Intramuscular triacylglycerol and insulin resistance: Guilty as charged or wrongly accused?

In the paper

“feeding rats a diet enriched with both fat and branched chain amino acids caused insulin resistance in association with elevated intramuscular levels of both even and odd chain acylcarnitine metabolites [64].”

What the sources say

• Supported

  The Results section reports that rats fed the high-fat/BCAA diet were insulin resistant after 15 weeks. The Discussion reports accumulation of even-chain acylcarnitines in skeletal muscle, along with C3 and C5 acylcarnitines (odd-chain species), in those rats. (LLM, conf=0.94)

  cites [64] Newgard, 2009, A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance, Cell Metab. source

In the paper

“The past decade of diabetes research has focused heavily on the foregoing scenario, and indeed the model is grounded in strong experimental evidence, albeit largely correlative.”

In the paper

“This relationship is evident in obese and diabetic humans as well as in several rodent and cell culture models of metabolic disease and/or chronic lipid exposure [3,40,41].”

What the sources say

• Not checked yetcites [3] An, 2004, Hepatic expression of malonyl-CoA decarboxylase reverses muscle, liver and whole-animal insulin resistance, Nat. Med. source
• Not checked yetcites [40] Hulver, 2005, Elevated stearoyl-CoA desaturase-1 expression in skeletal muscle contributes to abnormal fatty acid partitioning in obese humans, Cell Metab. source
• Not checked yetcites [41] Hulver, 2003, Skeletal muscle lipid metabolism with obesity, Am. J. Physiol. Endocrinol. Metab. source

In the paper

“Interest in this topic grew from numerous reports describing a strong negative association between IMTG content and insulin sensitivity [28].”

What the sources say

• Not checked yetcites [28] Goodpaster, 2002, Skeletal muscle triglyceride: marker or mediator of obesity-induced insulin resistance in type 2 diabetes mellitus?, Curr. Diab. Rep. source

In the paper

“muscle insulin resistance often (but not always [86]) coexists with abnormalities in mitochondrial morphology, reduced NADH:O2 oxidoreductase activity, diminished in vivo rates of ATP synthesis and TCA cycle flux, as well as low expression levels of genes involved in mitochondrial biogenesis and oxidative metabolism [47,49,59,68,78].”

What the sources say

• Not checked yetcites [47] Kelley, 2002, Dysfunction of mitochondria in human skeletal muscle in type 2 diabetes, Diabetes source
• Not checked yetcites [49] Koves, 2005, Peroxisome proliferator-activated receptor-gamma co-activator 1alpha-mediated metabolic remodeling of skeletal myocytes mimics exercise training and reverses lipid-induced mitochondrial inefficiency, J. Biol. Chem. source
• Not checked yetcites [59] Mootha, 2003, PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes, Nat. Genet. source
• Not checked yetcites [68] 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. U.S. A. source
• Not checked yetcites [78] Ritov, 2005, Deficiency of subsarcolemmal mitochondria in obesity and type 2 diabetes, Diabetes source

In the paper

“the mitochondrial dysfunction theory of insulin resistance predicts that impaired or insufficient mitochondrial uptake and oxidation of fatty acids results in their alternative use as substrates for generating harmful lipid signaling molecules [69].”

What the sources say

• Not checked yetcites [69] Petersen, 2006, New insights into the pathogenesis of insulin resistance in humans using magnetic resonance spectroscopy, Obesity (Silver Spring) source

In the paper

“Under resting conditions ATP demands are low and the ETS operates at only a small fraction of total respiratory capacity.”

In the paper

“This concept conflicts with compelling evidence that fatty acids and glucose compete as metabolic substrates [74].”

What the sources say

• Not checked yetcites [74] Randle, 1998, Regulatory interactions between lipids and carbohydrates: the glucose fatty acid cycle after 35 years, Diabetes Metab. Rev. source

In the paper

“These traits are most often observed in association with aging, severe obesity and type 2 diabetes but were also evident in young insulin-resistant offspring of parents with diabetes [60,62].”

What the sources say

• Not checked yetcites [60] Morino, 2006, Molecular mechanisms of insulin resistance in humans and their potential links with mitochondrial dysfunction, Diabetes source
• Not checked yetcites [62] Muoio, 2006, Obesity-related derangements in metabolic regulation, Annu. Rev. Biochem. source

In the paper

“Several of the even chain, fatty acid-derived acylcarnitine intermediates were elevated in muscle of obese rodents, but decreased after a 2-week exercise intervention that restored glucose tolerance.”

