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Cited by 551Mitochondrial Function and PathologyAdipose Tissue and MetabolismMetabolism, Diabetes, and Cancer

The role of mitochondria in the pathogenesis of type 2 diabetes

Open access
Patti, Mary-Elizabeth, Corvera, Silvia·2010·Endocrine Reviews
DOI 10.1210/er.2009-0027PMC PMC3365846
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Abstract

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-

AI snapshot

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.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1210/er.2009-0027

Cites

295 of 295 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 353 cited sources checked · 0 supported · 0 flagged

  • Findingcitation

    ADP and succinate-stimulated oxygen consumption is modestly reduced in permeabilized muscle fibers from obese individuals with type 2 DM.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [115] Boushel, 2007, Patients with type 2 diabetes have normal mitochondrial function in skeletal muscle., Diabetologia source

      Not checked in the free run.

  • Interpretationreasoning

    The imbalance between oxidative activity and nutrient load may lead to chronic accumulation of lipid oxidative metabolites that can mediate insulin resistance and secretory dysfunction.

    “This imbalance may lead in turn to chronic accumulation of lipid oxidative metabolites that can mediate insulin resistance and secretory dysfunction.”
    Quote in the paperSubstantial claim
  • Premisecitation

    Insulin resistance is common in high-risk individuals years before the onset of type 2 DM.

    “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).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites (27)(28)(29)

      Not checked in the free run.

  • Premisecitation

    Oxidative activity (e.g., citrate synthase, acyl CoA dehydrogenase) is a robust correlate of insulin sensitivity, even better than intramyocellular triglycerides or long-chain fatty acyl CoA.

    “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).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [110] Bruce, 2003, Muscle oxidative capacity is a better predictor of insulin sensitivity than lipid status., J Clin Endocrinol Metab source

      Not checked in the free run.

  • Premisecitation

    Global gene expression analysis demonstrated a 20-30% reduction in mRNA expression levels for multiple nuclear-encoded genes of the OXPHOS pathway in humans with type 2 DM.

    “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).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [121] Mootha, 2003, PGC-1α-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes., Nat Genet source

      Not checked in the free run.

    • cites [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 in the free run.

    • cites [123] Sreekumar, 2002, Gene expression profile in skeletal muscle of type 2 diabetes and the effect of insulin treatment., Diabetes source

      Not checked in the free run.

  • May combine two claims. 142
  • Classified as probably not a substantial claim. 18
  • The quote only partly states this claim. 1

  • May combine two claims.

    Findingcitation

    Rates of mitochondrial OXPHOS in offspring of type 2 diabetic subjects, assessed by 31P spectroscopy, are reduced by 30% in the fasting state, and TCA cycle flux is reduced by 30%.

    “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).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [117] Petersen, 2004, Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes., N Engl J Med source

      Not checked in the free run.

    • cites [118] Befroy, 2007, Impaired mitochondrial substrate oxidation in muscle of insulin-resistant offspring of type 2 diabetic patients., Diabetes source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Insulin-stimulated ATP synthesis is reduced by more than 90% in nonobese first-degree relatives of type 2 diabetics, more than would be expected from the 30% decrease in mitochondrial density and oxidative function observed in the same population.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    The enzymatic activity of OXPHOS complex I is reduced by about 40% in skeletal muscle biopsy samples from individuals with type 2 DM and by 20% in obese individuals.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [114] Ritov, 2005, Deficiency of subsarcolemmal mitochondria in obesity and type 2 diabetes., Diabetes source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Maximal ADP-stimulated respiration (state 3, malate and pyruvate as substrates) is decreased in mitochondria isolated from obese subjects with DM compared with obesity alone, and these differences persist after normalization to citrate synthase activity.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [119] Mogensen, 2007, Mitochondrial respiration is decreased in skeletal muscle of patients with type 2 diabetes., Diabetes source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    In cultured C2C12 mouse myoblasts, the mitochondrial reticulum is dynamic, with scission, branching, and fusion events occurring at 30-second intervals.

    “The comparison between successive frames reveals scission events (arrowheads), branching events (V), and fusion events (brackets) occurring at 30-sec intervals.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Both obesity and related inactivity are likely to contribute to the pathogenesis of diabetes.

    “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).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites (7)(8)(9)

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    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.

    “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).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S1 (asserted), S4 (based).

    Interpretationnone given

    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.

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The association between impaired mitochondrial function and type 2 diabetes is strong, but a causal pathogenic relationship remains uncertain.

    “We conclude that, whereas the association between impaired mitochondrial function and DM is strong, a causal pathogenic relationship remains uncertain.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    In addition to decreased mitochondrial density, there is an intrinsic defect(s) in TCA, OXPHOS, membrane potential, or adenine nucleotide transporters in mitochondria of individuals with established diabetes.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In Asian Indian subjects, expression of OXPHOS and TCA cycle genes, mtDNA content, and ATP production rates were higher in both nondiabetic and diabetic individuals compared with Northern European controls, despite lower overall insulin sensitivity.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [125] Nair, 2008, Asian Indians have enhanced skeletal muscle mitochondrial capacity to produce ATP in association with severe insulin resistance., Diabetes source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Human insulin resistance is accompanied by impaired in vivo mitochondrial oxidative function, linked at least in part to reduced mitochondrial density.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    In studies of muscle oxidative capacity, differences did not remain after normalization for mitochondrial mass by citrate synthase activity or mtDNA content, suggesting reduced mitochondrial mass might be a major contributor.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The magnitude of these changes is similar to the 38% lower muscle mitochondrial density in this same population, suggesting decreased mitochondrial density might be an important factor in reduced oxidative capacity in individuals with a family history of diabetes.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Additional mechanisms potentially linking impaired mitochondrial oxidative function to insulin resistance include reduced ATP synthesis for energy-requiring functions, abnormalities in calcium homeostasis, and reduced ATP production during exercise.

    “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”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [103] Lanner, 2008, Ca(2+) and insulin-mediated glucose uptake., Curr Opin Pharmacol source

      Not checked in the free run.

    • cites [104] Lebeche, 2008, Interplay between impaired calcium regulation and insulin signaling abnormalities in diabetic cardiomyopathy., Nat Clin Pract Cardiovasc Med source

      Not checked in the free run.

    • cites [105] Park, 2009, Chronic elevated calcium blocks AMPK-induced GLUT-4 expression in skeletal muscle, Am J Physiol Cell Physiol source

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    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Primary myotubes isolated from obese humans with type 2 DM display reduced basal lipid oxidation and insulin-stimulated glucose oxidation with no differences in OXPHOS gene expression.

