Reduced mitochondrial density and increased IRS-1 serine phosphorylation in muscle of insulin-resistant offspring of type 2 diabetic parents

Morino, Katsutaro; Petersen, Kitt Falk; Dufour, Sylvie; Befroy, Douglas E.; Frattini, Jared C.; Shatzkes, Nadine; Neschen, Susanne; White, Morris F.; Bilz, Stefan; Sono, Saki; Pypaert, Marc; Shulman, Gerald I.

doi:10.1172/jci25151

Cited by 722 publications

(590 citation statements)

References 40 publications

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“…Consistent with our hypothesis of lipid metabolites inducing insulin resistance (6,9,10,(17)(18)(19)(20), muscle triglyceride, lysophosphatidic acid, and long-chain acyl CoAs were markedly increased in MPGC-1␣ TG mice fed a high-fat diet compared with WT mice (Fig. 3 A, C, and D).…”

Section: Mechanism For Increased Insulin Resistance In Skeletal Musclsupporting

confidence: 88%

Paradoxical effects of increased expression of PGC-1α on muscle mitochondrial function and insulin-stimulated muscle glucose metabolism

Choi

Befroy

Codella

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

266

264

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Peroxisome proliferator-activated receptor-␥ coactivator (PGC)-1␣ has been shown to play critical roles in regulating mitochondria biogenesis, respiration, and muscle oxidative phenotype. Furthermore, reductions in the expression of PGC-1␣ in muscle have been implicated in the pathogenesis of type 2 diabetes. To determine the effect of increased muscle-specific PGC-1␣ expression on muscle mitochondrial function and glucose and lipid metabolism in vivo, we examined body composition, energy balance, and liver and muscle insulin sensitivity by hyperinsulinemic-euglycemic clamp studies and muscle energetics by using 31 P magnetic resonance spectroscopy in transgenic mice. Increased expression of PGC-1␣ in muscle resulted in a 2.4-fold increase in mitochondrial density, which was associated with an Ϸ60% increase in the unidirectional rate of ATP synthesis. Surprisingly, there was no effect of increased muscle PGC-1␣ expression on whole-body energy expenditure, and PGC-1␣ transgenic mice were more prone to fat-induced insulin resistance because of decreased insulin-stimulated muscle glucose uptake. The reduced insulin-stimulated muscle glucose uptake could most likely be attributed to a relative increase in fatty acid delivery/triglyceride reesterfication, as reflected by increased expression of CD36, acyl-CoA:diacylglycerol acyltransferase1, and mitochondrial acyl-CoA:glycerol-sn-3-phosphate acyltransferase, that may have exceeded mitochondrial fatty acid oxidation, resulting in increased intracellular lipid accumulation and an increase in the membrane to cytosol diacylglycerol content. This, in turn, caused activation of PKC , decreased insulin signaling at the level of insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation, and skeletal muscle insulin resistance.diacylglycerol ͉ fatty acid oxidation ͉ insulin resistance ͉ magnetic resonance spectroscopy ͉ mitochondria

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Section: Mechanism For Increased Insulin Resistance In Skeletal Musclsupporting

confidence: 88%

Paradoxical effects of increased expression of PGC-1α on muscle mitochondrial function and insulin-stimulated muscle glucose metabolism

Choi

Befroy

Codella

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

266

264

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“…In parallel, type 2 diabetes is associated with reduced expression of genes of oxidative metabolism as well as with repression of MFN2 [38][39][40]. In skeletal muscle of non-diabetic individuals with a family history of type 2 diabetes, decreased expression of nuclear genes encoding proteins of oxidative phosphorylation has been reported [39,40], along with reduced in vivo oxidative phosphorylation [35,41]. However, the role of mitochondria in the pathogenesis of insulin resistance and diabetes is still unclear.…”

Section: Discussionmentioning

confidence: 99%

Genes involved in mitochondrial biogenesis/function are induced in response to bilio-pancreatic diversion in morbidly obese individuals with normal glucose tolerance but not in type 2 diabetic patients

et al. 2009

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Aims/hypothesis The mechanisms allowing normalisation of insulin sensitivity and reversal of type 2 diabetes after bilio-pancreatic diversion (BPD) have not been elucidated. We studied whether the expression of genes relevant to mitochondrial biogenesis/function is induced in response to BPD and whether the response differs between morbidly obese patients with normal glucose tolerance (NGT) and patients with type 2 diabetes. Methods The effect of stable weight reduction after BPD on metabolic variables and expression of nuclear genes encoding for mitochondrial proteins or regulators of mitochondrial function was investigated in skeletal muscle. Insulin sensitivity was assessed by euglycaemic-hyperinsulinaemic clamp and substrate oxidation by indirect calorimetry.Results Both NGT and type 2 diabetic patients showed a net improvement of insulin sensitivity, with the latter also showing blood glucose normalisation. NGT patients had a large increase in glucose oxidation and substantial reduction in lipid oxidation. In contrast, type 2 diabetic patients had a blunted response to BPD in terms of glucose oxidation. NGT patients showed increased expression of genes encoding mitofusin 2, porin or citrate synthase; no significant changes were detected in diabetic patients. The expression of genes regulating mitochondrial activity (PGC-1β [also known as PPARGC1B], PGC-1α [also known as PPARGC1A], PPARδ [also known as PPARD], SIRT1) was induced only in NGT patients. Conclusions/interpretation These findings indicate that weight loss after BPD exerts a beneficial effect on insulin sensitivity via mechanisms that are independent of the Diabetologia