What the sources say

• Not checked yetcites [49] Koves, 2005, Peroxisome proliferator-activated receptor-gamma co-activator 1alpha-mediated metabolic remodeling of skeletal myocytes mimics exercise training and reverses lipid-induced mitochondrial inefficiency, J. Biol. Chem. source

In the paper

“skeletal muscles harbor enormous mitochondrial reserve, enabling exponential increases in energy output during vigorous physical activity.”

In the paper

“Expanded mitochondrial mass therefore affords the advantage of enhanced fat oxidation during moderate to high intensity exercise but should not have much impact at rest.”

In the paper

“which occurs when carbon flux through the β-oxidation machinery outpaces entry of acetyl-CoA (the final product of β-oxidation) into the TCA cycle.”

In the paper

“the mitochondrial dysfunction theory of insulin resistance implies that mitochondrial content and/or capacity dictates resting rates of fat oxidation.”

In the paper

“genetic ablation of Nur77, a transcriptional regulator of glucose utilization genes in skeletal muscle, increased susceptibility to diet-induced obesity and insulin resistance in parallel with elevated IMTG content and accumulation of even-chained acylcarnitine species [18].”

What the sources say

• Not checked yetcites [18] Chao, 2009, Insulin resistance and altered systemic glucose metabolism in mice lacking Nur77, Diabetes source

In the paper

“insulin resistant states were marked by increased whole body fat oxidation, impaired switching to carbohydrate substrate during the fasted to fed transition, and coincident reductions in muscle levels of several TCA cycle intermediates [50].”

What the sources say

• Not checked yetcites [50] Koves, 2008, Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance, Cell Metab. source

In the paper

“A similar phenotype was reported as a consequence of muscle-specific deletion of apoptosis inducing factor (AIF), a protein that plays a key role in regulating the ETS [70].”

What the sources say

• Not checked yetcites [70] Pospisilik, 2007, Targeted deletion of AIF decreases mitochondrial oxidative phosphorylation and protects from obesity and diabetes, Cell source

In the paper

“Considering that a moderate to severe deficit in mitochondrial function increases reliance on glycolytic metabolism, it is not so surprising that these genetic maneuvers elicited adaptations that enhance glucose uptake and insulin sensitivity.”

In the paper

“Although emerging reports appear to argue against a role for mitochondrial dysfunction as a root cause of muscle insulin resistance, the controversy might come down to a matter of definition.”

In the paper

“lowering of MCD activity in primary human skeletal myocytes using small interfering RNAs invoked a clear shift from fatty acid to glucose oxidation and a corresponding increase in both basal and insulinstimulated glucose uptake [13].”

What the sources say

• Not checked yetcites [13] Bouzakri, 2008, Malonyl coenzyme A decarboxylase regulates lipid and glucose metabolism in human skeletal muscle, Diabetes source

In the paper

“in contrast to the diabetic subjects, AIF null mice maintained insulin sensitivity and resisted the diabetogenic effects of a high fat diet.”

What the sources say

• Not checked yetcites [70] Pospisilik, 2007, Targeted deletion of AIF decreases mitochondrial oxidative phosphorylation and protects from obesity and diabetes, Cell source

In the paper

“the mcd−/− mice had decreased acylcarnitine accumulation in muscle, enhanced rates of glucose oxidation, and resisted diet-induced glucose intolerance, despite high intramuscular levels of triacylglycerol and long chain acyl-CoAs [50,88].”

What the sources say

• Not checked yetcites [50] Koves, 2008, Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance, Cell Metab. source
• Not checked yetcites [88] Ussher, 2009, Insulin-stimulated cardiac glucose oxidation is increased in high-fat diet-induced obese mice lacking malonyl CoA decarboxylase, Diabetes source

In the paper

“mice lacking the mitochondrial transcription factor A (TFAM) have reduced oxidative capacity but increased whole body glucose tolerance and enhanced insulin-stimulated glucose uptake in isolated muscles [95].”

