AMP-Activated Protein Kinase (AMPK) Is Activated in Muscle of Subjects With Type 2 Diabetes During Exercise

Musi, Nicolas; Fujii, Nobuharu; Hirshman, Michael F.; Ekberg, Ingvar; Fröberg, Sven O.; Ljungqvist, Olle; Thorell, Anders; Goodyear, Laurie J.

doi:10.2337/diabetes.50.5.921

Cited by 329 publications

(297 citation statements)

References 58 publications

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“…In skeletal muscle from lean type 2 diabetic patients [26,27] and obese participants [28], AMPK signalling in response to aminoimidazole carboxamide ribonucleotide (AICAR) or exercise appeared to be unchanged, although some studies have noticed modest reductions [29,30]. Thus, it is currently not clear whether a reduction in AMPK causes accumulation of skeletal muscle lipids and insulin resistance with obesity.…”

Section: Introductionmentioning

confidence: 99%

Reduced AMP-activated protein kinase activity in mouse skeletal muscle does not exacerbate the development of insulin resistance with obesity

et al. 2009

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Aims/hypothesis Obesity-related insulin resistance is associated with accumulation of bioactive lipids in skeletal muscle. The AMP-activated protein kinase (AMPK) regulates lipid oxidation in muscle by inhibiting acetyl-CoA carboxylase-2 (ACC2) and increasing mitochondrial biogenesis. We investigated whether reduced levels of muscle AMPK promote lipid accumulation and insulin resistance during high-fat feeding. Methods Male C57/BL6 wild-type mice and transgenic littermates overexpressing an α2AMPK kinase-dead (KD) in muscle were fed control or high-fat diet. Whole-body glucose homeostasis was assessed by glucose and insulin tolerance tests, and by measuring fasting and fed serum insulin and glucose. Insulin action in muscle was determined by measuring 2-deoxy-[ 3 H]glucose uptake and Akt phosphorylation in incubated soleus and extensor digitorum longus muscles. Muscle triacylglycerol, diacylglycerol and ceramide content was measured by thin-layer chromatography. Mitochondrial proteins were measured by immunoblotting. Results KD mice had reduced skeletal muscle α2AMPK activity (50% in gastrocnemius and >80% in soleus and extensor digitorum longus) and ACC2 Ser228 phosphorylation (90% in gastrocnemius). High-fat feeding increased body mass and adiposity, and impaired insulin and glucose tolerance; however, there were no differences between wild-type and KD littermates. High-fat feeding impaired insulin-stimulated muscle glucose uptake and Akt-phosphorylation, while increasing muscle triacylglycerol, diacylglycerol (p=0.07) and ceramide, but these effects were not exacerbated in KD mice. In response to high-fat feeding, mitochondrial proteins were increased to similar levels in wild-type and KD muscles. Conclusions/interpretation Obesity-induced lipid accumulation and insulin resistance were not exacerbated in AMPK KD mice, suggesting that reduced levels of muscle α2AMPK do not promote insulin resistance in the early phase of obesity-related diabetes.

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Section: Introductionmentioning

confidence: 99%

Reduced AMP-activated protein kinase activity in mouse skeletal muscle does not exacerbate the development of insulin resistance with obesity

et al. 2009

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“…This hypersensitivity of LCFA oxidation to oligomycin might be caused by a more potent activation of AMPK in cardiac myocytes from obese Zucker rats. In this respect, it should be noted that in skeletal muscle from both obese Zucker rats and type 2 diabetic patients, AMPK activity is still highly inducible (40,41).…”

Section: Discussionmentioning

confidence: 99%

Enhanced Sarcolemmal FAT/CD36 Content and Triacylglycerol Storage in Cardiac Myocytes From Obese Zucker Rats

et al. 2004

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In obesity, the development of cardiomyopathy is associated with the accumulation of myocardial triacylglycerols (TAGs), possibly stemming from elevation of myocardial long-chain fatty acid (LCFA) uptake. Because LCFA uptake is regulated by insulin and contractions, we examined in cardiac myocytes from lean and obese Zucker rats the effects of insulin and the contraction-mimetic agent oligomycin on the initial rate of LCFA uptake, subcellular distribution of FAT/CD36, and LCFA metabolism. In cardiac myocytes from obese Zucker rats, under basal conditions, FAT/CD36 was relocated to the sarcolemma at the expense of intracellular stores. In addition, the LCFA uptake rate, LCFA esterification rate into TAGs, and the intracellular unesterified LCFA concentration each were significantly increased. All these metabolic processes were normalized by the FAT/CD36 inhibitor sulfo-N-succinimidyloleate, indicating its antidiabetic potential. In cardiac myocytes isolated from lean rats, in vitro administration of insulin induced the translocation of FAT/ CD36 to the sarcolemma and stimulated initial rates of LCFA uptake and TAG esterification. In contrast, in myocytes from obese rats, insulin failed to alter the subcellular localization of FAT/CD36 and the rates of LCFA uptake and TAG esterification. In cardiac myocytes from lean and obese animals, oligomycin stimulated the initial rates of LCFA uptake and oxidation, although oligomycin only induced the translocation of FAT/CD36 to the sarcolemma in lean rats. The present results indicate that in cardiac myocytes from obese Zucker rats, a permanent relocation of FAT/CD36 to the sarcolemma is responsible for myocardial TAG accumulation. Furthermore, in vitro these cardiac myocytes, although sensitive to contraction-like stimulation, were completely insensitive to insulin, as the basal conditions in hyperinsulinemic, obese animals resemble the insulin-stimulated condition in lean littermates.