    “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).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S1 (asserted), S2 (checkable).

    Interpretationreasoning

    Levels of OXPHOS gene expression and function must be considered relative to the oxidative fuel load in an individual.

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    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.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Impaired metabolic flexibility correlates with intramyocellular accumulation of lipids, and 24-h RQ can predict subsequent weight gain.

    “Impaired flexibility also correlates with intramyocellular accumulation of lipids (107), and 24-h RQ can predict subsequent weight gain (110, 113).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [107] Simoneau, 1995, Skeletal muscle glycolytic and oxidative enzyme capacities are determinants of insulin sensitivity and muscle composition in obese women., FASEB J source

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    • cites [110] Bruce, 2003, Muscle oxidative capacity is a better predictor of insulin sensitivity than lipid status., J Clin Endocrinol Metab source

      Not checked in the free run.

    • cites [113] Zurlo, 1990, Low ratio of fat to carbohydrate oxidation as predictor of weight gain: study of 24-h RQ, Am J Physiol

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    Differences in OXPHOS gene expression between populations may reflect population-specific differences in obesity, physical fitness, or ethnicity.

    “These differences may reflect population-specific differences in obesity, physical fitness, or ethnicity.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    Increased tissue lipid load, as with obesity and/or sustained inactivity, may lead to accumulation of fatty acyl CoA, diacylglycerols, ceramides, products of incomplete oxidation, and ROS, all of which have been linked experimentally to reduced insulin signaling and action.

    “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).”
    Quote in the paperSubstantial claim0 of 7 sources checked
    • cites [96] Dresner, 1999, Effects of free fatty acids on glucose transport and IRS-1-associated phosphatidylinositol 3-kinase activity., J Clin Invest source

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    • cites [97] Savage, 2007, Disordered lipid metabolism and the pathogenesis of insulin resistance., Physiol Rev source

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    • cites [98] Koves, 2008, Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance., Cell Metab source

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    • cites [99] Holland, 2007, Inhibition of ceramide synthesis ameliorates glucocorticoid-, saturated-fat-, and obesity-induced insulin resistance., Cell Metab source

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    • cites [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 in the free run.

    • cites [101] Chibalin, 2008, Downregulation of diacylglycerol kinase δ contributes to hyperglycemia-induced insulin resistance., Cell source

      Not checked in the free run.

    • cites [102] Houstis, 2006, Reactive oxygen species have a causal role in multiple forms of insulin resistance., Nature source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Lipid excess has been linked experimentally to induction of insulin resistance and alterations in insulin signal transduction.

    “Moreover, lipid excess has been linked experimentally to induction of insulin resistance (96) and alterations in insulin signal transduction (97-99).”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [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 in the free run.

    • cites [97] Savage, 2007, Disordered lipid metabolism and the pathogenesis of insulin resistance., Physiol Rev source

      Not checked in the free run.

    • cites [98] Koves, 2008, Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance., Cell Metab source

      Not checked in the free run.

    • cites [99] Holland, 2007, Inhibition of ceramide synthesis ameliorates glucocorticoid-, saturated-fat-, and obesity-induced insulin resistance., Cell Metab source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    High OXPHOS expression in the Asian Indian population 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.

    “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).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Intramyocellular lipid excess strongly correlates with the severity of insulin resistance, even after correction for the degree of obesity, and has been observed in muscles of multiple fiber types.

    “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).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [94] Jacob, 1999, Association of increased intramyocellular lipid content with insulin resistance in lean nondiabetic offspring of type 2 diabetic subjects., Diabetes source

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    • cites [95] Malenfant, 2001, Fat content in individual muscle fibers of lean and obese subjects., Int J Obes Relat Metab Disord source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Genetic polymorphisms may also influence age-dependent reductions in expression.

    “Genetic polymorphisms may also influence age-dependent reductions in expression (137).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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 in the free run.

  • May combine two claims.

    Premisecitation

    PGC-1α has been recognized as an important coactivator in skeletal muscle, contributing to fiber type determination, glucose uptake, and oxidative capacity.

    “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).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Section IV.A

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  • May combine two claims.

    Premisecitation

    OXPHOS expression can be increased with exercise training, a potent insulin sensitizer.

    “Conversely, OXPHOS expression can be increased with exercise training (133, 135), a potent insulin sensitizer.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [133] Parikh, 2008, Molecular correlates for maximal oxygen uptake and type 1 fibers, Am J Physiol Endocrinol Metab source

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    • cites [135] Wright, 2007, Exercise-induced mitochondrial biogenesis begins before the increase in muscle PGC-1α expression., J Biol Chem source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Expression of multiple OXPHOS genes is markedly reduced in mice made insulin deficient by treatment with the β-cell toxin streptozotocin, and can be normalized by insulin.

    “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).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationreasoning

    Patterns of differential OXPHOS expression may be more readily detectable in disease states, yet not necessarily mirror other aspects of mitochondrial oxidative capacity.

    “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.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: OXPHOS gene expression is coordinately regulated.

  • May combine two claims.

    Premisecitation

    Alterations in muscle PGC-1α and -β mRNA expression are observed in humans with insulin resistance-being reduced by nearly 50% in muscle from individuals with diabetes and in some populations of normoglycemic insulin-resistant humans.

    “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).”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [121] Mootha, 2003, PGC-1α-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes., Nat Genet source

      Not checked in the free run.

    • cites [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

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    • cites [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 in the free run.

  • May combine two claims.

    Premisecitation

    Experimental insulin therapy does not modulate mitochondrial respiration, so mechanisms linking insulin action with OXPHOS gene expression remain unclear.

    “Moreover, experimental insulin therapy does not modulate mitochondrial respiration (144), so mechanisms linking insulin action with OXPHOS gene expression remain unclear.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [144] Rabøl, 2009, Effect of hyperglycemia on mitochondrial respiration in type 2 diabetes., J Clin Endocrinol Metab source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    PGC-1 activity can also be modulated at the level of translation and by posttranscriptional changes, including inhibitory GCN5-mediated acetylation and stimulatory sirtuin 1 mediated deacetylation.

    “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).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [147] Lerin, 2006, GCN5 acetyltransferase complex controls glucose metabolism through transcriptional repression of PGC-1α., Cell Metab source

      Not checked in the free run.

