity, and inactivity could directly contribute to increased cellular and mitochondrial ROS production.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > V. Conclusions
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“Mito DNA | 1 113%”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > V. Conclusions
What the sources say
- Not checked yetcites [261] Benton, 2008, Modest PGC-1α overexpression in muscle in vivo is sufficient to increase insulin sensitivity and palmitate oxidation in subsarcolemmal, not intermyofibrillar, mitochondria., J Biol Chem source
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“However, when sustained fuel excess (e.g., resulting from overnutrition or impaired fat storage) exceeds energetic demands and/or oxidative capacity, and/or appropriate compensatory mechanisms are insufficient (e.g., due to inactivity or failure of mitochondria to adapt to higher cellular oxidative demands), a vicious cycle of insulin resistance and impaired insulin secretion can be initiated (Fig”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > V. Conclusions
plainconditional- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In isolation, reductions in mitochondrial activity mediated by genetic factors (family history, ethnicity), epigenetic mechanisms, developmental exposures, and aging may not be sufficient to induce insulin resistance.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > V. Conclusions
hedged- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, individuals with a high oxidative capacity or adaptive responses would have high tolerance to large fuel loads.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > V. Conclusions
hedgeddirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In this context, interindividual variation in oxidative capacity and/or activity, fuel load, or ability to modulate mitochondrial activity (acute response), increase mitochondrial capacity (chronic response), or resolve oxidative stress could determine the set point of metabolic balance.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > V. Conclusions
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“Lai, 2008 (62) PGC-1␣ and PGC-1 2 60%, heart | muscle-specific KO”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > V. Conclusions
What the sources say
- Not checked yetcites [62] Lai, 2008, Transcriptional coactivators PGC-1α and PGC-lβ control overlapping programs required for perinatal maturation of the heart., Genes Dev source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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- It may state two separate claims as one. 142
- Probably not a substantial claim. 18
- The quote only partly states this claim. 1
None of the sources cited for this claim have been checked yet.
In the paper
“For example, rates of mitochondrial OXPHOS in offspring of type 2 diabetic subjects, as assessed by 31 P spectroscopy, are reduced by 30% in the fasting state (117), and TCA cycle flux, modeled using rates of 4-13 C-glutamate enrichment during infusion of 13 C-acetate, is reduced by 30% (118).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 3. Evidence for reduced muscle mitochondrial oxidative function in DM
What the sources say
- Not checked yetcites [117] Petersen, 2004, Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes., N Engl J Med source
- Not checked yetcites [118] Befroy, 2007, Impaired mitochondrial substrate oxidation in muscle of insulin-resistant offspring of type 2 diabetic patients., Diabetes source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Similarly, insulin-stimulated ATP synthesis is reduced by more than 90% in nonobese first-degree relatives of type 2 diabetics (120), more than would be expected from the 30% decrease in mitochondrial density and oxidative function observed in the same population.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 3. Evidence for reduced muscle mitochondrial oxidative function in DM
What the sources say
- Not checked yetcites [120] Petersen, 2005, Decreased insulin-stimulated ATP synthesis and phosphate transport in muscle of insulin-resistant offspring of type 2 diabetic parents, PLoS Med source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Ritov et al. (114) demonstrated that the enzymatic activity of OXPHOS complex I, as assessed by the activity of rotenone-sensitive NADH:O 2 oxidoreductase, was reduced by about 40% in skeletal muscle biopsy samples from individuals with type 2 DM and by 20% in obese individuals.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 3. Evidence for reduced muscle mitochondrial oxidative function in DM
What the sources say
- Not checked yetcites [114] Ritov, 2005, Deficiency of subsarcolemmal mitochondria in obesity and type 2 diabetes., Diabetes source
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Mogensen et al. (119) observed decreases in maximal ADP-stimulated respiration (state 3, malate and pyruvate as substrates) in mitochondria isolated from obese subjects with DM as compared with obesity alone; these differences persisted even after normalization to citrate synthase activity.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 3. Evidence for reduced muscle mitochondrial oxidative function in DM
What the sources say
- Not checked yetcites [119] Mogensen, 2007, Mitochondrial respiration is decreased in skeletal muscle of patients with type 2 diabetes., Diabetes source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The comparison between successive frames reveals scission events (arrowheads), branching events (V), and fusion events (brackets) occurring at 30-sec intervals.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > V. Conclusions
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Both obesity and related inactivity are likely to contribute to the pathogenesis of diabetes because the incidence of diabetes can be reduced by modest weight loss and exercise (7)(8)(9).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > Abstract
What the sources say
- Not checked yetcites (7)(8)(9)
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“However, insulin resistance is not predictive of diabetes in individuals without a family history of diabetes, indicating that additional unidentified factors are necessary for disease progression (30).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > A. Risk factors associated with type 2 diabetes
What the sources say
- Not checked yetcites [30] Goldfine, 2003, Insulin resistance is a poor predictor of type 2 diabetes in individuals with no family history of disease., Proc Natl Acad Sci USA source
hedged- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“However, we hypothesize that genetically determined and/or inactivity-mediated alterations in mitochondrial oxidative activity may directly impact adaptive responses to overnutrition, causing an imbalance between oxidative activity and nutrient load.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > Abstract
hedgedconditional- Asserted: fails — The authors may not put it forward as true.
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Probably not a substantial claim. The authors may not put it forward as true. The paper may give no reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We conclude that, whereas the association between impaired mitochondrial function and DM is strong, a causal pathogenic relationship remains uncertain.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > Abstract
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, these data suggest that in addition to decreased mitochondrial density, there is an additional intrinsic defect(s) in TCA, OXPHOS, membrane potential, or adenine nucleotide transporters in mitochondria of individuals with established diabetes.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 3. Evidence for reduced muscle mitochondrial oxidative function in DM
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“In these individuals, expression of OXPHOS and TCA cycle genes, mtDNA content, and ATP production rates were actually higher in both nondiabetic and diabetic individuals compared with Northern European controls, despite lower overall insulin sensitivity.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 3. Evidence for reduced muscle mitochondrial oxidative function in DM
What the sources say
- Not checked yetcites [125] Nair, 2008, Asian Indians have enhanced skeletal muscle mitochondrial capacity to produce ATP in association with severe insulin resistance., Diabetes source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Multiple studies suggest that human insulin resistance is indeed accompanied by impaired in vivo mitochondrial oxidative function-in turn linked, at least in part, to reduced mitochondrial density.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 3. Evidence for reduced muscle mitochondrial oxidative function in DM
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In each of these studies, differences in oxidative capacity did not remain after normalization for mitochondrial mass by citrate synthase activity or mtDNA content, respectively, suggesting that reduced mitochondrial mass might be a major contributor.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 3. Evidence for reduced muscle mitochondrial oxidative function in DM
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The magnitude of these changes is strikingly similar to the 38% lower muscle mitochondrial density, assessed by electron microscopy, in this same population-again suggesting that decreased mitochondrial density might be an important factor in reduced oxidative capacity in individuals with a family history of diabetes.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 3. Evidence for reduced muscle mitochondrial oxidative function in DM
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Additional mechanisms potentially linking impaired mitochondrial oxidative function to insulin resistance include: 1) reduced ATP synthesis for energyrequiring functions such as insulin-stimulated glucose uptake; 2) abnormalities in calcium homeostasis (necessary for exercise-induced glucose uptake) (103-105); and 3) reduced ATP production during exercise (106), potentially contributing to reduced”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 2. Potential mechanisms by which impaired muscle mitochondrial oxidative function could result in insulin resistance
What the sources say
- Not checked yetcites [103] Lanner, 2008, Ca(2+) and insulin-mediated glucose uptake., Curr Opin Pharmacol source
- Not checked yetcites [104] Lebeche, 2008, Interplay between impaired calcium regulation and insulin signaling abnormalities in diabetic cardiomyopathy., Nat Clin Pract Cardiovasc Med source
- Not checked yetcites [105] Park, 2009, Chronic elevated calcium blocks AMPK-induced GLUT-4 expression in skeletal muscle, Am J Physiol Cell Physiol source
- Not checked yetcites [106] Kacerovsky-Bielesz, 2009, Short-term exercise training does not stimulate skeletal muscle ATP synthesis in relatives of humans with type 2 diabetes., Diabetes source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“For example, primary myotubes isolated from obese humans with type 2 DM display reduced basal lipid oxidation and insulinstimulated glucose oxidation with no differences in OXPHOS gene expression (126).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 3. Evidence for reduced muscle mitochondrial oxidative function in DM
What the sources say
- Not checked yetcites [126] Frederiksen, 2008, Transcriptional profiling of myotubes from patients with type 2 diabetes: no evidence for a primary defect in oxidative phosphorylation genes., Diabetologia source
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These results also raise the question of whether levels of OXPHOS gene expression and function must be considered relative to the oxidative fuel load in an individual.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 3. Evidence for reduced muscle mitochondrial oxidative function in DM
hedgedcorrelational- Asserted: fails — The authors may not put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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Probably not a substantial claim. The authors may not put it forward as true. It may be too vague to check against evidence.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, mitochondrial functional capacity is likely to directly affect muscle metabolic function and, because of its large contribution to total body mass, to have a significant impact on whole-body metabolism.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 1. Role of mitochondria in muscle
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Impaired flexibility also correlates with intramyocellular accumulation of lipids (107), and 24-h RQ can predict subsequent weight gain (110, 113).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 3. Evidence for reduced muscle mitochondrial oxidative function in DM
What the sources say
- Not checked yetcites [107] Simoneau, 1995, Skeletal muscle glycolytic and oxidative enzyme capacities are determinants of insulin sensitivity and muscle composition in obese women., FASEB J source
- Not checked yetcites [110] Bruce, 2003, Muscle oxidative capacity is a better predictor of insulin sensitivity than lipid status., J Clin Endocrinol Metab source
- Not checked yetcites [113] Zurlo, 1990, Low ratio of fat to carbohydrate oxidation as predictor of weight gain: study of 24-h RQ, Am J Physiol
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These differences may reflect population-specific differences in obesity, physical fitness, or ethnicity.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 3. Evidence for reduced muscle mitochondrial oxidative function in DM
