AMPK activity and isoform protein expression are similar in muscle of obese subjects with and without type 2 diabetes

Højlund, Kurt; Mustard, Kirsty J.; Stæhr, Peter; Hardie, D. Grahame; Beck‐Nielsen, Henning; Richter, Erik A.; Wojtaszewski, Jørgen F. P.

doi:10.1152/ajpendo.00326.2003

Cited by 80 publications

(65 citation statements)

References 43 publications

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“…Furthermore, it was recently shown that skeletal muscle mitochondrial capacity for oxidative phosphorylation in Asian Indians with type 2 diabetes is the same as in nondiabetic Indians [39]. Similarly, we have shown that AMPK or ACC status does not appear to be implicated in type 2 diabetes in accordance with previous studies [40][41][42] and at odds with others [43]. While obese participants without type 2 diabetes do not show defective mitochondrial respiration, they do have a significant increase in citrate synthase activity and significantly reduced AMPK levels.…”

Section: Discussionsupporting

confidence: 92%

Intramyocellular lipid accumulation is associated with permanent relocation ex vivo and in vitro of fatty acid translocase (FAT)/CD36 in obese patients

et al. 2010

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Aims/hypothesis Intramyocellular lipids (IMCL) accumulation is a classical feature of metabolic diseases. We hypothesised that IMCL accumulate mainly as a consequence of increased adiposity and independently of type 2 diabetes. To test this, we examined IMCL accumulation in two different models and four different populations of participants: muscle biopsies and primary human muscle cells derived from non-obese and obese participants with or without type 2 diabetes. The mechanism regulating IMCL accumulation was also studied. Methods Muscle biopsies were obtained from ten non-obese and seven obese participants without type 2 diabetes, and from eight non-obese and eight obese type 2 diabetic patients. Mitochondrial respiration, citrate synthase activity and both ON, Canada Diabetologia (2010) 53:1151-1163 DOI 10.1007/s00125-010-1708 accumulation is dependent upon obesity or type 2 diabetes and is related to sarcolemmal FAT/CD36 relocation. In cultured myotubes, IMCL content and FAT/CD36 relocation are independent of type 2 diabetes, suggesting that distinct factors in obesity and type 2 diabetes contribute to permanent FAT/CD36 relocation ex vivo.

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Section: Discussionsupporting

confidence: 92%

Intramyocellular lipid accumulation is associated with permanent relocation ex vivo and in vitro of fatty acid translocase (FAT)/CD36 in obese patients

et al. 2010

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“…Because ACC2 is predominantly expressed in muscle and heart (42), our measurement of malonyl-CoA likely reflects the activity primarily of ACC2. Previous reports did not find decreased AMPK activity in insulin-resistant human muscle (43)(44)(45), whereas skeletal muscle from obese rats did display decreased AMPK and increased ACC activities (46). In studies with obese rat muscle, Lessard et al (46) demonstrated that the decrease in AMPK activity and phospho-ACC levels were normalized after rosiglitazone treatment, similar to what we observed in our study.…”

Section: Discussionsupporting

confidence: 90%

“…In this regard, previous studies have reported no change in skeletal muscle AMP kinase activity in type 2 diabetic subjects compared with control subjects. However, in two of these previous studies, the control group and type 2 diabetic groups were either both lean (44) or both obese (45), so that no differences in adiposity existed between the control and type 2 diabetic subjects. Thus, these results do not disagree with our own data because we found that differences in obesity correlated more closely with decreased AMP kinase activity than did the presence of diabetes.…”

Section: Discussionmentioning

confidence: 94%

Increased Malonyl-CoA Levels in Muscle From Obese and Type 2 Diabetic Subjects Lead to Decreased Fatty Acid Oxidation and Increased Lipogenesis; Thiazolidinedione Treatment Reverses These Defects

et al. 2006

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Increased accumulation of fatty acids and their derivatives can impair insulin-stimulated glucose disposal by skeletal muscle. To characterize the nature of the defects in lipid metabolism and to evaluate the effects of thiazolidinedione treatment, we analyzed the levels of triacylglycerol, longchain fatty acyl-coA, malonyl-CoA, fatty acid oxidation, AMP-activated protein kinase (AMPK), acetyl-CoA carboxylase (ACC), malonyl-CoA decarboxylase, and fatty acid transport proteins in muscle biopsies from nondiabetic lean, obese, and type 2 subjects before and after an euglycemic-hyperinsulinemic clamp as well as pre-and post-3-month rosiglitazone treatment. We observed that low AMPK and high ACC activities resulted in elevation of malonyl-CoA levels and lower fatty acid oxidation rates. These conditions, along with the basal higher expression levels of fatty acid transporters, led accumulation of longchain fatty acyl-coA and triacylglycerol in insulin-resistant muscle. During the insulin infusion, muscle fatty acid oxidation was reduced to a greater extent in the lean compared with the insulin-resistant subjects. In contrast, isolated muscle mitochondria from the type 2 subjects exhibited a greater rate of fatty acid oxidation compared with the lean group. All of these abnormalities in the type 2 diabetic group were reversed by rosiglitazone treatment. In conclusion, these studies have shown that elevated malonyl-CoA levels and decreased fatty acid oxidation are key abnormalities in insulin-resistant muscle, and, in type 2 diabetic patients, thiazolidinedione treatment can reverse these abnormalities.