    • cites [148] Lagouge, 2006, Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1α., Cell source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Short-term experimental induction of acute hyperglycemia in humans does not fully mirror this pattern of gene expression, suggesting that the response to insulin deficiency is not completely due to resultant hyperglycemia.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [143] Meugnier, 2007, Acute hyperglycemia induces a global downregulation of gene expression in adipose tissue and skeletal muscle of healthy subjects., Diabetes source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based).

    Interpretationnone given

    These multiple modes of PGC-1α regulation are likely to have evolved from the need to adapt mitochondrial energy metabolism in response to increasingly diverse inputs.

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    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.

    “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).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [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 in the free run.

    • cites [131] Hancock, 2008, High-fat diets cause insulin resistance despite an increase in muscle mitochondria., Proc Natl Acad Sci USA source

      Not checked in the free run.

    • cites [132] Sreekumar, 2002, Effects of caloric restriction on mitochondrial function and gene transcripts in rat muscle, Am J Physiol Endocrinol Metab source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    PGC-1α expression may also be reduced as a consequence of promoter methylation or caused by insulin itself, obesity, and sustained lipid exposure.

    “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).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [146] Barrès, 2009, Non-CpG methylation of the PGC-1α promoter through DNMT3B controls mitochondrial density., Cell Metab source

      Not checked in the free run.

    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Genetic background, 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.

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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 in the free run.

  • May combine two claims.

    Premisecitation

    UCP1 hinders the establishment of, or dissipates, a proton gradient of sufficient magnitude to sustain the synthetic activity of the mitochondrial ATPase, thus driving continuous accelerated electron transport.

    “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.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [150] Cannon, 1985, The biochemistry of an inefficient tissue: brown adipose tissue., Essays Biochem

      Not checked in the free run.

    • cites [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 in the free run.

    • cites [154] Jacobsson, 1985, Mitochondrial uncoupling protein from mouse brown fat. Molecular cloning, genetic mapping, and mRNA expression., J Biol Chem source

      Not checked in the free run.

    • cites [155] Ricquier, 1997, The mitochondrial uncoupling protein: structural and genetic studies., Prog Nucleic Acid Res Mol Biol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    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, the maintenance of a robust pathway for the folding and secretion of high abundance circulating proteins such as adiponectin, and interactions between mitochondrial function and components of the insulin-sign

    “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”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [159] Owen, 2002, The key role of anaplerosis and cataplerosis for citric acid cycle function., J Biol Chem source

      Not checked in the free run.

    • cites [160] Koh, 2007, Essential role of mitochondrial function in adiponectin synthesis in adipocytes., Diabetes source

      Not checked in the free run.

    • cites [161] Shi, 2008, Paradoxical effect of mitochondrial respiratory chain impairment on insulin signaling and glucose transport in adipose cells., J Biol Chem source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    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.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Recent work has led to reconsideration of the notion that the role of brown adipose tissue in human metabolism is minor, noting that humans possess adipose tissue depots that are cold-sensitive and hypermetabolic, as assessed by their very high uptake of labeled glucose.

    “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).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [152] Weber, 2004, Brown adipose tissue and nuclear medicine imaging., J Nucl Med

      Not checked in the free run.

    • cites [163] Nedergaard, 2007, Unexpected evidence for active brown adipose tissue in adult humans, Am J Physiol Endocrinol Metab source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mitochondrial density increases dramatically, and mitochondrial remodeling occurs during white adipocyte differentiation, suggesting that mitochondrial functions are required to support the multiple biological roles of mature white adipocytes.

    “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.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [156] Luo, 2008, Alteration of mitochondrial oxidative capacity during porcine preadipocyte differentiation and in response to leptin., Mol Cell Biochem source

      Not checked in the free run.

    • cites [157] Kim, 2004, Extracellular ATP is generated by ATP synthase complex in adipocyte lipid rafts., Exp Mol Med source

      Not checked in the free run.

    • cites [158] Wilson-Fritch, 2003, Mitochondrial biogenesis and remodeling during adipogenesis and in response to the insulin sensitizer rosiglitazone., Mol Cell Biol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    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.

    “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).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [149] Astrup, 1986, Thermogenesis in human brown adipose tissue and skeletal muscle induced by sympathomimetic stimulation., Acta Endocrinol Suppl (Copenh)

      Not checked in the free run.

    • cites [150] Cannon, 1985, The biochemistry of an inefficient tissue: brown adipose tissue., Essays Biochem

      Not checked in the free run.

    • cites [151] Cypess, 2009, Identification and importance of brown adipose tissue in adult humans., N Engl J Med source

      Not checked in the free run.

    • cites [152] Weber, 2004, Brown adipose tissue and nuclear medicine imaging., J Nucl Med

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Higher mitochondrial density and even UCP1 can be induced in response to pharmacological or genetic alterations of white adipocytes, suggesting that white adipose tissue could potentially be induced to acquire more oxidative metabolic phenotypes, promoting increased fuel consumption and thus energy expenditure.

    “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.”
    Quote in the paperNot a substantial claim0 of 8 sources checked
    • cites [170] Bogacka, 2005, Pioglitazone induces mitochondrial biogenesis in human subcutaneous adipose tissue in vivo., Diabetes source

      Not checked in the free run.

    • cites [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 in the free run.

    • cites [172] Loncar, 1991, Convertible adipose tissue in mice., Cell Tissue Res source

      Not checked in the free run.

    • cites [173] Orci, 2004, Rapid transformation of white adipocytes into fat-oxidizing machines., Proc Natl Acad Sci USA source

      Not checked in the free run.

    • cites [174] Ström, 2008, Attainment of brown adipocyte features in white adipocytes of hormone-sensitive lipase null mice, PLoS ONE source

      Not checked in the free run.

    • cites [175] Tiraby, 2003, Acquirement of brown fat cell features by human white adipocytes., J Biol Chem source

      Not checked in the free run.

    • cites [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 in the free run.

    • cites [177] Wilson-Fritch, 2004, Mitochondrial remodeling in adipose tissue associated with obesity and treatment with rosiglitazone., J Clin Invest source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    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.

    “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).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [162] Marette, 1991, Mechanism linking insulin resistance to defective thermogenesis in brown adipose tissue of obese diabetic SHR/N-cp rats., Int J Obes

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    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.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    White adipocytes display a high degree of plasticity, and regional differences in metabolic activity can be linked to varying mitochondria densities.

    “White adipocytes display a high degree of plasticity (168), and regional differences in metabolic activity can be linked to varying mitochondria densities (169).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [168] Cinti, 2002, Adipocyte differentiation and transdifferentiation: plasticity of the adipose organ., J Endocrinol Invest source

      Not checked in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    White adipocyte mitochondrial content is decreased in both rodent and human obesity and correlates with insulin resistance that accompanies obesity.