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Increased tissue lipid load, as with obesity, and/or sustained inactivity, may lead to the accumulation of fatty acyl coenzyme A (CoA), diacylglycerols, ceramides, products of incomplete oxidation, and ROS, all of which have been linked experimentally to reduced insulin signaling and action (96 -102).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 2. Potential mechanisms by which impaired muscle mitochondrial oxidative function could result in insulin resistance
What the sources say
- Not checked yetcites [96] Dresner, 1999, Effects of free fatty acids on glucose transport and IRS-1-associated phosphatidylinositol 3-kinase activity., J Clin Invest source
- Not checked yetcites [97] Savage, 2007, Disordered lipid metabolism and the pathogenesis of insulin resistance., Physiol Rev source
- Not checked yetcites [98] Koves, 2008, Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance., Cell Metab source
- Not checked yetcites [99] Holland, 2007, Inhibition of ceramide synthesis ameliorates glucocorticoid-, saturated-fat-, and obesity-induced insulin resistance., Cell Metab source
- Not checked yetcites [100] Yu, 2002, Mechanism by which fatty acids inhibit insulin activation of insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3-kinase activity in muscle., J Biol Chem source
- Not checked yetcites [101] Chibalin, 2008, Downregulation of diacylglycerol kinase δ contributes to hyperglycemia-induced insulin resistance., Cell source
- Not checked yetcites [102] Houstis, 2006, Reactive oxygen species have a causal role in multiple forms of insulin resistance., Nature source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Moreover, lipid excess has been linked experimentally to induction of insulin resistance (96) and alterations in insulin signal transduction (97-99).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 2. Potential mechanisms by which impaired muscle mitochondrial oxidative function could result in insulin resistance
What the sources say
- Not checked yetcites [96] Dresner, 1999, Effects of free fatty acids on glucose transport and IRS-1-associated phosphatidylinositol 3-kinase activity., J Clin Invest source
- Not checked yetcites [97] Savage, 2007, Disordered lipid metabolism and the pathogenesis of insulin resistance., Physiol Rev source
- Not checked yetcites [98] Koves, 2008, Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance., Cell Metab source
- Not checked yetcites [99] Holland, 2007, Inhibition of ceramide synthesis ameliorates glucocorticoid-, saturated-fat-, and obesity-induced insulin resistance., Cell Metab source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“For example, high OXPHOS expression in the population mentioned above may still be inadequate for appropriate and complete oxidation of a chronic high load of circulating lipids, whereas lower OXPHOS levels may be sufficient under conditions of a low circulating lipid load (see Fig. 5).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 3. Evidence for reduced muscle mitochondrial oxidative function in DM
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“Although it remains unclear whether any of these defects play a causal role in insulin resistance, intramyocellular lipid excess strongly correlates with the severity of insulin resistance, even after correction for the degree of obesity (94), and has been observed in muscles of multiple fiber types (95).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 2. Potential mechanisms by which impaired muscle mitochondrial oxidative function could result in insulin resistance
What the sources say
- Not checked yetcites [94] Jacob, 1999, Association of increased intramyocellular lipid content with insulin resistance in lean nondiabetic offspring of type 2 diabetic subjects., Diabetes source
- Not checked yetcites [95] Malenfant, 2001, Fat content in individual muscle fibers of lean and obese subjects., Int J Obes Relat Metab Disord source
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Genetic polymorphisms may also influence age-dependent reductions in expression (137).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 4. Factors affecting OXPHOS gene expression in muscle
What the sources say
- Not checked yetcites [137] Ling, 2004, Multiple environmental and genetic factors influence skeletal muscle PGC-1α and PGC-1β gene expression in twins., J Clin Invest source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“PGC-1␣ has been recognized as an important coactivator in skeletal muscle, contributing to fiber type determination, glucose uptake, and oxidative capacity (see Section IV.A).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 4. Factors affecting OXPHOS gene expression in muscle
What the sources say
- Not checked yetcites Section IV.A
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Conversely, OXPHOS expression can be increased with exercise training (133, 135), a potent insulin sensitizer.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 4. Factors affecting OXPHOS gene expression in muscle
What the sources say
- Not checked yetcites [133] Parikh, 2008, Molecular correlates for maximal oxygen uptake and type 1 fibers, Am J Physiol Endocrinol Metab source
- Not checked yetcites [135] Wright, 2007, Exercise-induced mitochondrial biogenesis begins before the increase in muscle PGC-1α expression., J Biol Chem source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Expression of multiple OXPHOS genes is also markedly reduced in mice made insulin deficient by treatment with the -cell toxin streptozotocin, and can be normalized by insulin (141).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 4. Factors affecting OXPHOS gene expression in muscle
What the sources say
- Not checked yetcites [141] Yechoor, 2002, Coordinated patterns of gene expression for substrate and energy metabolism in skeletal muscle of diabetic mice., Proc Natl Acad Sci USA source
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Additionally, because OXPHOS gene expression is coordinately regulated, patterns of differential OXPHOS expression may be more readily detectable in disease states, yet not necessarily mirror other aspects of mitochondrial oxidative capacity.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 4. Factors affecting OXPHOS gene expression in muscle
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Rests on an assumption: OXPHOS gene expression is coordinately regulated.
None of the sources cited for this claim have been checked yet.
In the paper
“Moreover, alterations in muscle PGC-1␣ and - mRNA expression are observed in humans with insulin resistance-being reduced by nearly 50% in muscle from individuals with diabetes (122, 145) and in some populations of normoglycemic insulin-resistant humans (121, 124, 137).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 4. Factors affecting OXPHOS gene expression in muscle
What the sources say
- Not checked yetcites [122] Patti, 2003, Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes: potential role of PGC1 and NRF1., Proc Natl Acad Sci USA source
- Not checked yetcites [145] Southgate, 2005, PGC-1α gene expression is down-regulated by Akt-mediated phosphorylation and nuclear exclusion of FoxO1 in insulin-stimulated skeletal muscle., FASEB J source
- Not checked yetcites [121] Mootha, 2003, PGC-1α-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes., Nat Genet source
- Not checked yetcites [124] Morino, 2005, Reduced mitochondrial density and increased IRS-1 serine phosphorylation in muscle of insulin-resistant offspring of type 2 diabetic parents., J Clin Invest source
- Not checked yetcites [137] Ling, 2004, Multiple environmental and genetic factors influence skeletal muscle PGC-1α and PGC-1β gene expression in twins., J Clin Invest source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Moreover, experimental insulin therapy does not modulate mitochondrial respiration (144), so mechanisms linking insulin action with OXPHOS gene expression remain unclear.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 4. Factors affecting OXPHOS gene expression in muscle
What the sources say
- Not checked yetcites [144] Rabøl, 2009, Effect of hyperglycemia on mitochondrial respiration in type 2 diabetes., J Clin Endocrinol Metab source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“PGC-1 activity can also be modulated at the level of translation and by posttranscriptional changes, including inhibitory GCN5-mediated acetylation (147) and stimulatory sirtuin 1 mediated deacetylation (148).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 4. Factors affecting OXPHOS gene expression in muscle
What the sources say
- Not checked yetcites [147] Lerin, 2006, GCN5 acetyltransferase complex controls glucose metabolism through transcriptional repression of PGC-1α., Cell Metab source
- Not checked yetcites [148] Lagouge, 2006, Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1α., Cell source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Short-term experimental induction of acute hyperglycemia in humans does not fully mirror this pattern of gene expression (143), suggesting that the response to insulin deficiency is not completely due to resultant hyperglycemia.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 4. Factors affecting OXPHOS gene expression in muscle
What the sources say
- Not checked yetcites [143] Meugnier, 2007, Acute hyperglycemia induces a global downregulation of gene expression in adipose tissue and skeletal muscle of healthy subjects., Diabetes source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These multiple modes of PGC-1␣ regulation are likely to have evolved from the need to adapt mitochondrial energy metabolism in response to increasingly diverse inputs.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 4. Factors affecting OXPHOS gene expression in muscle
hedgedconditional- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. It may be too vague to check against evidence. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“However, these responses are not observed in all studies of high-fat feeding; in fact, some studies demonstrate that high-fat feeding is associated with increased numbers of mitochondrial protein and DNA content, potentially mediated by chronic fatty acid activation of PPAR nuclear receptors (130 -132).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 4. Factors affecting OXPHOS gene expression in muscle
What the sources say
- Not checked yetcites [130] Garcia-Roves, 2007, Raising plasma fatty acid concentration induces increased biogenesis of mitochondria in skeletal muscle., Proc Natl Acad Sci USA source
- Not checked yetcites [131] Hancock, 2008, High-fat diets cause insulin resistance despite an increase in muscle mitochondria., Proc Natl Acad Sci USA source
- Not checked yetcites [132] Sreekumar, 2002, Effects of caloric restriction on mitochondrial function and gene transcripts in rat muscle, Am J Physiol Endocrinol Metab source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“In turn, PGC-1␣ expression may also be reduced as a consequence of promoter methylation (146) or caused by insulin itself (145), obesity (126), and sustained lipid exposure (126).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 4. Factors affecting OXPHOS gene expression in muscle
What the sources say
- Not checked yetcites [146] Barrès, 2009, Non-CpG methylation of the PGC-1α promoter through DNMT3B controls mitochondrial density., Cell Metab source
- Not checked yetcites [145] Southgate, 2005, PGC-1α gene expression is down-regulated by Akt-mediated phosphorylation and nuclear exclusion of FoxO1 in insulin-stimulated skeletal muscle., FASEB J source
- Not checked yetcites [126] Frederiksen, 2008, Transcriptional profiling of myotubes from patients with type 2 diabetes: no evidence for a primary defect in oxidative phosphorylation genes., Diabetologia source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Together, these seemingly disparate data suggest that genetic background (127), age at dietary intervention, specific dietary lipid composition, and duration of diet may be important variables to consider when analyzing the interaction between OXPHOS gene expression and diet.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 4. Factors affecting OXPHOS gene expression in muscle
What the sources say
- Not checked yetcites [127] Crunkhorn, 2007, Peroxisome proliferator activator receptor γ coactivator-1 expression is reduced in obesity: potential pathogenic role of saturated fatty acids and p38 mitogen-activated protein kinase activation., J Biol Chem source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
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In the paper
“UCP1 hinders the establishment of, or dissipates, a proton gradient of sufficient magnitude to sustain the synthetic activity of the mitochondrial ATPase (150, 153-155), thus driving continuous accelerated electron transport.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 1. Roles of mitochondria in adipose tissue
What the sources say
- Not checked yetcites [150] Cannon, 1985, The biochemistry of an inefficient tissue: brown adipose tissue., Essays Biochem
- Not checked yetcites [153] Bouillaud, 1985, Molecular approach to thermogenesis in brown adipose tissue: cDNA cloning of the mitochondrial uncoupling protein., Proc Natl Acad Sci USA source
- Not checked yetcites [154] Jacobsson, 1985, Mitochondrial uncoupling protein from mouse brown fat. Molecular cloning, genetic mapping, and mRNA expression., J Biol Chem source
- Not checked yetcites [155] Ricquier, 1997, The mitochondrial uncoupling protein: structural and genetic studies., Prog Nucleic Acid Res Mol Biol source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Among the mitochondrial functions that may be relevant for white adipose tissue function are the anaplerotic generation of metabolic intermediates for fatty acid synthesis and esterification (159), the maintenance of a robust pathway for the folding and secretion of high abundance circulating proteins such as adiponectin (160), and interactions between mitochondrial function and components of the”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 1. Roles of mitochondria in adipose tissue