What the sources say

• Not checked yetcites [95] Wredenberg, 2006, Respiratory chain dysfunction in skeletal muscle does not cause insulin resistance, Biochem. Biophys. Res. Commun. source

In the paper

“a broader interpretation of mitochondrial dysfunction encompasses perturbations that do not necessarily compromise oxidative potential. Thus, disturbances in mitochondrial fuel selection, anaplerotic and cataplerotic carbon flux, redox balance and production of reactive oxygen species (ROS) can occur in the absence of measurable defects in respiratory capacity [4,12,65].”

What the sources say

• Not checked yetcites [4] Anderson, 2009, Mitochondrial H2O2 emission and cellular redox state link excess fat intake to insulin resistance in both rodents and humans, J. Clin. Invest. source
• Not checked yetcites [12] Boucher, 2004, Biochemical mechanism of lipid-induced impairment of glucose-stimulated insulin secretion and reversal with a malate analogue, J. Biol. Chem. source
• Not checked yetcites [65] Noland, 2009, Carnitine insufficiency caused by aging and overnutrition compromises mitochondrial performance and metabolic control, J. Biol. Chem. source

In the paper

“These outcomes were associated with increased cell surface levels of the GLUT-4 glucose transporter, but surprisingly no enhancement in insulin signaling at the levels of IRS-1 tyrosine phosphorylation, PI3-kinase activity, or serine phosphorylation of Akt.”

What the sources say

• Not checked yetcites [13] Bouzakri, 2008, Malonyl coenzyme A decarboxylase regulates lipid and glucose metabolism in human skeletal muscle, Diabetes source

In the paper

“whole body or muscle-specific deletion of the redox regulatory protein, thioredoxin interaction protein (TXNIP), resulted in impaired oxidative muscle metabolism while also producing mice that were exquisitely insulin responsive, even after high fat feeding [38].”

What the sources say

• Not checked yetcites [38] Hui, 2008, Txnip balances metabolic and growth signaling via PTEN disulfide reduction, Proc. Natl. Acad. Sci. U.S.A. source

In the paper

“Thus, in theory, a surplus of both glucose and lipid fuel should raise mitochondrial membrane potential.”

In the paper

“persistently high rates of fat oxidation might foster a mitochondrial microenvironment that is conducive to ROS production.”

In the paper

“When energy delivery is high (overfeeding) but ATP consumption is low (physical inactivity), a high ATP/ADP ratio reduces proton flux through ATP synthase and slows electron transport through the ETS.”

In the paper

“These conditions increase mitochondrial membrane potential and the local ratio of NADH/NAD, which in turn imposes negative pressure on several TCA cycle enzymes.”

In the paper

“In both rodents and humans insulin resistant states were associated with increased mitochondrial H2O2 emission potential and decreased skeletal muscle levels of glutathione, a commonly used biomarker of oxidative/reductive stress due to its important role in detoxifying H2O2 [4].”

What the sources say

• Not checked yetcites [4] Anderson, 2009, Mitochondrial H2O2 emission and cellular redox state link excess fat intake to insulin resistance in both rodents and humans, J. Clin. Invest. source

In the paper

“Patients afflicted with these disorders present with nonketotic hypoglycemia, muscle weakness, pronounced elevations in long chain acylcarnitines and systemic carnitine depletion [91].”

What the sources say

• Not checked yetcites [91] Wanders, 1999, Disorders of mitochondrial fatty acyl-CoA beta-oxidation, J. Inherit. Metab. Dis. source

In the paper

“Clearly, exercise-induced mitochondrial adaptations and fiber type switching contribute to improved fitness and athletic performance; however, their presumed roles in combating obesity and diabetes are still based on circumstantial evidence.”

In the paper

“Both of these transgenic mouse models had increased expression of multiple mitochondrial proteins, leading to enhanced capacity for fat oxidation, but contrary to the predicted outcome they were more susceptible to whole body and skeletal muscle insulin resistance.”

What the sources say

• Not checked yetcites [19] Choi, 2008, Paradoxical effects of increased expression of PGC-1alpha on muscle mitochondrial function and insulin-stimulated muscle glucose metabolism, Proc. Natl. Acad. Sci. U.S.A. source
• Not checked yetcites [24] Finck, 2005, A potential link between muscle peroxisome proliferator-activated receptor-a signaling and obesity-related diabetes, Cell Metab. source

In the paper

“Much attention has centered on mitochondrial biogenesis and concomitant enhancement of oxidative capacity, both of which represent hallmark adaptations that occur in response to aerobic exercise training and coincide with insulin sensitization [35].”