    “White adipocyte mitochondrial content is decreased in both rodent and human obesity (177, 188 -191) and correlates with insulin resistance that accompanies obesity.”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [177] Wilson-Fritch, 2004, Mitochondrial remodeling in adipose tissue associated with obesity and treatment with rosiglitazone., J Clin Invest source

      Not checked in the free run.

    • cites [188] Choo, 2006, Mitochondria are impaired in the adipocytes of type 2 diabetic mice., Diabetologia source

      Not checked in the free run.

    • cites [189] Okamoto, 2007, Comparison of mitochondrial and macrophage content between subcutaneous and visceral fat in db/db mice., Exp Mol Pathol source

      Not checked in the free run.

    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In humans, white adipocyte mtDNA copy number is inversely correlated with age and BMI and directly correlated with basal and insulin-induced lipogenesis.

    “In humans, white adipocyte mtDNA copy number is inversely correlated with age and BMI and directly correlated with basal and insulin-induced lipogenesis (192).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [192] Kaaman, 2007, Strong association between mitochondrial DNA copy number and lipogenesis in human white adipose tissue., Diabetologia source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Both genetic and diet-induced obesity result in decreased mitochondrial density and OXPHOS activity in adipose tissue, potentially contributing to adipose tissue dysfunction and exacerbation of insulin resistance.

    “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.”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [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 in the free run.

    • cites [177] Wilson-Fritch, 2004, Mitochondrial remodeling in adipose tissue associated with obesity and treatment with rosiglitazone., J Clin Invest source

      Not checked in the free run.

    • cites [189] Okamoto, 2007, Comparison of mitochondrial and macrophage content between subcutaneous and visceral fat in db/db mice., Exp Mol Pathol source

      Not checked in the free run.

    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    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.

    “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.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [205] Nishino, 2008, FSP27 contributes to efficient energy storage in murine white adipocytes by promoting the formation of unilocular lipid droplets., J Clin Invest

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    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).

    “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).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [211] Benard, 2006, Physiological diversity of mitochondrial oxidative phosphorylation, Am J Physiol Cell Physiol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Electron microscopy demonstrates that mitochondrial area is 44% lower in liver than in heart with smaller size, fewer cristae, and lower matrix density.

    “Electron microscopy demonstrates that mitochondrial area is 44% lower in liver than in heart (210) with smaller size, fewer cristae, and lower matrix density.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [210] Veltri, 1990, Distinct genomic copy number in mitochondria of different mammalian organs., J Cell Physiol source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    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.

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    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 'excess capacity' in liver.

    “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”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [211] Benard, 2006, Physiological diversity of mitochondrial oxidative phosphorylation, Am J Physiol Cell Physiol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Isolated hepatic mitochondria have relative reductions in OXPHOS proteins, respiratory chain cytochromes, and maximal activity of complexes III and IV.

    “Functionally, isolated hepatic mitochondria have relative reductions in OXPHOS proteins, respiratory chain cytochromes, and maximal activity of complexes III and IV (211).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [211] Benard, 2006, Physiological diversity of mitochondrial oxidative phosphorylation, Am J Physiol Cell Physiol source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Transcriptional coactivators PGC-1α and -1β 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.

    “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).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [56] Wu, 1999, Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1., Cell source

      Not checked in the free run.

    • cites [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 in the free run.

  • May combine two claims.

    Premisecitation

    LIRKO mice are also dyslipidemic and susceptible to atherosclerosis.

    “Interestingly, these mice are also dyslipidemic and susceptible to atherosclerosis (209).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [209] Biddinger, 2008, Hepatic insulin resistance is sufficient to produce dyslipidemia and susceptibility to atherosclerosis., Cell Metab source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    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.

    “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.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationcitation

    Mechanisms whereby obesity results in a reduction in adipose mitochondrial density are not known but could be mediated by decreased expression of PGC-1α, as observed in obese humans.

    “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).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    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.

    “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).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [208] Michael, 2000, Loss of insulin signaling in hepatocytes leads to severe insulin resistance and progressive hepatic dysfunction., Mol Cell source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Reduced mtDNA content could reduce adipocyte capacity for lipid storage, promoting ectopic lipid accumulation in peripheral tissues such as muscle and liver.

    “Thus, reduced mtDNA content could reduce adipocyte capacity for lipid storage, promoting ectopic lipid accumulation in peripheral tissues such as muscle and liver.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Mitochondrial levels in white adipocytes are also increased in response to adrenergic stimulation, β-3 agonists, and CB1 blockade in mice, again in parallel with enhanced insulin sensitivity.

    “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.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [195] Bogacka, 2005, Structural and functional consequences of mitochondrial biogenesis in human adipocytes in vitro., J Clin Endocrinol Metab source

      Not checked in the free run.

    • cites [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 in the free run.

    • cites [200] Tedesco, 2008, Cannabinoid type 1 receptor blockade promotes mitochondrial biogenesis through endothelial nitric oxide synthase expression in white adipocytes., Diabetes source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Reduced OXPHOS activity in NASH is accompanied by increased tissue long-chain acylcarnitines and reduced short-chain acylcarnitines, despite normal CPT1 activity and increased expression of β-oxidation genes.

    “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).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [236] Kohjima, 2007, Re-evaluation of fatty acid metabolism-related gene expression in nonalcoholic fatty liver disease., Int J Mol Med

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    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 generation of ROS.

    “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”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [220] Nakamura, 2009, Palmitate induces insulin resistance in H4IIEC3 hepatocytes through reactive oxygen species produced by mitochondria., J Biol Chem source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Byproducts of incomplete fatty acid oxidation could act in concert with adipose tissue-derived inflammatory signals (e.g., TNFα), and altered expression and activation of proinflammatory and profibrotic genes, to increase production of ROS and ultimately contribute to the development of NASH and cirrhosis.

    “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).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [235] Sanyal, 2001, Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities., Gastroenterology source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the first study, severe obesity (mean BMI 52 kg/m2) was associated with reduced expression 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-1α and genes known to be regulated by thyroid hormone.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [232] Pihlajamäki, 2009, Thyroid hormone-related regulation of gene expression in human fatty liver., J Clin Endocrinol Metab source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    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 T3, suggesting that functional hepatic thyroid hormone resistance could contribute to reduced expression of mitochondrial oxidative genes in this context.