What the sources say
- Not checked yetcites [159] Owen, 2002, The key role of anaplerosis and cataplerosis for citric acid cycle function., J Biol Chem source
- Not checked yetcites [160] Koh, 2007, Essential role of mitochondrial function in adiponectin synthesis in adipocytes., Diabetes source
- Not checked yetcites [161] Shi, 2008, Paradoxical effect of mitochondrial respiratory chain impairment on insulin signaling and glucose transport in adipose cells., J Biol Chem source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Rather, alterations in relative utilization of substrates, an imbalance between fuel load and cellular energy requirements, and/or differential thresholds for generation of or resolution of oxidative stress in this setting may contribute to differential susceptibility to insulin resistance in muscle.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 4. Factors affecting OXPHOS gene expression in muscle
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
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In the paper
“However, recent work has led to reconsideration of this notion, noting that humans possess adipose tissue depots that are cold-sensitive and hypermetabolic, as assessed by their very high uptake of labeled glucose (152,163).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 2. Potential mechanisms by which impaired adipose tissue mitochondrial oxidative capacity could result in insulin resistance
What the sources say
- Not checked yetcites [152] Weber, 2004, Brown adipose tissue and nuclear medicine imaging., J Nucl Med
- Not checked yetcites [163] Nedergaard, 2007, Unexpected evidence for active brown adipose tissue in adult humans, Am J Physiol Endocrinol Metab source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
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In the paper
“However, mitochondrial density increases dramatically, and mitochondrial remodeling occurs during white adipocyte differentiation (156 -158), suggesting that mitochondrial functions are required to support the multiple biological roles of mature white adipocytes.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 1. Roles of mitochondria in adipose tissue
What the sources say
- Not checked yetcites [156] Luo, 2008, Alteration of mitochondrial oxidative capacity during porcine preadipocyte differentiation and in response to leptin., Mol Cell Biochem source
- Not checked yetcites [157] Kim, 2004, Extracellular ATP is generated by ATP synthase complex in adipocyte lipid rafts., Exp Mol Med source
- Not checked yetcites [158] Wilson-Fritch, 2003, Mitochondrial biogenesis and remodeling during adipogenesis and in response to the insulin sensitizer rosiglitazone., Mol Cell Biol source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
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In the paper
“The role of adipose tissue mitochondria is most apparent in brown adipose tissue, where flux through the ETC generates heat in the process of thermogenesis, a potentially important mechanism regulating systemic metabolism even in adult humans (149 -152).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 1. Roles of mitochondria in adipose tissue
What the sources say
- Not checked yetcites [149] Astrup, 1986, Thermogenesis in human brown adipose tissue and skeletal muscle induced by sympathomimetic stimulation., Acta Endocrinol Suppl (Copenh)
- Not checked yetcites [150] Cannon, 1985, The biochemistry of an inefficient tissue: brown adipose tissue., Essays Biochem
- Not checked yetcites [151] Cypess, 2009, Identification and importance of brown adipose tissue in adult humans., N Engl J Med source
- Not checked yetcites [152] Weber, 2004, Brown adipose tissue and nuclear medicine imaging., J Nucl Med
hedgeddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Higher mitochondrial density and even UCP1 can be induced in response to pharmacological or genetic alterations of white adipocytes (170 -177), suggesting that white adipose tissue could potentially be induced to acquire more oxidative metabolic phenotypes, promoting increased fuel consumption and thus energy expenditure.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 2. Potential mechanisms by which impaired adipose tissue mitochondrial oxidative capacity could result in insulin resistance
What the sources say
- Not checked yetcites [170] Bogacka, 2005, Pioglitazone induces mitochondrial biogenesis in human subcutaneous adipose tissue in vivo., Diabetes source
- Not checked yetcites [171] Himms-Hagen, 2000, Multilocular fat cells in WAT of CL-316243-treated rats derive directly from white adipocytes, Am J Physiol Cell Physiol source
- Not checked yetcites [172] Loncar, 1991, Convertible adipose tissue in mice., Cell Tissue Res source
- Not checked yetcites [173] Orci, 2004, Rapid transformation of white adipocytes into fat-oxidizing machines., Proc Natl Acad Sci USA source
- Not checked yetcites [174] Ström, 2008, Attainment of brown adipocyte features in white adipocytes of hormone-sensitive lipase null mice, PLoS ONE source
- Not checked yetcites [175] Tiraby, 2003, Acquirement of brown fat cell features by human white adipocytes., J Biol Chem source
- Not checked yetcites [176] Toh, 2008, Up-regulation of mitochondrial activity and acquirement of brown adipose tissue-like property in the white adipose tissue of fsp27 deficient mice, PLoS ONE source
- Not checked yetcites [177] Wilson-Fritch, 2004, Mitochondrial remodeling in adipose tissue associated with obesity and treatment with rosiglitazone., J Clin Invest source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“The large capacity of brown adipose tissue mitochondria to oxidize fatty acids results in a measurable impact on whole-body metabolism; increased brown adipose tissue abundance correlates negatively with fuel storage and weight gain in rodents, and vice versa (162).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 2. Potential mechanisms by which impaired adipose tissue mitochondrial oxidative capacity could result in insulin resistance
What the sources say
- Not checked yetcites [162] Marette, 1991, Mechanism linking insulin resistance to defective thermogenesis in brown adipose tissue of obese diabetic SHR/N-cp rats., Int J Obes
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, impaired mitochondrial capacity in brown adipose tissue might be functionally linked to impaired thermogenesis and energy expenditure, and thus increased susceptibility to obesity-linked insulin resistance.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 2. Potential mechanisms by which impaired adipose tissue mitochondrial oxidative capacity could result in insulin resistance
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“White adipocytes display a high degree of plasticity (168), and regional differences in metabolic activity can be linked to varying mitochondria densities (169).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 2. Potential mechanisms by which impaired adipose tissue mitochondrial oxidative capacity could result in insulin resistance
What the sources say
- Not checked yetcites [168] Cinti, 2002, Adipocyte differentiation and transdifferentiation: plasticity of the adipose organ., J Endocrinol Invest source
- Not checked yetcites [169] Deveaud, 2004, Regional differences in oxidative capacity of rat white adipose tissue are linked to the mitochondrial content of mature adipocytes., Mol Cell Biochem source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“White adipocyte mitochondrial content is decreased in both rodent and human obesity (177, 188 -191) and correlates with insulin resistance that accompanies obesity.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 3. Evidence for reduced adipose tissue mitochondrial capacity in DM
What the sources say
- Not checked yetcites [177] Wilson-Fritch, 2004, Mitochondrial remodeling in adipose tissue associated with obesity and treatment with rosiglitazone., J Clin Invest source
- Not checked yetcites [188] Choo, 2006, Mitochondria are impaired in the adipocytes of type 2 diabetic mice., Diabetologia source
- Not checked yetcites [189] Okamoto, 2007, Comparison of mitochondrial and macrophage content between subcutaneous and visceral fat in db/db mice., Exp Mol Pathol source
- Not checked yetcites [190] Rong, 2007, Adipose mitochondrial biogenesis is suppressed in db/db and high-fat diet-fed mice and improved by rosiglitazone., Diabetes source
- Not checked yetcites [191] Sutherland, 2008, Time course of high-fat diet-induced reductions in adipose tissue mitochondrial proteins: potential mechanisms and the relationship to glucose intolerance, Am J Physiol Endocrinol Metab source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“In humans, white adipocyte mtDNA copy number is inversely correlated with age and BMI and directly correlated with basal and insulin-induced lipogenesis (192).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 3. Evidence for reduced adipose tissue mitochondrial capacity in DM
What the sources say
- Not checked yetcites [192] Kaaman, 2007, Strong association between mitochondrial DNA copy number and lipogenesis in human white adipose tissue., Diabetologia source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Conversely, both genetic and dietinduced obesity result in decreased mitochondrial density and OXPHOS activity in adipose tissue (127, 177, 189 -191), potentially contributing to adipose tissue dysfunction and exacerbation of insulin resistance.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 4. Factors affecting mitochondrial OXPHOS expression and function in adipose tissue
What the sources say
- Not checked yetcites [127] Crunkhorn, 2007, Peroxisome proliferator activator receptor γ coactivator-1 expression is reduced in obesity: potential pathogenic role of saturated fatty acids and p38 mitogen-activated protein kinase activation., J Biol Chem source
- Not checked yetcites [177] Wilson-Fritch, 2004, Mitochondrial remodeling in adipose tissue associated with obesity and treatment with rosiglitazone., J Clin Invest source
- Not checked yetcites [189] Okamoto, 2007, Comparison of mitochondrial and macrophage content between subcutaneous and visceral fat in db/db mice., Exp Mol Pathol source
- Not checked yetcites [190] Rong, 2007, Adipose mitochondrial biogenesis is suppressed in db/db and high-fat diet-fed mice and improved by rosiglitazone., Diabetes source
- Not checked yetcites [191] Sutherland, 2008, Time course of high-fat diet-induced reductions in adipose tissue mitochondrial proteins: potential mechanisms and the relationship to glucose intolerance, Am J Physiol Endocrinol Metab source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“For example, Toh et al. (176) and Nishino,et al. (205) find that mice deficient in Fsp27, a lipid droplet protein that promotes lipid storage in white and brown adipocytes, have increased whole-body energy expenditure, resistance to diet-induced obesity, and enhanced insulin sensitivity.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 4. Factors affecting mitochondrial OXPHOS expression and function in adipose tissue
What the sources say
- Not checked yetcites [176] Toh, 2008, Up-regulation of mitochondrial activity and acquirement of brown adipose tissue-like property in the white adipose tissue of fsp27 deficient mice, PLoS ONE source
- Not checked yetcites [205] Nishino, 2008, FSP27 contributes to efficient energy storage in murine white adipocytes by promoting the formation of unilocular lipid droplets., J Clin Invest
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Protein expression of multiple OXPHOS components and Tfam (expressed per milligram of protein) and citrate synthase activity are also lower in liver (e.g., 7% that of cardiac muscle) (211).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 1. Role of mitochondria in liver
What the sources say
- Not checked yetcites [211] Benard, 2006, Physiological diversity of mitochondrial oxidative phosphorylation, Am J Physiol Cell Physiol source
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Electron microscopy demonstrates that mitochondrial area is 44% lower in liver than in heart (210) with smaller size, fewer cristae, and lower matrix density.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 1. Role of mitochondria in liver
What the sources say
- Not checked yetcites [210] Veltri, 1990, Distinct genomic copy number in mitochondria of different mammalian organs., J Cell Physiol source
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Current reports support the hypothesis that brown adipocytes and myocytes share a common cellular lineage, potentially explaining their similarity with regard to containing mitochondria specialized in fuel oxidation.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 4. Factors affecting mitochondrial OXPHOS expression and function in adipose tissue
hedgedconditional- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“Despite lower OXPHOS capacity, state 3 respiration and respiratory control ratio are equivalent in liver and muscle, indicating differences in relative substrate concentrations and lower”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 1. Role of mitochondria in liver
What the sources say
- Not checked yetcites [211] Benard, 2006, Physiological diversity of mitochondrial oxidative phosphorylation, Am J Physiol Cell Physiol source
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
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It may state two separate claims as one.