What the sources say

• Not checked yetcites [35] Holloszy, 1984, Adaptations of skeletal muscle to endurance exercise and their metabolic consequences, J. Appl. Physiol. source

In the paper

“The obesity-related decline in free carnitine was associated with increased whole body fat oxidation, muscle accumulation of long chain acylcarnitines, a corresponding decline in short chain acylcarnitine species, and impaired substrate switching from fatty acid to pyruvate when measured in isolated mitochondria.”

What the sources say

• Not checked yetcites [65] Noland, 2009, Carnitine insufficiency caused by aging and overnutrition compromises mitochondrial performance and metabolic control, J. Biol. Chem. source

In the paper

“This metabolite derives from acetyl-CoA via the action of carnitine acetyltransferase (CrAT), a mitochondrial enzyme that converts short chain CoA species to their acylcarnitine counterparts while also regenerating free CoA [21].”

What the sources say

• Not checked yetcites [21] Cordente, 2004, Redesign of carnitine acetyltransferase specificity by protein engineering, J. Biol. Chem. source

In the paper

“carnitine therapy improved glucose tolerance and insulin responsiveness in rodent models of aging, genetic diabetes and high fat feeding [65,71], while also reversing obesity-related derangements in mitochondrial fuel selection [65].”

What the sources say

• Not checked yetcites [65] Noland, 2009, Carnitine insufficiency caused by aging and overnutrition compromises mitochondrial performance and metabolic control, J. Biol. Chem. source
• Not checked yetcites [71] Power, 2007, Carnitine revisited: potential use as adjunctive treatment in diabetes, Diabetologia source

In the paper

“l-carnitine is an FDA-approved therapy for inborn errors in metabolism [56].”

What the sources say

• Not checked yetcites [56] Longo, 2006, Disorders of carnitine transport and the carnitine cycle, Am. J. Med. Genet. C. Semin. Med. Genet. source

In the paper

“The salutary impact of physical activity on insulin sensitivity, and metabolic health in general, has been well recognized for decades.”

In the paper

“The MCK-PGC1α transgene caused a 2.4-fold increase in mitochondrial content of type II fibers without affecting type I fibers [19].”

What the sources say

• Not checked yetcites [19] Choi, 2008, Paradoxical effects of increased expression of PGC-1alpha on muscle mitochondrial function and insulin-stimulated muscle glucose metabolism, Proc. Natl. Acad. Sci. U.S.A. source

In the paper

“In the MCK-PPARα mice, administration of oxfenicine, a pharmacological inhibitor of β-oxidation, improved glucose tolerance, suggesting excessive fat oxidation contributed to the diabetic phenotype [24].”

What the sources say

• Not checked yetcites [24] Finck, 2005, A potential link between muscle peroxisome proliferator-activated receptor-a signaling and obesity-related diabetes, Cell Metab. source

In the paper

“The resulting boost in oxidative power enabled superior exercise performance relative to wild-type mice [15] but did not change fat mass, total body energy expenditure or weight gain during a high fat diet.”

What the sources say

• Not checked yetcites [15] Calvo, 2008, Muscle-specific expression of PPARgamma coactivator-1alpha improves exercise performance and increases peak oxygen uptake, J. Appl. Physiol. source

In the paper

“Equally plausible however, the combined increases in IMTG and mitochondrial content may have encouraged preferential oxidation of lipid substrate, thereby antagonizing the drive for glucose uptake and utilization as predicted by the Randle hypothesis.”

In the paper

“Both acute and chronic exercise induce muscle expression of glycerolipid biosynthetic enzymes, which is coupled to increased IMTG synthesis and content [42,80].”

What the sources say

• Not checked yetcites [42] Ikeda, 2002, Up-regulation of SREBP-1c and lipogenic genes in skeletal muscles after exercise training, Biochem. Biophys. Res. Commun. source
• Not checked yetcites [80] Schenk, 2007, Acute exercise increases triglyceride synthesis in skeletal muscle and prevents fatty acid-induced insulin resistance, J. Clin. Invest. source

In the paper

“Interestingly however, DGAT1 overexpression was also accompanied by a complex set of mitochondrial abnormalities, including altered morphology, a 45% reduction in mtDNA and increased mRNA expression of metabolic genes such as CPT1 and uncoupling protein 3 [53].”