    “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).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [232] Pihlajamäki, 2009, Thyroid hormone-related regulation of gene expression in human fatty liver., J Clin Endocrinol Metab source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Accumulation of lipid within hepatocytes is a key marker of insulin resistance in humans and a major contributor to nonalcoholic fatty liver disease, nonalcoholic steatohepatitis (NASH), and cirrhosis.

    “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”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    With aging, chronic ROS exposure, and/or the development of insulin resistance related to obesity or sustained lipid accumulation, OXPHOS expression may fall.

    “With aging, chronic ROS exposure, and/or the development of insulin resistance related to obesity or sustained lipid accumulation, OXPHOS expression may fall.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    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.

    “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”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [229] Cheng, 2009, Foxo1 integrates insulin signaling with mitochondrial function in the liver., Nat Med source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S1 (asserted), S4 (based). May combine two claims.

    Interpretationnone given

    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.

    “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.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationreasoning

    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.

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Transgenic mice expressing lipoprotein lipase in the liver have a 2-fold increase in hepatic triglyceride content and are insulin resistant.

    “Transgenic mice expressing lipoprotein lipase in the liver have a 2-fold increase in hepatic triglyceride content and are insulin resistant (219).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [219] Kim, 2001, Tissue-specific overexpression of lipoprotein lipase causes tissue-specific insulin resistance., Proc Natl Acad Sci USA source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Fatty acid-induced reductions in insulin receptor number and function in the liver may also reduce hepatic insulin clearance, causing systemic hyperinsulinemia, itself a contributor to both insulin resistance and reduced mitochondrial function.

    “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).”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [211] Benard, 2006, Physiological diversity of mitochondrial oxidative phosphorylation, Am J Physiol Cell Physiol source

      Not checked in the free run.

    • cites [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 in the free run.

    • cites [214] Kotronen, 2008, Increased liver fat, impaired insulin clearance, and hepatic and adipose tissue insulin resistance in type 2 diabetes., Gastroenterology source

      Not checked in the free run.

    • cites [227] Park, 2006, Mechanism of glucose intolerance in mice with dominant negative mutation of CEACAM1, Am J Physiol Endocrinol Metab source

      Not checked in the free run.

    • cites [228] Liu, 2009, Prolonged exposure to insulin suppresses mitochondrial production in primary hepatocytes., J Biol Chem source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Hepatic lipid accumulation is associated with obesity in humans, particularly central (abdominal) in location, and in parallel with low adiponectin levels.

    “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).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [214] Kotronen, 2008, Increased liver fat, impaired insulin clearance, and hepatic and adipose tissue insulin resistance in type 2 diabetes., Gastroenterology source

      Not checked in the free run.

    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationcitation

    Excessive hepatic lipid accumulation may play a central, pathogenic role in insulin resistance.

    “One possibility is that excessive hepatic lipid accumulation may play a central, pathogenic role in insulin resistance.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Enzymatic activity of complexes I-V is reduced in liver extracts from patients with NASH and is inversely correlated with BMI and HOMA-IR.

    “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).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [233] Pérez-Carreras, 2003, Defective hepatic mitochondrial respiratory chain in patients with nonalcoholic steatohepatitis., Hepatology source

      Not checked in the free run.

    • cites [234] Greenfield, 2008, Recent advances in nonalcoholic fatty liver disease., Curr Opin Gastroenterol source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Several differences in study population may account for the discordant findings between the two data sets: much greater degree of adiposity and hepatic steatosis in the first; differences in ethnicity (Caucasian-Americans vs. Japanese); and differences in insulin sensitivity and glycemia.

    “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)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Up-regulation of these OXPHOS genes was also positively associated with expression of several genes linked to mitochondrial biogenesis (e.g., PGC-1β, ERRα, NRF, thyroid hormone receptor) and both ROS generation (e.g., NADPH oxidase) and attenuation (e.g., glutathione peroxidase).

    “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).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [231] Takamura, 2008, Obesity upregulates genes involved in oxidative phosphorylation in livers of diabetic patients., Obesity (Silver Spring) source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mitochondrial diabetes only develops upon aging, with an average age of onset between 35 and 40 years for MIDD and 48 years for the 14577 T>C mutation.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [246] Maassen, 2004, Mitochondrial diabetes: molecular mechanisms and clinical presentation, Diabetes source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Activation of UCP2 leads to decreased ATP production, which impairs insulin secretion.

    “However, it also leads to decreased ATP production, which impairs insulin secretion.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    In the presence of excess FFA, the normal feedback loop is compromised by direct activation of UCP2 by FFA, as well as an effect of FFA to increase the amount of UCP2.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Low levels of ROS are necessary for insulin secretion, but chronic, high mitochondrial ROS production can have a deleterious effect on β-cell function.

    “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).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [254] Li, 2008, The sensitivity of pancreatic β-cells to mitochondrial injuries triggered by lipotoxicity and oxidative stress., Biochem Soc Trans source

      Not checked in the free run.

    • cites [255] Rachek, 2006, Protection of INS-1 cells from free fatty acid-induced apoptosis by targeting hOGG1 to mitochondria., Diabetes source

      Not checked in the free run.

    • cites [256] Simmons, 2005, Progressive accumulation of mitochondrial DNA mutations and decline in mitochondrial function lead to β-cell failure., J Biol Chem source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    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.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    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-1α overexpression on whole-body glucose homeostasis.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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 in the free run.

  • May combine two claims.

    Premisecitation

    Clonal cytosolic hybrid cells harboring mitochondria derived from MIDD patients exhibit impaired calcium handling and elevated ROS under metabolic stress.

    “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).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [247] Maechler, 2006, In β-cells, mitochondria integrate and generate metabolic signals controlling insulin secretion., Int J Biochem Cell Biol source

      Not checked in the free run.

    • cites [248] Andrade, 2006, Diabetes-associated mitochondrial DNA mutation A3243G impairs cellular metabolic pathways necessary for β-cell function., Diabetologia source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Overexpression of PGC-1α in myotubes causes approximately 2-fold increases in mtDNA and oxygen consumption and a 50% increase in mitochondrial density.

    “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).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [56] Wu, 1999, Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1., Cell source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    β-cell specific deletion of Tfam reduces insulin secretory capacity and β-cell mass, yielding so-called mitochondrial DM.

    “Consistent with this possibility, ␤-cell specific deletion of Tfam reduces insulin secretory capacity and ␤-cell mass, yielding so-called mitochondrial DM (241).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [241] Silva, 2000, Impaired insulin secretion and β-cell loss in tissue-specific knockout mice with mitochondrial diabetes., Nat Genet source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Chronically increased ROS production can induce β-cell death and result in gradual onset of diabetes.