In the paper
“Functionally, isolated hepatic mitochondria have relative reductions in OXPHOS proteins, respiratory chain cytochromes, and maximal activity of complexes III and IV (211).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 1. Role of mitochondria in liver
What the sources say
- Not checked yetcites [211] Benard, 2006, Physiological diversity of mitochondrial oxidative phosphorylation, Am J Physiol Cell Physiol source
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“In addition, the transcriptional coactivators PGC-1␣ and -1 (56) play a critical role in the expansion of the mitochondrial reticulum and in the induction of UCP1 and the brown adipose tissue thermogenic program during the perinatal period (59).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 4. Factors affecting mitochondrial OXPHOS expression and function in adipose tissue
What the sources say
- Not checked yetcites [56] Wu, 1999, Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1., Cell source
- Not checked yetcites [59] Sonoda, 2007, PGC-1β controls mitochondrial metabolism to modulate circadian activity, adaptive thermogenesis, and hepatic steatosis., Proc Natl Acad Sci USA source
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Interestingly, these mice are also dyslipidemic and susceptible to atherosclerosis (209).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > C. Liver
What the sources say
- Not checked yetcites [209] Biddinger, 2008, Hepatic insulin resistance is sufficient to produce dyslipidemia and susceptibility to atherosclerosis., Cell Metab source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, mechanisms that induce and maintain active mitochondria in adipocytes can bypass defects in insulin signaling, and indeed, insulin signaling may repress mitochondrial gene expression and/or function.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 3. Evidence for reduced adipose tissue mitochondrial capacity in DM
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“The mechanisms whereby obesity results in a reduction in adipose mitochondrial density are not known but could be mediated by decreased expression of PGC-1␣, as observed in obese humans (206).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 4. Factors affecting mitochondrial OXPHOS expression and function in adipose tissue
What the sources say
- Not checked yetcites [206] Semple, 2004, Expression of the thermogenic nuclear hormone receptor coactivator PGC-1α is reduced in the adipose tissue of morbidly obese subjects., Int J Obes Relat Metab Disord source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“For example, liver-specific insulin receptor knockout (LIRKO) mice develop insulin resistance, glucose intolerance, impaired insulin suppression of hepatic glucose production, and altered patterns of hepatic gene expression (208).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > C. Liver
What the sources say
- Not checked yetcites [208] Michael, 2000, Loss of insulin signaling in hepatocytes leads to severe insulin resistance and progressive hepatic dysfunction., Mol Cell source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, reduced mtDNA content could reduce adipocyte capacity for lipid storage, promoting ectopic lipid accumulation in peripheral tissues such as muscle and liver.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 3. Evidence for reduced adipose tissue mitochondrial capacity in DM
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Mitochondrial levels in white adipocytes are also increased in response to adrenergic stimulation, -3 agonists, and CB1 blockade in mice (195,199,200), again in parallel with enhanced insulin sensitivity.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 3. Evidence for reduced adipose tissue mitochondrial capacity in DM
What the sources say
- Not checked yetcites [195] Bogacka, 2005, Structural and functional consequences of mitochondrial biogenesis in human adipocytes in vitro., J Clin Endocrinol Metab source
- Not checked yetcites [199] Granneman, 2005, Metabolic and cellular plasticity in white adipose tissue I: effects of β3-adrenergic receptor activation, Am J Physiol Endocrinol Metab source
- Not checked yetcites [200] Tedesco, 2008, Cannabinoid type 1 receptor blockade promotes mitochondrial biogenesis through endothelial nitric oxide synthase expression in white adipocytes., Diabetes source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Although these data cannot address whether such changes are indeed pathogenic, it is interesting that reduced OXPHOS activity in this setting is accompanied by increased tissue long-chain acylcarnitines and reduced short-chain acylcarnitines, despite normal CPT1 activity and increased expression of -oxidation genes (230, 236).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 3. Evidence for impaired liver mitochondrial function in diabetes and NASH
What the sources say
- Not checked yetcites [230] Misu, 2007, Genes involved in oxidative phosphorylation are coordinately upregulated with fasting hyperglycaemia in livers of patients with type 2 diabetes., Diabetologia source
- Not checked yetcites [236] Kohjima, 2007, Re-evaluation of fatty acid metabolism-related gene expression in nonalcoholic fatty liver disease., Int J Mol Med
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Although these effects could be mediated by accumulation of fatty acyl CoA, diacylglycerols, and ceramides (as in muscle; Section III.A), it is intriguing that effects of fatty acids in liver cells can be prevented by inhibition of CPT1, indicating a critical role for mitochondrial oxidation in inducing lipid-mediated insulin resistance, perhaps via products of incomplete oxidation and/or”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 2. Potential mechanisms by which impaired hepatic mitochondrial function could influence hepatic insulin sensitivity
What the sources say
- Not checked yetcites [220] Nakamura, 2009, Palmitate induces insulin resistance in H4IIEC3 hepatocytes through reactive oxygen species produced by mitochondria., J Biol Chem source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“Byproducts of incomplete fatty acid oxidation could act in concert with adipose tissue-derived inflammatory signals (e.g., TNF␣), and altered expression and activation of proinflammatory (e.g., IL-1R family) and profibrotic genes (e.g., TGFB1, FGFR2), to increase production of ROS and ultimately contribute to the development of NASH and cirrhosis (235).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 3. Evidence for impaired liver mitochondrial function in diabetes and NASH
What the sources say
- Not checked yetcites [235] Sanyal, 2001, Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities., Gastroenterology source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“In the first (232), severe obesity (mean BMI 52 kg/m 2 ) was associated with reduced ex-pression of seven of 25 genes encoding OXPHOS genes; expression of these genes was inversely correlated with hepatic lipid accumulation and paralleled by reduced expression of PGC-1␣ and genes known to be regulated by thyroid hormone.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 3. Evidence for impaired liver mitochondrial function in diabetes and NASH
What the sources say
- Not checked yetcites [232] Pihlajamäki, 2009, Thyroid hormone-related regulation of gene expression in human fatty liver., J Clin Endocrinol Metab source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Interestingly, reduced expression of OXPHOS genes (e.g., COX7C, ATP5C1) was also observed in mice fed a high-fat diet and normalized by acute therapy with thyroid hormone T 3suggesting that functional hepatic thyroid hormone resistance could contribute to reduced expression of mitochondrial oxidative genes in this context (232).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 3. Evidence for impaired liver mitochondrial function in diabetes and NASH
What the sources say
- Not checked yetcites [232] Pihlajamäki, 2009, Thyroid hormone-related regulation of gene expression in human fatty liver., J Clin Endocrinol Metab source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Because accumulation of lipid within hepatocytes is a key marker of insulin resistance in humans (207) and a major contributor to nonalcoholic fatty liver disease, nonalcoholic steatohepatitis (NASH), and cirrhosis, we will first consider relationships between hepatic lipid metabolism and insulin resistance, and in Section III.C.3 will review evidence linking DM and hepatic steatosis to”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 2. Potential mechanisms by which impaired hepatic mitochondrial function could influence hepatic insulin sensitivity
What the sources say
- Not checked yetcites [207] Kotronen, 2008, Tissue specificity of insulin resistance in humans: fat in the liver rather than muscle is associated with features of the metabolic syndrome., Diabetologia source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“With aging, chronic ROS exposure, and/or the development of insulin resistance related to obesity or sustained lipid accumulation, OXPHOS expression may fall.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 3. Evidence for impaired liver mitochondrial function in diabetes and NASH
hedgedconditional- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper may give no reason why it holds.
In the paper
“Indeed, a recent paper demonstrated that mice with hepatic insulin resistance due to deletions of the major insulin receptor substrates (IRS-1 and IRS-2) have impaired mitochondrial function and biogenesis, as demonstrated by reduced NADH oxidation, reduced ATP production rates, reduced numbers of mitochondria per cell, reduced fatty acid oxidation, and increased hepatic triglyceride accumulation”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 2. Potential mechanisms by which impaired hepatic mitochondrial function could influence hepatic insulin sensitivity
What the sources say
- Not checked yetcites [229] Cheng, 2009, Foxo1 integrates insulin signaling with mitochondrial function in the liver., Nat Med source
boosteddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We hypothesize that modest obesity may be associated with compensatory up-regulation of OXPHOS gene expression in response to sustained lipid load and/or functional defects in complete fatty acid oxidation.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 3. Evidence for impaired liver mitochondrial function in diabetes and NASH
hedgedcorrelational- Asserted: fails — The authors may not put it forward as true.
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Probably not a substantial claim. The authors may not put it forward as true. The paper may give no reason why it holds. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Although this may be an appropriate response, limiting oxidative stress, it may also contribute to a vicious cycle of further impairments in oxidative capacity, increased lipid accumulation, and progressive insulin resistance.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 3. Evidence for impaired liver mitochondrial function in diabetes and NASH
hedgedconditional- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper may give no reason why it holds. It may state two separate claims as one.
In the paper
“Transgenic mice expressing lipoprotein lipase in the liver have a 2-fold increase in hepatic triglyceride content and are insulin resistant (219).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 2. Potential mechanisms by which impaired hepatic mitochondrial function could influence hepatic insulin sensitivity
What the sources say
- Not checked yetcites [219] Kim, 2001, Tissue-specific overexpression of lipoprotein lipase causes tissue-specific insulin resistance., Proc Natl Acad Sci USA source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Fatty acid-induced reductions in insulin receptor number and function in the liver (211) may also reduce hepatic insulin clearance (226), causing systemic hyperinsulinemia, itself a contributor to both insulin resistance and reduced mitochondrial function (214,227,228).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 2. Potential mechanisms by which impaired hepatic mitochondrial function could influence hepatic insulin sensitivity
What the sources say
- Not checked yetcites [211] Benard, 2006, Physiological diversity of mitochondrial oxidative phosphorylation, Am J Physiol Cell Physiol source
- Not checked yetcites [226] Seppälä-Lindroos, 2002, Fat accumulation in the liver is associated with defects in insulin suppression of glucose production and serum free fatty acids independent of obesity in normal men., J Clin Endocrinol Metab source
- Not checked yetcites [214] Kotronen, 2008, Increased liver fat, impaired insulin clearance, and hepatic and adipose tissue insulin resistance in type 2 diabetes., Gastroenterology source
- Not checked yetcites [227] Park, 2006, Mechanism of glucose intolerance in mice with dominant negative mutation of CEACAM1, Am J Physiol Endocrinol Metab source
- Not checked yetcites [228] Liu, 2009, Prolonged exposure to insulin suppresses mitochondrial production in primary hepatocytes., J Biol Chem source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Although the relative roles of each of these possibilities is incompletely understood, hepatic lipid accumulation is associated with obesity in humans, particularly central (abdominal) in location (214, 215), and in parallel with low adiponectin levels (216).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 2. Potential mechanisms by which impaired hepatic mitochondrial function could influence hepatic insulin sensitivity
What the sources say
- Not checked yetcites [214] Kotronen, 2008, Increased liver fat, impaired insulin clearance, and hepatic and adipose tissue insulin resistance in type 2 diabetes., Gastroenterology source
- Not checked yetcites [215] Petersen, 2005, Reversal of nonalcoholic hepatic steatosis, hepatic insulin resistance, and hyperglycemia by moderate weight reduction in patients with type 2 diabetes., Diabetes source
- Not checked yetcites [216] Koska, 2008, Increased fat accumulation in liver may link insulin resistance with subcutaneous abdominal adipocyte enlargement, visceral adiposity, and hypoadiponectinemia in obese individuals., Am J Clin Nutr source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“One possibility is that excessive hepatic lipid accumulation may play a central, pathogenic role in insulin resistance.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 2. Potential mechanisms by which impaired hepatic mitochondrial function could influence hepatic insulin sensitivity
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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Probably not a substantial claim.
None of the sources cited for this claim have been checked yet.