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“…Importantly, AMPK activity in skeletal muscle from patients with type 2 diabetes appears to be intact. Basal activity is similar to matched controls (13,34), and the enzyme can be activated normally by acute exercise (13) and metformin in vivo (13,35) and by AICAR in vitro (36). These reports also suggest that skeletal muscle insulin resistance is unlikely to be initiated by dysfunction of the AMPK trimer.…”

Section: Discussionmentioning

confidence: 62%

Ablation of AMP-Activated Protein Kinase α2 Activity Exacerbates Insulin Resistance Induced by High-Fat Feeding of Mice

et al. 2008

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OBJECTIVE-We determined whether muscle AMP-activated protein kinase (AMPK) has a role in the development of insulin resistance.RESEARCH DESIGN AND METHODS-Muscle-specific transgenic mice expressing an inactive form of the AMPK ␣2 catalytic subunit (␣2i TG) and their wild-type littermates were fed either a high-fat (60% kcal fat) or a control (10% kcal fat) diet for 30 weeks.RESULTS-Compared with wild-type mice, glucose tolerance in ␣2i TG mice was slightly impaired on the control diet and significantly impaired on the high-fat diet. To determine whether the whole-body glucose intolerance was associated with impaired insulin sensitivity in skeletal muscle, glucose transport in response to submaximal insulin (450 U/ml) was measured in isolated soleus muscles. On the control diet, insulin-stimulated glucose transport was reduced by ϳ50% in ␣2i TG mice compared with wild-type mice. High-fat feeding partially decreased insulin-stimulated glucose transport in wild-type mice, while high-fat feeding resulted in a full blunting of insulin-stimulated glucose transport in the ␣2i TG mice. High-fat feeding in ␣2i TG mice was accompanied by decreased expression of insulin signaling proteins in gastrocnemius muscle. CONCLUSIONS-The lack of skeletal muscle AMPK ␣2 activity exacerbates the development of glucose intolerance and insulin resistance caused by high-fat feeding and supports the thesis that AMPK ␣2 is an important target for the prevention/amelioration of skeletal muscle insulin resistance through lifestyle (exercise) and pharmacologic (e.g., metformin) treatments. Diabetes 57: 2958-2966, 2008 T he development of insulin resistance in skeletal muscle precedes the onset of type 2 diabetes by decades (1). Although the underlying mechanism is not fully understood, in recent years there has been growing interest in AMP-activated protein kinase (AMPK) as a potential target to attenuate skeletal muscle insulin resistance. As examples, two well-known therapies for type 2 diabetes, physical exercise and metformin, both activate AMPK in skeletal muscle (2). Despite this emphasis on AMPK, there is little direct evidence showing that AMPK is in fact critical in the development of skeletal muscle insulin resistance.AMPK is an energy-sensing enzyme that is activated by acute increases in the cellular AMP-to-ATP ratio. In skeletal muscle, AMPK activity is increased by stimuli such as exercise, hypoxia, ischemia, and osmotic stress, all of which reduced cellular energy level (2). When intracellular ATP decreases, AMPK acts to switch off ATP-consuming pathways, such as glycogen, fatty acid, and protein synthesis pathways, and acts to switch on alternative pathways for ATP regeneration, such as glucose transport, glycolysis, and fatty acid oxidation. AMPK may also play a role in enhancing insulin sensitivity and/or responsiveness for glucose transport (3-6) in skeletal muscle.AMPK is a heterotrimeric serine/threonine kinase that consists of a catalytic ␣-subunit and regulatory ␤-and ␥-subunits (7-11). In skeletal muscle, ␣2 (12,13) i...

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AMPK activity and isoform protein expression are similar in muscle of obese subjects with and without type 2 diabetes

Cited by 80 publications

References 43 publications

Intramyocellular lipid accumulation is associated with permanent relocation ex vivo and in vitro of fatty acid translocase (FAT)/CD36 in obese patients

Intramyocellular lipid accumulation is associated with permanent relocation ex vivo and in vitro of fatty acid translocase (FAT)/CD36 in obese patients

Increased Malonyl-CoA Levels in Muscle From Obese and Type 2 Diabetic Subjects Lead to Decreased Fatty Acid Oxidation and Increased Lipogenesis; Thiazolidinedione Treatment Reverses These Defects

Ablation of AMP-Activated Protein Kinase α2 Activity Exacerbates Insulin Resistance Induced by High-Fat Feeding of Mice

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