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“…AMPK phosphorylation and protein production For western blotting, muscle lysates were prepared as previously described [30]. Proteins (50 μg) from the muscle lysates were separated by 10% SDS-PAGE and transferred to nitrocellulose membranes.…”

Section: Methodsmentioning

confidence: 99%

Effects of peroxisome proliferator-activated receptor (PPAR)-α and PPAR-γ agonists on glucose and lipid metabolism in patients with type 2 diabetes mellitus

et al. 2007

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Aims/hypothesis The aim of the study was to examine the effects of pioglitazone (PIO), a peroxisome proliferatoractivated receptor (PPAR)-γ agonist, and fenofibrate (FENO), a PPAR-α agonist, as monotherapy and in combination on glucose and lipid metabolism. Subjects and methods Fifteen type 2 diabetic patients received FENO (n=8) or PIO (n=7) for 3 months, followed by the addition of the other agent for 3 months in an openlabel study. Subjects received a 4 h hyperinsulinaemiceuglycaemic clamp and a hepatic fat content measurement at 0, 3 and 6 months. Results Following PIO, fasting plasma glucose (FPG) (p<0.05) and HbA 1c (p<0.01) decreased, while plasma adiponectin (AD) (5.5±0.9 to 13.8±3.5 μg/ml [SEM], p<0.03) and the rate of insulin-stimulated total-body glucose disposal (R d ) (23.8 ± 3.8 to 40.5 ± 4.4 μmol kg −1 min −1 , p < 0.005) increased. After FENO, FPG, HbA 1c , AD and R d did not change. PIO reduced fasting NEFA (784±53 to 546± 43 μmol/l, p<0.05), triacylglycerol (2.12±0.28 to 1.61± 0.22 mmol/l, p<0.05) and hepatic fat content (20.4±4.8 to 10.2±2.5%, p<0.02). Following FENO, fasting NEFA and hepatic fat content did not change, while triacylglycerol decreased (2.20± 0.14 to 1.59± 0.13 mmol/l, p<0.01).Addition of FENO to PIO had no effect on R d , FPG, HbA 1c , NEFA, hepatic fat content or AD, but triacylglycerol decreased (1.61±0.22 to 1.00±0.15 mmol/l, p<0.05). Addition of PIO to FENO increased R d (24.9±4.4 to 36.1± 2.2 μmol kg −1 min −1 , p<0.005) and AD (4.1±0.8 to 13.1± 2.5 μg/ml, p<0.005) and reduced FPG (p<0.05), HbA 1c (p<0.05), NEFA (p<0.01), hepatic fat content (18.3±3.1 to 13.5±2.1%, p<0.03) and triacylglycerol (1.59±0.13 to 0.96±0.9 mmol/l, p<0.01). Muscle adenosine 5′-monophosphate-activated protein kinase (AMPK) activity did not change following FENO; following the addition of PIO, muscle AMPK activity increased significantly (phosphorylated AMPK:total AMPK ratio 1.2±0.2 to 2.2±0.3, p<0.01). Conclusions/interpretation We conclude that PPAR-α therapy has no effect on NEFA or glucose metabolism and that addition of a PPAR-α agonist to a PPAR-γ agent causes a further decrease in plasma triacylglycerol, but has no effect on NEFA or glucose metabolism.

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AMP-Activated Protein Kinase (AMPK) Is Activated in Muscle of Subjects With Type 2 Diabetes During Exercise

Cited by 329 publications

References 58 publications

Reduced AMP-activated protein kinase activity in mouse skeletal muscle does not exacerbate the development of insulin resistance with obesity

Reduced AMP-activated protein kinase activity in mouse skeletal muscle does not exacerbate the development of insulin resistance with obesity

Enhanced Sarcolemmal FAT/CD36 Content and Triacylglycerol Storage in Cardiac Myocytes From Obese Zucker Rats

Effects of peroxisome proliferator-activated receptor (PPAR)-α and PPAR-γ agonists on glucose and lipid metabolism in patients with type 2 diabetes mellitus

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