    “Chronically increased ROS production could also induce ␤-cell death and result in gradual onset of diabetes (249 -253).”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [251] Newsholme, 2007, Diabetes associated cell stress and dysfunction: role of mitochondrial and non-mitochondrial ROS production and activity., J Physiol source

      Not checked in the free run.

    • cites [252] Nishikawa, 2007, Impact of mitochondrial ROS production in the pathogenesis of diabetes mellitus and its complications., Antioxid Redox Signal source

      Not checked in the free run.

    • cites [253] Robertson, 2009, β-Cell deterioration during diabetes: what’s in the gun?, Trends Endocrinol Metab source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mitochondrial metabolism is also required for the transient, controlled production of ROS, which is required for the mitochondrial signaling pathways that trigger granule exocytosis.

    “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).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [239] Evans, 2003, Are oxidative stress-activated signaling pathways mediators of insulin resistance and β-cell dysfunction?, Diabetes source

      Not checked in the free run.

    • cites [240] Leloup, 2009, Mitochondrial reactive oxygen species are obligatory signals for glucose-induced insulin secretion., Diabetes source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In these animals, mitochondrial density and OXPHOS gene expression are more than double basal levels, and large increases in UCP2 gene expression are observed.

    “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.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Mitochondrial dysfunction in β-cells would be expected to reduce insulin secretion and thus promote the development of DM.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Both rapid (first phase) and more prolonged (second phase) insulin secretion are dependent on glucose metabolism and mitochondrial oxidative capacity.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [237] O'Connor, 1980, Comparison of storage- and signal-limited models of pancreatic insulin secretion, Am J Physiol

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Transgenic mice expressing human PGC-1α 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.

    “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).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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 in the free run.

  • May combine two claims.

    Premisecitation

    The lowest level of PGC-1α overexpression in rat muscle by electroporation resulted in modest up-regulation of mitochondrial proteins, increased palmitate oxidation, and increased insulin-stimulated glucose uptake.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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 in the free run.

  • May combine two claims.

    Premisecitation

    In hybrid cell lines derived from probands with the 14577 T>C mutation, mitochondrial respiratory chain complex I activity and O2 consumption rates are decreased by 65 and 62%, respectively.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    This modest PGC-1α overexpression was accompanied by decreased levels of ROS and inflammatory signaling.

    “Importantly, this modest PGC-1␣ overexpression also was accompanied by decreased levels of ROS and inflammatory signaling.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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 in the free run.

  • May combine two claims.

    Premisereasoning

    Mitochondrial function in β-cells is highly regulated by the levels and activities of UCPs, which are in turn regulated by ROS produced by the activity of the ETC.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    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.

    “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).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [260] Koshkin, 2003, Mitochondrial functional state in clonal pancreatic β-cells exposed to free fatty acids., J Biol Chem source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Despite these effects, insulin sensitivity is normal in PGC-1α transgenic mice fed a chow diet and is reduced during high-fat feeding.

    “Despite these effects, insulin sensitivity is normal in PGC-1␣ transgenic mice fed a chow diet and, surprisingly, is reduced during high-fat feeding.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [267] Calvo, 2008, Muscle-specific expression of PPARγ coactivator-1α improves exercise performance and increases peak oxygen uptake., J Appl Physiol source

      Not checked in the free run.

    • cites [268] Lin, 2002, Transcriptional co-activator PGC-1 α drives the formation of slow-twitch muscle fibers., Nature source

      Not checked in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Inducible overexpression of PGC-1α in skeletal muscle results in increased mitochondrial density and a robust increase in expression of OXPHOS genes and genes necessary for fatty acid oxidation.

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [265] Wende, 2007, A role for the transcriptional coactivator PGC-1α in muscle refueling., J Biol Chem source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Whole-body transgenic overexpression of PGC-1β resulted in increased oxidative metabolism, protection from obesity induced by high-fat diet or hyperphagia, and enhanced insulin sensitivity.

    “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).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Although low-intensity exercise performance did not differ in this model, high-performance exercise was impaired, in parallel with failure to mobilize stored glycogen.

    “Although low-intensity exercise performance did not differ in this model, high-performance exercise was impaired, in parallel with failure to mobilize stored glycogen.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [265] Wende, 2007, A role for the transcriptional coactivator PGC-1α in muscle refueling., J Biol Chem source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In adults, PGC-1α induction led to a more modest mitochondrial proliferation, which was nevertheless accompanied by cardiomyopathy.

    “In adults, PGC-1␣ induction led to a more modest mitochondrial proliferation, which was nevertheless surprisingly accompanied by cardiomyopathy.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Functionally, whole-body PGC-1α-null mice show decreases in ATP levels, state 3 respiration, and metabolic efficiency, and cardiac and skeletal muscle performance is reduced in response to stress.

    “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.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [68] Arany, 2005, Transcriptional coactivator PGC-1 α controls the energy state and contractile function of cardiac muscle., Cell Metab source

      Not checked in the free run.

    • cites [69] Lin, 2004, Defects in adaptive energy metabolism with CNS-linked hyperactivity in PGC-1α null mice., Cell source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In this model, ATP synthesis rate and exercise performance are increased, and fatty acid oxidation is also enhanced.

    “In this model, ATP synthesis rate and exercise performance are increased, and fatty acid oxidation is also enhanced.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [267] Calvo, 2008, Muscle-specific expression of PPARγ coactivator-1α improves exercise performance and increases peak oxygen uptake., J Appl Physiol source

      Not checked in the free run.

    • cites [268] Lin, 2002, Transcriptional co-activator PGC-1 α drives the formation of slow-twitch muscle fibers., Nature source

      Not checked in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Muscle function appears compromised in these animals, as evidenced by decreased voluntary exercise, muscle atrophy, and decreased insulin sensitivity.

    “Muscle function appears compromised, as evidenced by decreased voluntary exercise, muscle atrophy, and decreased insulin sensitivity.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Modest overexpression of PGC-1α and transgenic overexpression of PGC-1β increase oxidative metabolism and insulin sensitivity.

    “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.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [271] Arany, 2007, The transcriptional coactivator PGC-1β drives the formation of oxidative type IIX fibers in skeletal muscle., Cell Metab source

      Not checked in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Muscle-specific transgenic overexpression of PGC-1β results in increased oxidative fiber content and increased expression of OXPHOS and multiple other mitochondrial genes.

