Dataset Information

Downregulation of AMPK accompanies leucine- and glucose-induced increases in protein synthesis and insulin resistance in rat skeletal muscle.

ABSTRACT:

Objective

Branched-chain amino acids, such as leucine and glucose, stimulate protein synthesis and increase the phosphorylation and activity of the mammalian target of rapamycin (mTOR) and its downstream target p70S6 kinase (p70S6K). We examined in skeletal muscle whether the effects of leucine and glucose on these parameters and on insulin resistance are mediated by the fuel-sensing enzyme AMP-activated protein kinase (AMPK).

Research design and methods

Rat extensor digitorum longus (EDL) muscle was incubated with different concentrations of leucine and glucose with or without AMPK activators. Muscle obtained from glucose-infused rats was also used as a model.

Results

In the EDL, incubation with 100 or 200 ?mol/l leucine versus no added leucine suppressed the activity of the ?2 isoform of AMPK by 50 and 70%, respectively, and caused concentration-dependent increases in protein synthesis and mTOR and p70S6K phosphorylation. Very similar changes were observed in EDL incubated with 5.5 or 25 mmol/l versus no added glucose and in muscle of rats infused with glucose in vivo. Incubation of the EDL with the higher concentrations of both leucine and glucose also caused insulin resistance, reflected by a decrease in insulin-stimulated Akt phosphorylation. Coincubation with the AMPK activators AICAR and ?-lipoic acid substantially prevented all of those changes and increased the phosphorylation of specific sites of mTOR inhibitors raptor and tuberous sclerosis complex 2 (TSC2). In contrast, decreases in AMPK activity induced by leucine and glucose were not associated with a decrease in raptor or TSC2 phosphorylation.

Conclusions

The results indicate that both leucine and glucose modulate protein synthesis and mTOR/p70S6 and insulin signaling in skeletal muscle by a common mechanism. They also suggest that the effects of both molecules are associated with a decrease in AMPK activity and that AMPK activation prevents them.

SUBMITTER: Saha AK

PROVIDER: S-EPMC3279521 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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Publications

Downregulation of AMPK accompanies leucine- and glucose-induced increases in protein synthesis and insulin resistance in rat skeletal muscle.

Saha Asish K AK Xu X Julia XJ Lawson Ebony E Deoliveira Rosangela R Brandon Amanda E AE Kraegen Edward W EW Ruderman Neil B NB

Diabetes 20100803 10

<h4>Objective</h4>Branched-chain amino acids, such as leucine and glucose, stimulate protein synthesis and increase the phosphorylation and activity of the mammalian target of rapamycin (mTOR) and its downstream target p70S6 kinase (p70S6K). We examined in skeletal muscle whether the effects of leucine and glucose on these parameters and on insulin resistance are mediated by the fuel-sensing enzyme AMP-activated protein kinase (AMPK).<h4>Research design and methods</h4>Rat extensor digitorum lon ...[more]

PMID: 20682696

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Project description:Systemic lupus erythematosus (SLE) patients may show increased insulin resistance (IR) when compared with their healthy peers. Exercise training has been shown to improve insulin sensitivity in other insulin-resistant populations, but it has never been tested in SLE. Therefore, the aim of the present study was to assess the efficacy of a moderate-intensity exercise training program on insulin sensitivity and potential underlying mechanisms in SLE patients with mild/inactive disease. A 12-week, randomized controlled trial was conducted. Nineteen SLE patients were randomly assigned into two groups: trained (SLE-TR, n?=?9) and non-trained (SLE-NT, n?=?10). Before and after 12?weeks of the exercise training program, patients underwent a meal test (MT), from which surrogates of insulin sensitivity and beta-cell function were determined. Muscle biopsies were performed after the MT for the assessment of total and membrane GLUT4 and proteins related to insulin signaling [Akt and AMP-activated protein kinase (AMPK)]. SLE-TR showed, when compared with SLE-NT, significant decreases in fasting insulin [-39 vs. +14%, p?=?0.009, effect size (ES)?=?-1.0] and in the insulin response to MT (-23 vs. +21%, p?=?0.007, ES?=?-1.1), homeostasis model assessment IR (-30 vs. +15%, p?=?0.005, ES?=?-1.1), a tendency toward decreased proinsulin response to MT (-19 vs. +6%, p?=?0.07, ES?=?-0.9) and increased glucagon response to MT (+3 vs. -3%, p?=?0.09, ES?=?0.6), and significant increases in the Matsuda index (+66 vs. -31%, p?=?0.004, ES?=?0.9) and fasting glucagon (+4 vs. -8%, p?=?0.03, ES?=?0.7). No significant differences between SLT-TR and SLT-NT were observed in fasting glucose, glucose response to MT, and insulinogenic index (all p?>?0.05). SLE-TR showed a significant increase in AMPK Thr 172 phosphorylation when compared to SLE-NT (+73 vs. -12%, p?=?0.014, ES?=?1.3), whereas no significant differences between groups were observed in Akt Ser 473 phosphorylation, total and membrane GLUT4 expression, and GLUT4 translocation (all p?>?0.05). In conclusion, a 12-week moderate-intensity aerobic exercise training program improved insulin sensitivity in SLE patients with mild/inactive disease. This effect appears to be partially mediated by the increased insulin-stimulated skeletal muscle AMPK phosphorylation. Clinical Trial Registration:www.ClinicalTrials.gov, identifier NCT01515163.

Dataset Information

Downregulation of AMPK accompanies leucine- and glucose-induced increases in protein synthesis and insulin resistance in rat skeletal muscle.

Objective

Research design and methods

Results

Conclusions

Publications

Downregulation of AMPK accompanies leucine- and glucose-induced increases in protein synthesis and insulin resistance in rat skeletal muscle.

Similar Datasets

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