In the paper
“Indeed, enzymatic activity of complexes I-V is reduced in liver extracts from patients with NASH and is inversely correlated with BMI and HOMA-IR (233, 234).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 3. Evidence for impaired liver mitochondrial function in diabetes and NASH
What the sources say
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Although these two data sets appear to be discordant (i.e., obesity-linked down-regulation of mitochondrial oxidative gene expression in the first, and up-regulation in the second), several differences in the study population may account for these findings: 1) much greater degree of adiposity and hepatic steatosis in the first; 2) differences in ethnicity (Caucasian-Americans vs. Japanese); and 3)”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 3. Evidence for impaired liver mitochondrial function in diabetes and NASH
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Up-regulation of these OXPHOS genes was also positively associated with expression of several genes linked to mitochondrial biogenesis (e.g., PGC-1, ERR␣, NRF, thyroid hormone receptor) and both ROS generation (e.g., NADPH oxidase) and attenuation (e.g., glutathione peroxidase).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 3. Evidence for impaired liver mitochondrial function in diabetes and NASH
What the sources say
- Not checked yetcites [231] Takamura, 2008, Obesity upregulates genes involved in oxidative phosphorylation in livers of diabetic patients., Obesity (Silver Spring) source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Interestingly, mitochondrial diabetes only develops upon aging, with an average age of onset between 35 and 40 yr for MIDD and 48 yr for 14577 TϾC.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 2. Evidence for reduced -cell mitochondrial capacity in DM
What the sources say
- Not checked yetcites [246] Maassen, 2004, Mitochondrial diabetes: molecular mechanisms and clinical presentation, Diabetes source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“However, it also leads to decreased ATP production, which impairs insulin secretion.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 3. Factors affecting mitochondrial function in -cells
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“B, In the presence of excess FFA, this normal feedback loop is compromised by a direct activation of UCP2 by FFA, as well as an effect of FFA to increase the amount of UCP2.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > FIG. 4.
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Low levels of ROS are necessary for insulin secretion, but chronic, high mitochondrial ROS production can have a deleterious effect on -cell function (254 -256).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 3. Factors affecting mitochondrial function in -cells
What the sources say
- Not checked yetcites [254] Li, 2008, The sensitivity of pancreatic β-cells to mitochondrial injuries triggered by lipotoxicity and oxidative stress., Biochem Soc Trans source
- Not checked yetcites [255] Rachek, 2006, Protection of INS-1 cells from free fatty acid-induced apoptosis by targeting hOGG1 to mitochondria., Diabetes source
- Not checked yetcites [256] Simmons, 2005, Progressive accumulation of mitochondrial DNA mutations and decline in mitochondrial function lead to β-cell failure., J Biol Chem source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, UCPs must uncouple respiration sufficiently to mitigate toxic levels of ROS, but not enough to decrease ATP and ROS below the levels necessary for insulin secretion.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 3. Factors affecting mitochondrial function in -cells
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“However, these same animals displayed increased liver gluconeogenic enzyme levels and impaired insulin suppression of hepatic glucose production, thus nullifying the potentially beneficial effect of modest muscle PGC-1␣ overexpression on whole-body glucose homeostasis.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > A. PGC-1 ␣ and  overexpression
What the sources say
- Not checked yetcites [262] Liang, 2009, Whole body overexpression of PGC-1α has opposite effects on hepatic and muscle insulin sensitivity, Am J Physiol Endocrinol Metab source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Consistent with this view, clonal cytosolic hybrid cells harboring mitochondria derived from MIDD patients exhibit impaired calcium handling and elevated ROS under metabolic stress (247, 248).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 2. Evidence for reduced -cell mitochondrial capacity in DM
What the sources say
- Not checked yetcites [247] Maechler, 2006, In β-cells, mitochondria integrate and generate metabolic signals controlling insulin secretion., Int J Biochem Cell Biol source
- Not checked yetcites [248] Andrade, 2006, Diabetes-associated mitochondrial DNA mutation A3243G impairs cellular metabolic pathways necessary for β-cell function., Diabetologia source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“PGC-1␣ and related coactivators are critical for the regulation of mitochondrial oxidative capacity, as demonstrated by the approximately 2-fold increases in mtDNA and oxygen consumption and a 50% increase in mitochondrial density in myotubes overexpressing PGC-1␣ (56).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > A. PGC-1 ␣ and  overexpression
What the sources say
- Not checked yetcites [56] Wu, 1999, Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1., Cell source
boosteddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Consistent with this possibility, -cell specific deletion of Tfam reduces insulin secretory capacity and -cell mass, yielding so-called mitochondrial DM (241).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 2. Evidence for reduced -cell mitochondrial capacity in DM
What the sources say
- Not checked yetcites [241] Silva, 2000, Impaired insulin secretion and β-cell loss in tissue-specific knockout mice with mitochondrial diabetes., Nat Genet source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Chronically increased ROS production could also induce -cell death and result in gradual onset of diabetes (249 -253).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 2. Evidence for reduced -cell mitochondrial capacity in DM
What the sources say
- Not checked yetcites [249] Hou, 2008, Reactive oxygen species-mediated pancreatic β-cell death is regulated by interactions between stress-activated protein kinases, p38 and c-Jun N-terminal kinase, and mitogen-activated protein kinase phosphatases., Endocrinology source
- Not checked yetcites [250] Lim, 2008, Induction of apoptosis of β-cells of the pancreas by advanced glycation end-products, important mediators of chronic complications of diabetes mellitus., Ann NY Acad Sci source
- Not checked yetcites [251] Newsholme, 2007, Diabetes associated cell stress and dysfunction: role of mitochondrial and non-mitochondrial ROS production and activity., J Physiol source
- Not checked yetcites [252] Nishikawa, 2007, Impact of mitochondrial ROS production in the pathogenesis of diabetes mellitus and its complications., Antioxid Redox Signal source
- Not checked yetcites [253] Robertson, 2009, β-Cell deterioration during diabetes: what’s in the gun?, Trends Endocrinol Metab source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“Mitochondrial metabolism is also required for the transient, controlled production of ROS, which is required for the mitochondrial signaling pathways that trigger granule exocytosis (239, 240).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > D. Pancreatic -cells 1. Roles of mitochondria in -cells
What the sources say
- Not checked yetcites [239] Evans, 2003, Are oxidative stress-activated signaling pathways mediators of insulin resistance and β-cell dysfunction?, Diabetes source
- Not checked yetcites [240] Leloup, 2009, Mitochondrial reactive oxygen species are obligatory signals for glucose-induced insulin secretion., Diabetes source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In these animals, mitochondrial density and OXPHOS gene expression are more than double basal levels, and large increases in UCP2 gene expression are also observed.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > A. PGC-1 ␣ and  overexpression
What the sources say
- Not checked yetcites [263] Miura, 2003, Overexpression of peroxisome proliferator-activated receptor γ coactivator-1α down-regulates GLUT4 mRNA in skeletal muscles., J Biol Chem source
- Not checked yetcites [264] Miura, 2006, Overexpression of peroxisome proliferator-activated receptor γ co-activator-1α leads to muscle atrophy with depletion of ATP., Am J Pathol source
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Given the crucial role of mitochondrial ATP generation, anaplerosis, and ROS production in insulin secretion, mitochondrial dysfunction in -cells would be expected to reduce insulin secretion and thus promote the development of DM.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 2. Evidence for reduced -cell mitochondrial capacity in DM
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“Both rapid (first phase) and more prolonged (second phase) insulin secretion (237) are dependent on glucose metabolism and mitochondrial oxidative capacity; glucose oxidation increases the ATP/ADP ratio, inhibiting plasma membrane K-ATP channels and allowing voltage-gated calcium channels to open.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > D. Pancreatic -cells 1. Roles of mitochondria in -cells
What the sources say
- Not checked yetcites [237] O'Connor, 1980, Comparison of storage- and signal-limited models of pancreatic insulin secretion, Am J Physiol
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Similarly, transgenic mice expressing human PGC-1␣ driven by its own promoter displayed a modest (30% higher than basal) increase in mRNA expression of several OXPHOS genes, fiber type switching, and enhanced muscle insulin sensitivity (262).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > A. PGC-1 ␣ and  overexpression
What the sources say
- Not checked yetcites [262] Liang, 2009, Whole body overexpression of PGC-1α has opposite effects on hepatic and muscle insulin sensitivity, Am J Physiol Endocrinol Metab source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“The lowest level of PGC-1␣ overexpression was achieved in rat muscle by means of electroporation (261).This resulted in modest up-regulation of mitochondrial proteins, increased palmitate oxidation, and increased insulin-stimulated glucose uptake.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > A. PGC-1 ␣ and  overexpression
What the sources say
- Not checked yetcites [261] Benton, 2008, Modest PGC-1α overexpression in muscle in vivo is sufficient to increase insulin sensitivity and palmitate oxidation in subsarcolemmal, not intermyofibrillar, mitochondria., J Biol Chem source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In this case, mitochondrial respiratory chain complex I activity and O 2 consumption rates are decreased by 65 and 62%, respectively, in hybrid cell lines derived from probands.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 2. Evidence for reduced -cell mitochondrial capacity in DM
What the sources say
- Not checked yetcites [245] Tawata, 2000, A new mitochondrial DNA mutation at 14577 T/C is probably a major pathogenic mutation for maternally inherited type 2 diabetes., Diabetes source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Importantly, this modest PGC-1␣ overexpression also was accompanied by decreased levels of ROS and inflammatory signaling.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > A. PGC-1 ␣ and  overexpression
What the sources say
- Not checked yetcites [262] Liang, 2009, Whole body overexpression of PGC-1α has opposite effects on hepatic and muscle insulin sensitivity, Am J Physiol Endocrinol Metab source
plaincorrelationalSingle case- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Mitochondrial function in -cells is highly regulated by the levels and activities of UCPs, in turn regulated by ROS produced by the activity of the ETC.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 3. Factors affecting mitochondrial function in -cells
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“The levels and activity of UCP2 and the rate of ROS production are both increased by high-fat diet and hyperphagia, possibly through the actions of nonesterified fatty acids and their ceramide derivatives (260).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > 3. Factors affecting mitochondrial function in -cells
What the sources say
- Not checked yetcites [260] Koshkin, 2003, Mitochondrial functional state in clonal pancreatic β-cells exposed to free fatty acids., J Biol Chem source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Despite these effects, insulin sensitivity is normal in PGC-1␣ transgenic mice fed a chow diet and, surprisingly, is reduced during high-fat feeding.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > A. PGC-1 ␣ and  overexpression
What the sources say
- Not checked yetcites [267] Calvo, 2008, Muscle-specific expression of PPARγ coactivator-1α improves exercise performance and increases peak oxygen uptake., J Appl Physiol source
- Not checked yetcites [268] Lin, 2002, Transcriptional co-activator PGC-1 α drives the formation of slow-twitch muscle fibers., Nature source
- Not checked yetcites [269] Sandri, 2006, PGC-1α protects skeletal muscle from atrophy by suppressing FoxO3 action and atrophy-specific gene transcription., Proc Natl Acad Sci USA source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Inducible overexpression of PGC-1␣ in skeletal muscle ( 265) results in increased mitochondrial density and a robust increase in expression of OXPHOS genes and genes necessary for fatty acid oxidation.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > A. PGC-1 ␣ and  overexpression
What the sources say
- Not checked yetcites [265] Wende, 2007, A role for the transcriptional coactivator PGC-1α in muscle refueling., J Biol Chem source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Consistent with these findings, whole-body transgenic overexpression of PGC-1 resulted in increased oxidative metabolism, protection from obesity induced by high-fat diet or hyperphagia, and enhanced insulin sensitivity (272).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > A. PGC-1 ␣ and  overexpression
What the sources say
- Not checked yetcites [272] Kamei, 2003, PPARγ coactivator 1β/ERR ligand 1 is an ERR protein ligand, whose expression induces a high-energy expenditure and antagonizes obesity., Proc Natl Acad Sci USA source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Although low-intensity exercise performance did not differ in this model, high-performance exercise was impaired, in parallel with failure to mobilize stored glycogen.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > A. PGC-1 ␣ and  overexpression
What the sources say
- Not checked yetcites [265] Wende, 2007, A role for the transcriptional coactivator PGC-1α in muscle refueling., J Biol Chem source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“In adults, PGC-1␣ induction led to a more modest mitochondrial proliferation, which was nevertheless surprisingly accompanied by cardiomyopathy.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > A. PGC-1 ␣ and  overexpression