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“…Several other studies have investigated the mechanisms by which OXPHOS and mitochondrial function decline during aging and with T2DM. Diminished mitochondrial content and mitochondrial copy number are believed to influence OXPHOS in diabetic muscle (22,(28)(29)(30). Oxidative stress, mitochondrial DNA mutations, and apoptosis are other mechanisms suggested to influence mitochondrial function and OXPHOS expression during aging (31,32).…”

Section: Figurementioning

confidence: 99%

Genetic and epigenetic factors are associated with expression of respiratory chain component NDUFB6 in human skeletal muscle

Ling¹,

Poulsen²,

Simonsson³

et al. 2007

J. Clin. Invest.

174

156

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Insulin resistance and type 2 diabetes are associated with decreased expression of genes that regulate oxidative phosphorylation in skeletal muscle. To determine whether this defect might be inherited or acquired, we investigated the association of genetic, epigenetic, and nongenetic factors with expression of NDUFB6, a component of the respiratory chain that is decreased in muscle from diabetic patients. Expression of NDUFB6 was influenced by age, with lower gene expression in muscle of elderly subjects. Heritability of NDUFB6 expression in muscle was estimated to be approximately 60% in twins. A polymorphism in the NDUFB6 promoter region that creates a possible DNA methylation site (rs629566, A/G) was associated with a decline in muscle NDUFB6 expression with age. Although young subjects with the rs629566 G/G genotype exhibited higher muscle NDUFB6 expression, this genotype was associated with reduced expression in elderly subjects. This was subsequently explained by the finding of increased DNA methylation in the promoter of elderly, but not young, subjects carrying the rs629566 G/G genotype. Furthermore, the degree of DNA methylation correlated negatively with muscle NDUFB6 expression, which in turn was associated with insulin sensitivity. Our results demonstrate that genetic, epigenetic, and nongenetic factors associate with NDUFB6 expression in human muscle and suggest that genetic and epigenetic factors may interact to increase age-dependent susceptibility to insulin resistance. IntroductionAlthough reduced physical activity, obesity, and aging increase susceptibility to type 2 diabetes mellitus (T2DM), not all individuals exposed to these risk factors develop the disease. A likely reason is that genetic variation modifies susceptibility to T2DM. Furthermore, the interaction between genetic and nongenetic factors may be even more complex and involve epigenetic factors such as DNA methylation. Insulin-resistant offspring of patients with T2DM and elderly subjects are characterized by impaired mitochondrial function in skeletal muscle (1, 2). Furthermore, nuclear-encoded genes regulating oxidative phosphorylation (OXPHOS), and their transcriptional regulators, PPARγ coactivator 1α (PGC-1α) and PGC-1β, show reduced expression in skeletal muscle of patients with T2DM (3, 4). Nevertheless, it remains unknown whether this is an inherited or acquired defect. We previously showed that an age-dependent decrease in muscle PGC-1α and PGC-1β expression is partially under genetic control and is influenced by the PGC-1α Gly482Ser polymorphism (5). This common variant in the PGC-1α gene has also been associated with increased risk of T2DM (6-8). We hypothesized that the effect of age on mitochondrial function can be determined by both genetic and epigenetic factors. To address this we selected the NDUFB6 gene from the first respiratory complex for further studies, because NDUFB6 is among the set of OXPHOS genes showing significant reduction in muscle from patients with T2DM compared with healthy control subjects and

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Reduced mitochondrial density and increased IRS-1 serine phosphorylation in muscle of insulin-resistant offspring of type 2 diabetic parents

Cited by 722 publications

References 40 publications

Paradoxical effects of increased expression of PGC-1α on muscle mitochondrial function and insulin-stimulated muscle glucose metabolism

Paradoxical effects of increased expression of PGC-1α on muscle mitochondrial function and insulin-stimulated muscle glucose metabolism

Genes involved in mitochondrial biogenesis/function are induced in response to bilio-pancreatic diversion in morbidly obese individuals with normal glucose tolerance but not in type 2 diabetic patients

Genetic and epigenetic factors are associated with expression of respiratory chain component NDUFB6 in human skeletal muscle

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