What the sources say

• Not checked yetcites [53] Liu, 2009, Paradoxical coupling of triglyceride synthesis and fatty acid oxidation in skeletal muscle overexpressing DGAT1, Diabetes source

In the paper

“The study implies that sequestration of fatty acid into IMTG guards against less desirable fates.”

In the paper

“A recent study in humans showed that the insulin sensitizing properties of a single exercise session corresponded with elevated IMTG content and lower muscle levels of DAG, ceramide and muscle glycogen, all measured the day after exercise and following a lipid perfusion [80].”

What the sources say

• Not checked yetcites [80] Schenk, 2007, Acute exercise increases triglyceride synthesis in skeletal muscle and prevents fatty acid-induced insulin resistance, J. Clin. Invest. source

In the paper

“Thus, these findings revealed a strong association between improved insulin action and enhanced mitochondrial activity, but without corresponding reductions in leading candidate mediators of insulin resistance.”

In the paper

“In line with this scenario, contraction caused a robust reduction in IMTG content of the obese muscles; however, diacylglycerol, monoacylglycerol and long chain acyl-CoAs were either unchanged or increased.”

What the sources say

• Not checked yetcites [83] Thyfault, 2007, Contraction of insulin-resistant muscle normalizes insulin action in association with increased mitochondrial activity and fatty acid catabolism, Am. J. Physiol. Cell Physiol. source

In the paper

“In this investigation the experimental protocol resulted in decreased glycogen levels but did not affect IMTG levels.”

What the sources say

• Not checked yetcites [25] Frosig, 2009, Reduced malonyl-CoA content in recovery from exercise correlates with improved insulin-stimulated glucose uptake in human skeletal muscle, Am. J. Physiol. Endocrinol. Metab. source

In the paper

“Analysis of mitochondrial-derived acylcarnitines showed that the contraction regimen elicited marked increases in β-oxidation and mitochondrial carbon flux, in parallel with reduced malonyl-CoA levels.”

What the sources say

• Not checked yetcites [83] Thyfault, 2007, Contraction of insulin-resistant muscle normalizes insulin action in association with increased mitochondrial activity and fatty acid catabolism, Am. J. Physiol. Cell Physiol. source

In the paper

“Both the endogenous supply and mitochondrial use of fatty acid substrate appeared to be greater in muscle from the obese versus lean rats, despite similar rates of glycogen depletion.”

What the sources say

• Not checked yetcites [83] Thyfault, 2007, Contraction of insulin-resistant muscle normalizes insulin action in association with increased mitochondrial activity and fatty acid catabolism, Am. J. Physiol. Cell Physiol. source

In the paper

“Deficiency of ATGL in whole body knockout mice results in severe metabolic disruptions, cardiac dysfunction and premature death [29], which occurs in association with increased tissue lipid droplet accumulation, decreased DAG and ceramide levels, and inhibition of both fatty acid oxidation and mRNA expression of oxidative genes.”

What the sources say

• Not checked yetcites [29] Haemmerle, 2006, Defective lipolysis and altered energy metabolism in mice lacking adipose triglyceride lipase, Science source

In the paper

“Deficiency of ATGL in whole body knockout mice results in severe metabolic disruptions, cardiac dysfunction and premature death [29], which occurs in association with increased tissue lipid droplet accumulation, decreased DAG and ceramide levels, and inhibition of both fatty acid oxidation and mRNA expression of oxidative genes.”

What the sources say

• Not checked yetcites [29] Haemmerle, 2006, Defective lipolysis and altered energy metabolism in mice lacking adipose triglyceride lipase, Science source

In the paper

“Still, the animal models permit proof-of-concept experiments that are difficult, or even impossible, to accomplish in humans.”

In the paper

“As a result, these mice exhibit increased glucose use, depleted liver and muscle glycogen levels, and enhanced whole body and skeletal muscle insulin sensitivity [29,39,48].”

What the sources say

• Not checked yetcites [29] Haemmerle, 2006, Defective lipolysis and altered energy metabolism in mice lacking adipose triglyceride lipase, Science source
• Not checked yetcites [39] Huijsman, 2009, Adipose triacylglycerol lipase deletion alters whole body energy metabolism and impairs exercise performance in mice, Am. J. Physiol. Endocrinol. Metab. source
• Not checked yetcites [48] Kienesberger, 2009, Adipose triglyceride lipase deficiency causes tissue-specific changes in insulin signaling, J. Biol. Chem. source