What the sources say
- Not checked yetcites [266] Russell, 2004, Cardiac-specific induction of the transcriptional coactivator peroxisome proliferator-activated receptor γ coactivator-1α promotes mitochondrial biogenesis and reversible cardiomyopathy in a developmental stage-dependent manner., Circ Res source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
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In the paper
“Functionally, decreases in ATP levels, state 3 respiration, and metabolic efficiency are seen, and cardiac and skeletal muscle performance is reduced in response to stress.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > B. PGC-1 knockout models
What the sources say
- Not checked yetcites [61] Lehman, 2008, The transcriptional coactivator PGC-1α is essential for maximal and efficient cardiac mitochondrial fatty acid oxidation and lipid homeostasis, Am J Physiol Heart Circ Physiol source
- Not checked yetcites [67] Leone, 2005, PGC-1α deficiency causes multi-system energy metabolic derangements: muscle dysfunction, abnormal weight control and hepatic steatosis, PLoS Biol source
- Not checked yetcites [68] Arany, 2005, Transcriptional coactivator PGC-1 α controls the energy state and contractile function of cardiac muscle., Cell Metab source
- Not checked yetcites [69] Lin, 2004, Defects in adaptive energy metabolism with CNS-linked hyperactivity in PGC-1α null mice., Cell source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“In this model, ATP synthesis rate and exercise performance are increased, and fatty acid oxidation is also enhanced.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > A. PGC-1 ␣ and  overexpression
What the sources say
- Not checked yetcites [267] Calvo, 2008, Muscle-specific expression of PPARγ coactivator-1α improves exercise performance and increases peak oxygen uptake., J Appl Physiol source
- Not checked yetcites [268] Lin, 2002, Transcriptional co-activator PGC-1 α drives the formation of slow-twitch muscle fibers., Nature source
- Not checked yetcites [269] Sandri, 2006, PGC-1α protects skeletal muscle from atrophy by suppressing FoxO3 action and atrophy-specific gene transcription., Proc Natl Acad Sci USA source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Muscle function appears compromised, as evidenced by decreased voluntary exercise, muscle atrophy, and decreased insulin sensitivity.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > A. PGC-1 ␣ and  overexpression
What the sources say
- Not checked yetcites [263] Miura, 2003, Overexpression of peroxisome proliferator-activated receptor γ coactivator-1α down-regulates GLUT4 mRNA in skeletal muscles., J Biol Chem source
- Not checked yetcites [264] Miura, 2006, Overexpression of peroxisome proliferator-activated receptor γ co-activator-1α leads to muscle atrophy with depletion of ATP., Am J Pathol source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Taken together, these studies suggest that modest overexpression of PGC-1␣ (261, 262) and transgenic overexpression of PGC-1 (271, 272) increase oxidative metabolism and insulin sensitivity.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > A. PGC-1 ␣ and  overexpression
What the sources say
- Not checked yetcites [261] Benton, 2008, Modest PGC-1α overexpression in muscle in vivo is sufficient to increase insulin sensitivity and palmitate oxidation in subsarcolemmal, not intermyofibrillar, mitochondria., J Biol Chem source
- Not checked yetcites [262] Liang, 2009, Whole body overexpression of PGC-1α has opposite effects on hepatic and muscle insulin sensitivity, Am J Physiol Endocrinol Metab source
- Not checked yetcites [271] Arany, 2007, The transcriptional coactivator PGC-1β drives the formation of oxidative type IIX fibers in skeletal muscle., Cell Metab source
- Not checked yetcites [272] Kamei, 2003, PPARγ coactivator 1β/ERR ligand 1 is an ERR protein ligand, whose expression induces a high-energy expenditure and antagonizes obesity., Proc Natl Acad Sci USA source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Muscle-specific transgenic overexpression of PGC-1 results in increased oxidative fiber content and increased expression of OXPHOS and multiple other mitochondrial genes.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > A. PGC-1 ␣ and  overexpression
What the sources say
- Not checked yetcites [271] Arany, 2007, The transcriptional coactivator PGC-1β drives the formation of oxidative type IIX fibers in skeletal muscle., Cell Metab source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“By contrast, highlevel overexpression of PGC-1␣ may actually reduce insulin sensitivity via reduced glycolysis and/or glucose oxidation (265) or myofibrillar disruption/myopathy, potentially limiting exercise tolerance.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > A. PGC-1 ␣ and  overexpression
What the sources say
- Not checked yetcites [265] Wende, 2007, A role for the transcriptional coactivator PGC-1α in muscle refueling., J Biol Chem source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“In these animals, both muscle glucose uptake and glycogen deposition were increased.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > A. PGC-1 ␣ and  overexpression
What the sources say
- Not checked yetcites [265] Wende, 2007, A role for the transcriptional coactivator PGC-1α in muscle refueling., J Biol Chem source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
In the paper
“When higher levels of PGC-1␣ overexpression are restricted to heart during early life (266), increased neonatal mitochondrial proliferation is observed, but it is accompanied by myofibrillar displacement.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > A. PGC-1 ␣ and  overexpression
What the sources say
- Not checked yetcites [266] Russell, 2004, Cardiac-specific induction of the transcriptional coactivator peroxisome proliferator-activated receptor γ coactivator-1α promotes mitochondrial biogenesis and reversible cardiomyopathy in a developmental stage-dependent manner., Circ Res source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“These mice consistently display 30 -60% reductions in OXPHOS gene expression in muscle, normal to decreased mitochondrial density in skeletal muscle, and decreased cristae density in heart.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > B. PGC-1 knockout models
What the sources say
- Not checked yetcites [61] Lehman, 2008, The transcriptional coactivator PGC-1α is essential for maximal and efficient cardiac mitochondrial fatty acid oxidation and lipid homeostasis, Am J Physiol Heart Circ Physiol source
- Not checked yetcites [67] Leone, 2005, PGC-1α deficiency causes multi-system energy metabolic derangements: muscle dysfunction, abnormal weight control and hepatic steatosis, PLoS Biol source
- Not checked yetcites [68] Arany, 2005, Transcriptional coactivator PGC-1 α controls the energy state and contractile function of cardiac muscle., Cell Metab source
- Not checked yetcites [69] Lin, 2004, Defects in adaptive energy metabolism with CNS-linked hyperactivity in PGC-1α null mice., Cell source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Mitochondrial energetics are impaired, with 60% decreases in ATP levels in muscle homogenates and concomitant increases in AMP kinase activation, probably as a compensatory response to decreased mitochondrial functionality.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > A. PGC-1 ␣ and  overexpression
What the sources say
- Not checked yetcites [263] Miura, 2003, Overexpression of peroxisome proliferator-activated receptor γ coactivator-1α down-regulates GLUT4 mRNA in skeletal muscles., J Biol Chem source
- Not checked yetcites [264] Miura, 2006, Overexpression of peroxisome proliferator-activated receptor γ co-activator-1α leads to muscle atrophy with depletion of ATP., Am J Pathol source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“For example, in cultured myotubes overexpressing PGC-1␣ (273), lipid content is decreased in the serum-starved condition, reflecting increased oxidation of lipids; by contrast, in the serum-replete state, intracellular fatty acid levels are increased, likely due to both increased de novo fatty acid synthesis from glucose and fatty acid synthesis by chain elongation (273).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > A. PGC-1 ␣ and  overexpression
What the sources say
- Not checked yetcites [273] Espinoza, 2009
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“These animals display normal mitochondrial biogenesis during development but die early after birth due to failure of perinatal mitochondrial proliferation and consequent cardiac failure (62).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > B. PGC-1 knockout models
What the sources say
- Not checked yetcites [62] Lai, 2008, Transcriptional coactivators PGC-1α and PGC-lβ control overlapping programs required for perinatal maturation of the heart., Genes Dev source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“In these mice, insulin sensitivity is normal and glucose tolerance is enhanced, consistent with a need for enhanced fuel utilization in response to inefficient mitochondrial ATP production.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > C. Other mitochondrial function defects
What the sources say
- Not checked yetcites [282] Wang, 1999, Dilated cardiomyopathy and atrioventricular conduction blocks induced by heart-specific inactivation of mitochondrial DNA gene expression., Nat Genet source
plaindirectSingle case- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“PGC-1-null mice have more striking hepatic phenotypes, with hepatic insulin resistance, even on normal chow, and steatosis with high-fat feeding (59,65,66).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > B. PGC-1 knockout models
What the sources say
- Not checked yetcites [59] Sonoda, 2007, PGC-1β controls mitochondrial metabolism to modulate circadian activity, adaptive thermogenesis, and hepatic steatosis., Proc Natl Acad Sci USA source
- Not checked yetcites [65] Vianna, 2006, Hypomorphic mutation of PGC-1β causes mitochondrial dysfunction and liver insulin resistance., Cell Metab source
- Not checked yetcites [66] Lelliott, 2006, Ablation of PGC-1β results in defective mitochondrial activity, thermogenesis, hepatic function, and cardiac performance, PLoS Biol source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Similarly, skeletal and cardiac muscle-specific deletion of Tfam causes severe OXPHOS deficits, dilated cardiomyopathy, and death during early postnatal life (282).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > C. Other mitochondrial function defects
What the sources say
- Not checked yetcites [282] Wang, 1999, Dilated cardiomyopathy and atrioventricular conduction blocks induced by heart-specific inactivation of mitochondrial DNA gene expression., Nat Genet source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
In the paper
“Pospisilik et al. (274) used an alternative strategy to test whether experimentally induced respiratory chain complex deficiency would induce metabolic phenotypes.Tissue-specific ablation of the nuclear-encoded gene, mitochondrial apoptosis-inducing factor (AIF), produced modest defects in respiratory chain gene expression and function, as expected; however, both muscle-and liverspecific null mice”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > C. Other mitochondrial function defects
What the sources say
- Not checked yetcites [274] Pospisilik, 2007, Targeted deletion of AIF decreases mitochondrial oxidative phosphorylation and protects from obesity and diabetes., Cell source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“PGC-1-null mice (59, 62, 65, 66) display phenotypes similar to, but not identical to, those of PGC-1␣ knockouts, including reduced expression of OXPHOS genes, reduced ATP synthesis, reduced exercise capacity, and impaired thermogenesis (59,62).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > B. PGC-1 knockout models
What the sources say
- Not checked yetcites [59] Sonoda, 2007, PGC-1β controls mitochondrial metabolism to modulate circadian activity, adaptive thermogenesis, and hepatic steatosis., Proc Natl Acad Sci USA source
- Not checked yetcites [62] Lai, 2008, Transcriptional coactivators PGC-1α and PGC-lβ control overlapping programs required for perinatal maturation of the heart., Genes Dev source
- Not checked yetcites [65] Vianna, 2006, Hypomorphic mutation of PGC-1β causes mitochondrial dysfunction and liver insulin resistance., Cell Metab source
- Not checked yetcites [66] Lelliott, 2006, Ablation of PGC-1β results in defective mitochondrial activity, thermogenesis, hepatic function, and cardiac performance, PLoS Biol source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“PGC-1␣ and PGC-1 are both required for the full complement of OXPHOS gene expression, the establishment of correct fuel partitioning, and optimal metabolic efficiency because whole-body and tissue-specific knockout of either of these genes leads to deranged multiorgan metabolic phenotypes that are more evident during energetic stress.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > B. PGC-1 knockout models
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“The nuclearencoded mitochondrial transcription factor Tfam is essential for transcription of mtDNA and thus mitochondrial development, as indicated by the embryonic lethality of Tfam-null mice (281).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > C. Other mitochondrial function defects
What the sources say
- Not checked yetcites [281] Larsson, 1998, Mitochondrial transcription factor A is necessary for mtDNA maintenance and embryogenesis in mice., Nat Genet source
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, lack of PGC-1␣ per se does not lead to insulin resistance, despite clear alterations in muscle and metabolic phenotypes.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > B. PGC-1 knockout models
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Despite pronounced muscle and brown adipose tissue functional impairments seen in models of PGC-1␣ deficiency, mitochondrial density in muscle and brown adipose tissue is not notably decreased, indicating the possible compensatory role of PGC-1 in mitochondrial biogenesis.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > B. PGC-1 knockout models
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Skeletal muscle-specific Tfam deficiency is accompanied by increased AMP kinase activation and increased glycolysis, indicating that compensatory mechanisms to maintain ATP levels are activated in response to impaired mitochondrial energetics (282).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > C. Other mitochondrial function defects
What the sources say
- Not checked yetcites [282] Wang, 1999, Dilated cardiomyopathy and atrioventricular conduction blocks induced by heart-specific inactivation of mitochondrial DNA gene expression., Nat Genet source
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
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It may state two separate claims as one.