    “Muscle-specific transgenic overexpression of PGC-1␤ results in increased oxidative fiber content and increased expression of OXPHOS and multiple other mitochondrial genes.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [271] Arany, 2007, The transcriptional coactivator PGC-1β drives the formation of oxidative type IIX fibers in skeletal muscle., Cell Metab source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    High-level overexpression of PGC-1α may reduce insulin sensitivity via reduced glycolysis and/or glucose oxidation or myofibrillar disruption/myopathy, potentially limiting exercise tolerance.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [265] Wende, 2007, A role for the transcriptional coactivator PGC-1α in muscle refueling., J Biol Chem source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In these animals, both muscle glucose uptake and glycogen deposition were increased.

    “In these animals, both muscle glucose uptake and glycogen deposition were increased.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [265] Wende, 2007, A role for the transcriptional coactivator PGC-1α in muscle refueling., J Biol Chem source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    When higher levels of PGC-1α overexpression are restricted to heart during early life, increased neonatal mitochondrial proliferation is observed, but it is accompanied by myofibrillar displacement.

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Whole-body PGC-1α-null 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.

    “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.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [68] Arany, 2005, Transcriptional coactivator PGC-1 α controls the energy state and contractile function of cardiac muscle., Cell Metab source

      Not checked in the free run.

    • cites [69] Lin, 2004, Defects in adaptive energy metabolism with CNS-linked hyperactivity in PGC-1α null mice., Cell source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mitochondrial energetics are impaired in these animals, with 60% decreases in ATP levels in muscle homogenates and concomitant increases in AMP kinase activation.

    “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.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In cultured myotubes overexpressing PGC-1α, lipid content is decreased in the serum-starved condition, reflecting increased oxidation of lipids; 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.

    “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).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [273] Espinoza, 2009

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Double PGC-1α and PGC-1β muscle-specific knockout mice display normal mitochondrial biogenesis during development but die early after birth due to failure of perinatal mitochondrial proliferation and consequent cardiac failure.

    “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).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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 in the free run.

  • May combine two claims.

    Premisecitation

    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.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [282] Wang, 1999, Dilated cardiomyopathy and atrioventricular conduction blocks induced by heart-specific inactivation of mitochondrial DNA gene expression., Nat Genet source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    PGC-1β-null mice have more striking hepatic phenotypes, with hepatic insulin resistance, even on normal chow, and steatosis with high-fat feeding.

    “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).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [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 in the free run.

    • cites [65] Vianna, 2006, Hypomorphic mutation of PGC-1β causes mitochondrial dysfunction and liver insulin resistance., Cell Metab source

      Not checked in the free run.

    • cites [66] Lelliott, 2006, Ablation of PGC-1β results in defective mitochondrial activity, thermogenesis, hepatic function, and cardiac performance, PLoS Biol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Skeletal and cardiac muscle-specific deletion of Tfam causes severe OXPHOS deficits, dilated cardiomyopathy, and death during early postnatal life.

    “Similarly, skeletal and cardiac muscle-specific deletion of Tfam causes severe OXPHOS deficits, dilated cardiomyopathy, and death during early postnatal life (282).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [282] Wang, 1999, Dilated cardiomyopathy and atrioventricular conduction blocks induced by heart-specific inactivation of mitochondrial DNA gene expression., Nat Genet source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Tissue-specific ablation of AIF produced modest defects in respiratory chain gene expression and function; both muscle- and liver-specific null mice had increased insulin sensitivity, reduced fat mass, and improved glucose tolerance.

    “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”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [274] Pospisilik, 2007, Targeted deletion of AIF decreases mitochondrial oxidative phosphorylation and protects from obesity and diabetes., Cell source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    PGC-1β-null mice display phenotypes similar to, but not identical to, those of PGC-1α knockouts, including reduced expression of OXPHOS genes, reduced ATP synthesis, reduced exercise capacity, and impaired thermogenesis.

    “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).”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [65] Vianna, 2006, Hypomorphic mutation of PGC-1β causes mitochondrial dysfunction and liver insulin resistance., Cell Metab source

      Not checked in the free run.

    • cites [66] Lelliott, 2006, Ablation of PGC-1β results in defective mitochondrial activity, thermogenesis, hepatic function, and cardiac performance, PLoS Biol source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    PGC-1α and PGC-1β are both required for the full complement of OXPHOS gene expression, the establishment of correct fuel partitioning, and optimal metabolic efficiency.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Tfam is essential for transcription of mtDNA and thus mitochondrial development, as indicated by the embryonic lethality of Tfam-null mice.

    “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).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [281] Larsson, 1998, Mitochondrial transcription factor A is necessary for mtDNA maintenance and embryogenesis in mice., Nat Genet source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Lack of PGC-1α per se does not lead to insulin resistance, despite clear alterations in muscle and metabolic phenotypes.

    “Thus, lack of PGC-1␣ per se does not lead to insulin resistance, despite clear alterations in muscle and metabolic phenotypes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Despite pronounced muscle and brown adipose tissue functional impairments in PGC-1α deficiency, mitochondrial density in muscle and brown adipose tissue is not notably decreased, indicating a possible compensatory role of PGC-1β in mitochondrial biogenesis.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    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.

    “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).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [282] Wang, 1999, Dilated cardiomyopathy and atrioventricular conduction blocks induced by heart-specific inactivation of mitochondrial DNA gene expression., Nat Genet source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    ERRγ interacts with PGC-1 to regulate expression of ERRα.

    “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).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ERRα-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.

    “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).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [277] Luo, 2003, Reduced fat mass in mice lacking orphan nuclear receptor estrogen-related receptor α., Mol Cell Biol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Both lines of whole-body PGC-1α knockout animals display cold sensitivity, likely related to impaired mitochondrial function in brown adipose tissue.

    “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).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [69] Lin, 2004, Defects in adaptive energy metabolism with CNS-linked hyperactivity in PGC-1α null mice., Cell source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Such alterations in mitochondrial activity could be mediated by genetic factors (family history, ethnicity), epigenetic mechanisms, developmental exposures, and aging.

    “In turn, such alterations in mitochondrial activity could be mediated by genetic factors (family history, ethnicity), epigenetic mechanisms, developmental exposures, and aging.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Individuals with low oxidative capacity and/or suboptimal adaptive responses would be intolerant to moderate-high fuel loads, leading to lipid accumulation, incomplete oxidation, production of ROS, and acute insulin resistance.

    “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).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    PGC-1β whole-body knockout reduced mitochondrial DNA by 20% and OXPHOS mRNA by 20-40% (Lelliot, 2006).

    “Lelliot, 2006 PGC-1␤ whole-body KO 2 20% 20 -40% 2 mRNA | (66)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [66] Lelliott, 2006, Ablation of PGC-1β results in defective mitochondrial activity, thermogenesis, hepatic function, and cardiac performance, PLoS Biol source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    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.

    “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.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    DNA polymerase γ is a mtDNA polymerase critical for maintenance of mtDNA.

    “DNA polymerase ␥ is a mtDNA polymerase critical for maintenance of mtDNA.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    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.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    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.

    “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).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    PGC-1α whole-body knockout reduced mitochondrial DNA by 30% and OXPHOS mRNA by 40-60% (Leone, 2005).

    “Leone, 2005 PGC-1␣ whole-body KO 30% 2 40 -60% 2 mRNA | (67)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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 in the free run.

  • May combine two claims.

    Premisecitation

    PGC-1α transgenic expression increases OXPHOS mRNA and protein levels, with increases ranging from 130% to 500% across transgenic models.

    “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”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    PGC-1α whole-body knockout results in normal mitochondrial DNA but reduced OXPHOS mRNA by 30-60% and cytochrome C protein by 50% (Lin, 2004; Arany, 2005).

    “Lin, 2004 (69); PGC-1␣ whole-body KO Normal 30 -60% 2 mRNA; | Arany, 50% 2 CytC | 2005 (68) protein”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [69] Lin, 2004, Defects in adaptive energy metabolism with CNS-linked hyperactivity in PGC-1α null mice., Cell source

      Not checked in the free run.

    • cites [68] Arany, 2005, Transcriptional coactivator PGC-1 α controls the energy state and contractile function of cardiac muscle., Cell Metab source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Excessive ROS can induce both insulin resistance and mitochondrial dysfunction.

    “In turn, excessive ROS can induce both insulin resistance and mitochondrial dysfunction.”
    Quote in the paperSubstantial claim

  • May combine two claims. The quote only partly states this claim.

    Interpretationreasoning

    With time, mitochondrial damage ensues, further exacerbating the impairment of oxidative capacity.

    “With time, mitochondrial damage ensues, further exacerbating the process.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    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.

    “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).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [288] Bonnard, 2008, Mitochondrial dysfunction results from oxidative stress in the skeletal muscle of diet-induced insulin-resistant mice., J Clin Invest

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Together, these factors contribute to progressively impaired insulin sensitivity, insulin secretion, and heightened risk of DM.

    “Together, these factors contribute to progressively impaired insulin sensitivity, insulin secretion, and heightened risk of DM.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationnone given

    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.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    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 (β-cells).

    “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).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Oxidative stress can induce mitochondrial dysfunction in parallel with insulin resistance-perhaps an adaptive response aimed at limiting further oxidative damage.

    “Thus, oxidative stress can induce mitochondrial dysfunction in parallel with insulin resistance-perhaps an adaptive response aimed at limiting further oxidative damage.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    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.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Mice null for the mitochondrial helicase Twinkle have impaired respiratory chain activity and muscle atrophy, but no defect in exercise capacity.

    “Mice null for the mitochondrial helicase Twinkle have impaired respiratory chain activity and muscle atrophy, but no defect in exercise capacity (285).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [285] Tyynismaa, 2004, Twinkle helicase is essential for mtDNA maintenance and regulates mtDNA copy number., Hum Mol Genet source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    With time, insufficient oxidative capacity could be resolved by compensatory mechanisms that increase oxidative capacity or decrease fuel load; insufficient compensation could result in chronic insulin resistance.

    “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).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    An individual's intrinsic mitochondrial oxidative capacity is determined by numerous factors including genetic and ethnic background, intrauterine exposures, and age.

    “An individual's intrinsic mitochondrial oxidative capacity is determined by numerous factors including genetic and ethnic background, intrauterine exposures, and age.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Over time, this phenotype could contribute to reduced voluntary exercise and increase the likelihood of an imbalance between mitochondrial activity and fatty acid load.

    “Over time, this phenotype could contribute to reduced voluntary exercise and increase the likelihood of an imbalance between mitochondrial activity and fatty acid load.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    PGC-1α muscle-specific knockout results in normal mitochondrial DNA but reduced OXPHOS mRNA by 30-40% (Handschin, 2007).

    “Handschin, PGC-1␣ muscle-specific Normal 30 -40% 2 mRNA | 2007 KO | (63, 64)”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

  • May combine two claims.

    Premisecitation

    PGC-1β whole-body hypomorph reduced mitochondrial DNA by 30% and OXPHOS mRNA by 20-30% (Vianna, 2006).

    “Vianna, 2006 PGC-1␤ whole-body 2 30% 20 -30% 2 mRNA | (65) hypomorph”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [65] Vianna, 2006, Hypomorphic mutation of PGC-1β causes mitochondrial dysfunction and liver insulin resistance., Cell Metab source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    PGC-1β whole-body hypomorph results in normal mitochondrial DNA but reduced OXPHOS mRNA by 30-40% (Sonoda, 2007).

    “Sonoda, 2007 PGC-1␤ whole-body Normal 30 -40% 2 mRNA | (59) hypomorph”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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 in the free run.

155 of 155

  • 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.”
8 of 8

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?

  • T2DM and GDM are associated with a reduced number and function of mitochondria within skeletal muscle cells.

    “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]

    Section 3, “Evidence for reduced muscle mitochondrial oxidative function in DM” (page not provided), reports reduced skeletal-muscle mitochondrial oxidative activity and suggests reduced mitochondrial mass or density in type 2 diabetes. It does not establish a reduced mitochondrial number, and the passages found do not address gestational diabetes (GDM). (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Obesity and T2DM are associated with mitochondrial dysfunction indicated by low expression of mtDNA and reduction of OXPHOS proteins in rodents and humans.

    “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

  • Mitochondrial dysfunction has been described in muscle, liver and adipose tissue during ageing and metabolic syndrome.

    “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

  • Deficiency in mitochondrial activity in muscle is associated with obesity and T2DM.

    “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

  • 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.

    “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

Cites

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Flagged first, then by citations

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Related

Authors
Patti, M.-E., & Corvera, S.
Affiliations
  • Joslin Diabetes Center (US)
  • Harvard University (US)
ORCID
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
DOI
10.1210/er.2009-0027
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
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 › 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.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

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