In the paper
“Although the physiological effects of the related gene ERR␥ remain unclear, it interacts with PGC-1 to regulate expression of ERR␣ (278), and polymorphisms at this locus were found to be associated with increased glucose area under the curve in a genetic analysis of Old Order Amish subjects (279).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > C. Other mitochondrial function defects
What the sources say
- Not checked yetcites [278] Liu, 2005, Estrogen-related receptor-γ and peroxisome proliferator-activated receptor-γ coactivator-1α regulate estrogen-related receptor-α gene expression via a conserved multi-hormone response element., J Mol Endocrinol source
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Interestingly, ERR␣-null mice have reduced body weight and are normoglycemic, in parallel with up-regulation of medium-chain acyl-CoA dehydrogenase and reduced lipogenesis, both of which may contribute to resistance to diet-induced obesity (277).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > C. Other mitochondrial function defects
What the sources say
- Not checked yetcites [277] Luo, 2003, Reduced fat mass in mice lacking orphan nuclear receptor estrogen-related receptor α., Mol Cell Biol source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“In addition, both lines of whole-body PGC-1␣ knockout animals display cold sensitivity, likely related to impaired mitochondrial function in brown adipose tissue (67, 69) (Table 2).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > B. PGC-1 knockout models
What the sources say
- Not checked yetcites [67] Leone, 2005, PGC-1α deficiency causes multi-system energy metabolic derangements: muscle dysfunction, abnormal weight control and hepatic steatosis, PLoS Biol source
- Not checked yetcites [69] Lin, 2004, Defects in adaptive energy metabolism with CNS-linked hyperactivity in PGC-1α null mice., Cell source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In turn, such alterations in mitochondrial activity could be mediated by genetic factors (family history, ethnicity), epigenetic mechanisms, developmental exposures, and aging.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > V. Conclusions
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Conversely, individuals with low oxidative capacity and/or subopti-mal adaptive responses would be intolerant to moderatehigh fuel loads, leading to lipid accumulation, incomplete oxidation, production of ROS, and acute insulin resistance (Fig. 5B).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > V. Conclusions
hedgeddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Lelliot, 2006 PGC-1 whole-body KO 2 20% 20 -40% 2 mRNA | (66)”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > V. Conclusions
What the sources say
- Not checked yetcites [66] Lelliott, 2006, Ablation of PGC-1β results in defective mitochondrial activity, thermogenesis, hepatic function, and cardiac performance, PLoS Biol source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Nevertheless, results from multiple mouse models now indicate that absolute deficiency of the PGC-1 family of coactivators or mitochondrial OXPHOS per se does not directly produce insulin resistance.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > V. Conclusions
hedged- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“DNA polymerase ␥ is a mtDNA polymerase critical for maintenance of mtDNA.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > C. Other mitochondrial function defects
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, we interpret the current data to indicate that an individual's intrinsic mitochondrial oxidative activity may determine the magnitude of chronic cellular dysfunction and influence adaptive responses to chronic fuel excess, as with obesity or inactivity.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > V. Conclusions
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“With regard to the first question, mild deficiencies in mitochondrial activity, and/or an inability to increase activity and capacity in response to cellular energy demand, could explain the reduced exercise ability seen in individuals with a family history of DM (106).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > V. Conclusions
What the sources say
- Not checked yetcites [106] Kacerovsky-Bielesz, 2009, Short-term exercise training does not stimulate skeletal muscle ATP synthesis in relatives of humans with type 2 diabetes., Diabetes source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Leone, 2005 PGC-1␣ whole-body KO 30% 2 40 -60% 2 mRNA | (67)”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > V. Conclusions
What the sources say
- Not checked yetcites [67] Leone, 2005, PGC-1α deficiency causes multi-system energy metabolic derangements: muscle dysfunction, abnormal weight control and hepatic steatosis, PLoS Biol source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“180% 1 COXIV | protein | 130% 1 mRNA | | 150 -200% | 1 mRNA | | | 150 -250% | 1 mRNA | | | | 170 -300% | 1 mRNA | 200 -500% | 1 mRNA and | protein”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > V. Conclusions
What the sources say
- Not checked yetcites [261] Benton, 2008, Modest PGC-1α overexpression in muscle in vivo is sufficient to increase insulin sensitivity and palmitate oxidation in subsarcolemmal, not intermyofibrillar, mitochondria., J Biol Chem source
- Not checked yetcites [262] Liang, 2009, Whole body overexpression of PGC-1α has opposite effects on hepatic and muscle insulin sensitivity, Am J Physiol Endocrinol Metab source
- Not checked yetcites [263] Miura, 2003, Overexpression of peroxisome proliferator-activated receptor γ coactivator-1α down-regulates GLUT4 mRNA in skeletal muscles., J Biol Chem source
- Not checked yetcites [264] Miura, 2006, Overexpression of peroxisome proliferator-activated receptor γ co-activator-1α leads to muscle atrophy with depletion of ATP., Am J Pathol source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Lin, 2004 (69); PGC-1␣ whole-body KO Normal 30 -60% 2 mRNA; | Arany, 50% 2 CytC | 2005 (68) protein”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > V. Conclusions
What the sources say
- Not checked yetcites [69] Lin, 2004, Defects in adaptive energy metabolism with CNS-linked hyperactivity in PGC-1α null mice., Cell source
- Not checked yetcites [68] Arany, 2005, Transcriptional coactivator PGC-1 α controls the energy state and contractile function of cardiac muscle., Cell Metab source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In turn, excessive ROS can induce both insulin resistance and mitochondrial dysfunction.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > V. Conclusions
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“With time, mitochondrial damage ensues, further exacerbating the process.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > V. Conclusions
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one. The quote only partly states this claim.
None of the sources cited for this claim have been checked yet.
In the paper
“Similarly, exposure of muscle cells in vitro to saturated fatty acids or high-fat feeding in mice results in alterations in mitochondrial structure and insulin resistance, both of which are reversed by antioxidants (286 -288).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > V. Conclusions
What the sources say
- Not checked yetcites [286] Stump, 2003, Effect of insulin on human skeletal muscle mitochondrial ATP production, protein synthesis, and mRNA transcripts., Proc Natl Acad Sci USA source
- Not checked yetcites [287] Anderson, 2009, Substrate-specific derangements in mitochondrial metabolism and redox balance in the atrium of the type 2 diabetic human heart., J Am Coll Cardiol source
- Not checked yetcites [288] Bonnard, 2008, Mitochondrial dysfunction results from oxidative stress in the skeletal muscle of diet-induced insulin-resistant mice., J Clin Invest
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Together, these factors contribute to progressively impaired insulin sensitivity, insulin secretion, and heightened risk of DM.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > V. Conclusions
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Chronic fuel excess, in the setting of suboptimal oxidative activity, results in fatty acid accumulation, incomplete oxidation, increased oxidative stress, and ROS generation leading to impairment in oxidative capacity, compounding the deleterious effects of fuel excess.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > V. Conclusions
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Failure of complete oxidation can lead to accumulation of lipid intermediates, incomplete fatty acid oxidation products, and ROS, inducing both insulin resistance (muscle, liver, adipose) and altered secretion (-cells).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > V. Conclusions
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, oxidative stress can induce mitochondrial dysfunction in parallel with insulin resistance-perhaps an adaptive response aimed at limiting further oxidative damage.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > V. Conclusions
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Resulting lipid accumulation and oxidative stress can alter transcriptional responses and damage mitochondria, further reducing OXPHOS capacity, compounding the deleterious effects of fuel excess and increasing diabetes risk.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > V. Conclusions
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
In the paper
“Mice null for the mitochondrial helicase Twinkle have impaired respiratory chain activity and muscle atrophy, but no defect in exercise capacity (285).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > C. Other mitochondrial function defects
What the sources say
- Not checked yetcites [285] Tyynismaa, 2004, Twinkle helicase is essential for mtDNA maintenance and regulates mtDNA copy number., Hum Mol Genet source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“With time, insufficient oxidative capacity could be resolved by compensatory mechanisms that increase oxidative capacity (e.g., exercise, mitochondrial biogenesis) (Fig. 5C, top right) or decrease fuel load (weight loss) (Fig. 5C, middle right).Insufficient compensation could result in chronic insulin resistance (Fig. 5C, bottom right).”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > V. Conclusions
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“An individual's intrinsic mitochondrial oxidative capacity is determined by numerous factors including genetic and ethnic background, intrauterine exposures, and age.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > V. Conclusions
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper may give no reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Over time, this phenotype could contribute to reduced voluntary exercise and increase the likelihood of an imbalance between mitochondrial activity and fatty acid load.”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > V. Conclusions
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Handschin, PGC-1␣ muscle-specific Normal 30 -40% 2 mRNA | 2007 KO | (63, 64)”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > V. Conclusions
What the sources say
- Not checked yetcites [63] Handschin, 2007, Skeletal muscle fiber-type switching, exercise intolerance, and myopathy in PGC-1α muscle-specific knock-out animals., J Biol Chem source
- Not checked yetcites [64] Handschin, 2007, Abnormal glucose homeostasis in skeletal muscle-specific PGC-1α knockout mice reveals skeletal muscle-pancreatic β-cell crosstalk., J Clin Invest source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Vianna, 2006 PGC-1 whole-body 2 30% 20 -30% 2 mRNA | (65) hypomorph”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > V. Conclusions
What the sources say
- Not checked yetcites [65] Vianna, 2006, Hypomorphic mutation of PGC-1β causes mitochondrial dysfunction and liver insulin resistance., Cell Metab source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
In the paper
“Sonoda, 2007 PGC-1 whole-body Normal 30 -40% 2 mRNA | (59) hypomorph”
§ The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes > V. Conclusions
What the sources say
- Not checked yetcites [59] Sonoda, 2007, PGC-1β controls mitochondrial metabolism to modulate circadian activity, adaptive thermogenesis, and hepatic steatosis., Proc Natl Acad Sci USA source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper relies on this without support.
Skeletal muscle accounts for more than 80% of insulin-stimulated glucose disposal in humans.
“Skeletal muscle is the largest insulin-sensitive organ in humans, accounting for more than 80% of insulinstimulated glucose disposal.”
The paper relies on this without support.
Mitochondria are particularly important for skeletal muscle function given the high oxidative demands imposed by intermittent contraction.
“Mitochondria are particularly important for skeletal muscle function, given the high oxidative demands imposed on this tissue by intermittent contraction.”
The paper relies on this without support.
Healthy muscle tissue predominantly oxidizes lipid in the fasting state and transitions to carbohydrate oxidation during the fed state.
“For example, healthy muscle tissue predominantly oxidizes lipid in the fasting state, as evidenced by low respiratory quotient (RQ), with subsequent tran-sition to carbohydrate oxidation (increased RQ) during the fed state.”
The paper relies on this without support.
OXPHOS gene expression is coordinately regulated.
“Additionally, because OXPHOS gene expression is coordinately regulated, patterns of differential OXPHOS expression may be more readily detectable in disease states, yet not necessarily mirror other aspects of mitochondrial oxidative capacity.”
The paper relies on this without support.
Changes in the levels of OXPHOS and other oxidative genes must occur in response to cellular energetic and metabolic needs, and in a coordinated manner that ensures the stoichiometric assembly of the products of distinct genes into functional complexes.
“Changes in the levels of OXPHOS and other oxidative genes must occur in response to cellular energetic and metabolic needs, and in a coordinated manner that ensures the stoichiometric assembly of the products of distinct genes into functional complexes.”
The paper relies on this without support.
Coordination of OXPHOS gene expression in muscle is mediated in part by the action of coactivators and corepressors.
“As in other tissues, the coordination of OXPHOS gene expression in muscle is mediated in part by the action of coactivators and corepressors.”
The paper relies on this without support.
Brown adipocyte mitochondria contain high levels of CPT1b, which is critical for the entry of fatty acids into the mitochondria for β-oxidation.
“Thus, brown adipocyte mitochondria also contain high levels of CPT1b, which is critical for the entry of fatty acids into the mitochondria for -oxidation.”
The paper relies on this without support.
β-Oxidation generates large amounts of reducing equivalents for the ETC.
“-Oxidation, in turn, generates large amounts of reducing equivalents for the ETC.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Separate to insulin sensitivity, T2DM and GDM are associated with a reduced number and function of mitochondria within skeletal muscle cells [126].”
From The Pathophysiology of Gestational Diabetes Mellitus (2018) · cites this paper as [126]
Experimental — accuracy not yet measuredIn the citing paper
“In several of the models studied including rodents and humans, these diseases are associated with mitochondrial dysfunction indicated by low expression of mtDNA and reduction of the levels of proteins involved in oxidative phosphorylation (OXPHOS).”
From Mitochondrial Activity and Dynamics Changes Regarding Metabolism in Ageing and Obesity (2017) · cites this paper as Patti and Corvera, 2010
In the citing paper
“Thus, mitochondrial dysfunction has been described in the main organs involved in the development of metabolic syndrome during ageing such as muscle, liver and adipose tissue (Patti and Corvera, 2010).”
From Mitochondrial Activity and Dynamics Changes Regarding Metabolism in Ageing and Obesity (2017) · cites this paper as Patti and Corvera, 2010
In the citing paper
“On the other hand, deficiency in mitochondrial activity in muscle is associated with obesity and T2DM.”
From Mitochondrial Activity and Dynamics Changes Regarding Metabolism in Ageing and Obesity (2017) · cites this paper as Patti and Corvera, 2010
In the citing paper
“mitochondrial dysfunction has been described in the main organs involved in the development of metabolic syndrome during ageing such as muscle, liver and adipose tissue (Patti and Corvera, 2010).”
From Mitochondrial Activity and Dynamics Changes Regarding Metabolism in Ageing and Obesity (2017) · cites this paper as Patti and Corvera, 2010
In the citing paper
“In several of the models studied including rodents and humans, these diseases are associated with mitochondrial dysfunction indicated by low expression of mtDNA and reduction of the levels of proteins involved in oxidative phosphorylation (OXPHOS).”
From Mitochondrial Activity and Dynamics Changes Regarding Metabolism in Ageing and Obesity (2017) · cites this paper as Patti and Corvera, 2010
In the citing paper
“Finally, we evaluated whether Paribs could improve acquired defects in mitochondrial function, such as the decreased mitochondrial activity observed in skeletal muscle cells of obese humans (Patti and Corvera, 2010).”
From Pharmacological Inhibition of poly(ADP-ribose) polymerases improves fitness and mitochondrial function in skeletal muscle (2014) · cites this paper as Patti and Corvera, 2010
Citations
Cites
1 retracted
Southgate, R. J., Bruce, C. R., Carey, A. L., Steinberg, G. R., Walder, K., Monks, R., Watt, M. J., Hawley, J. A., Birnbaum, M. J., & Febbraio, M. A. (2005) · The FASEB Journal · doi:10.1096/fj.05-3993fje · Cited by 74
RetractedReduction in the incidence of type 2 diabetes with lifestyle intervention or metformin
(2002) · New England Journal of Medicine · doi:10.1056/nejmoa012512 · Cited by 19,011
Tuomilehto, J., Lindström, J., Eriksson, J. G., Valle, T. T., Hämäläinen, H., Ilanne-Parikka, P., Keinänen-Kiukaanniemi, S., Laakso, M., Louheranta, A., Rastas, M., et al. (2001) · New England Journal of Medicine · doi:10.1056/nejm200105033441801 · Cited by 10,873
Mootha, V. K., Lindgren, C. M., Eriksson, K.-F., Subramanian, A., Sihag, S., Lehar, J., Puigserver, P., Carlsson, E., Ridderstråle, M., Laurila, E., et al. (2003) · Nature Genetics · doi:10.1038/ng1180 · Cited by 10,197
Prevalence of Overweight and Obesity in the United States, 1999-2004
Ogden, C. L., Carroll, M. D., Curtin, L. R., McDowell, M. A., Tabak, C. J., & Flegal, K. M. (2006) · JAMA · doi:10.1001/jama.295.13.1549 · Cited by 8,720
How mitochondria produce reactive oxygen species
Murphy, M. P. (2009) · Biochemical Journal · doi:10.1042/bj20081386 · Cited by 8,207
Identification and Importance of Brown Adipose Tissue in Adult Humans
Cypess, A. M., Lehman, S., Williams, G., Tal, I., Rodman, D., Goldfine, A. B., Kuo, F. C., Palmer, E. L., Tseng, Y.-H., Doria, A., et al. (2009) · New England Journal of Medicine · doi:10.1056/nejmoa0810780 · Cited by 4,399
Prevalence of Overweight and Obesity in the United States
Crespo, C. J., & Smit, E. (2003) · Human Kinetics eBooks · doi:10.5040/9781718206601.ch-001 · Cited by 4,382
Wu, Z., Puigserver, P., Andersson, U., Zhang, C., Adelmant, G., Mootha, V., Troy, A., Cinti, S., Lowell, B., Scarpulla, R. C., et al. (1999) · Cell · doi:10.1016/s0092-8674(00)80611-x · Cited by 4,139
Lagouge, M., Argmann, C., Gerhart-Hines, Z., Meziane, H., Lerin, C., Daussin, F., Messadeq, N., Milne, J., Lambert, P., Elliott, P., et al. (2006) · Cell · doi:10.1016/j.cell.2006.11.013 · Cited by 4,057
Cited by
Sorted by citations
DeFronzo, R. A., Ferrannini, E., Groop, L., Henry, R. R., Herman, W. H., Holst, J. J., Hu, F. B., Kahn, C. R., Raz, I., Shulman, G. I., et al. (2015) · Nature Reviews Disease Primers · doi:10.1038/nrdp.2015.19 · Cited by 2,611
The Pathophysiology of Gestational Diabetes Mellitus
Plows, J. F., Stanley, J. L., Baker, P. N., Reynolds, C. M., & Vickers, M. H. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19113342 · Cited by 1,874
“Separate to insulin sensitivity, T2DM and GDM are associated with a reduced number and function of mitochondria within skeletal muscle cells [126].”
BackgroundMitochondrial electron transport chain, ROS generation and uncoupling (Review)
Zhao, R., Jiang, S., Zhang, L., & Yu, Z. (2019) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2019.4188 · Cited by 1,511
Incalza, M. A., D’Oria, R., Natalicchio, A., Perrini, S., Laviola, L., & Giorgino, F. (2017) · Vascular Pharmacology · doi:10.1016/j.vph.2017.05.005 · Cited by 1,419
Insulin action and resistance in obesity and type 2 diabetes
Czech, M. P. (2017) · Nature Medicine · doi:10.1038/nm.4350 · Cited by 1,258
Metadata
- Authors
- Patti, M.-E., & Corvera, S.
- Affiliations
- Joslin Diabetes Center (US)
- Harvard University (US)
- Venue
- Endocrine Reviews
- Publisher
- The Endocrine Society
- Published
- 2010-06-01
- Volume
- 31
- Issue
- 3
- Pages
- 364-395
- ISSN
- 0163-769X (ISSN-L)
- 1945-7189
- PMC
- PMC3365846
- OpenAlex
- W2166954428
- Cited by
- 551
- References
- 297
- Citations by year
- 2026: 18 · 2025: 19 · 2024: 26 · 2023: 30 · 2022: 32 · 2021: 42 · 2020: 27 · 2019: 38 · 2018: 38 · 2017: 36 · 2016: 40 · 2015: 35 · 2014: 51 · 2013: 39 · 2012: 36
- FWCI
- 3.37
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Endocrine Reviews (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Joslin Diabetes Center
- National Institutes of Health (DK32520, LM008748, DK 36836)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK080366, DK36836, DK-062948, R21DK080366, DK 32520, P30DK032520, R01DK060837, DK060837, R01DK062948, P30DK036836)
- U.S. National Library of Medicine (U54LM008748, LM 008748)
- National Center for Research Resources (M01RR001032)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- type 2 diabetes pathogenesis, mitochondrial dysfunction, insulin resistance, oxidative stress, PGC-1, mitochondrial biogenesis, skeletal muscle, adipose tissue, liver, pancreatic beta cells, obesity, overnutrition, lipid peroxidation, energy homeostasis, mitochondrial morphology
- MeSH terms
- Animals, Diabetes Mellitus, Type 2, Humans, Insulin Resistance, Mitochondria, Oxidative Phosphorylation
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-10-10, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-10 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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