Research Article: Muscle Mitochondrial ATP Synthesis and Glucose Transport/Phosphorylation in Type 2 Diabetes

Date Published: May 1, 2007

Publisher: Public Library of Science

Author(s): Julia Szendroedi, Albrecht I Schmid, Marek Chmelik, Christian Toth, Attila Brehm, Martin Krssak, Peter Nowotny, Michael Wolzt, Werner Waldhausl, Michael Roden, Gerald I Shulman

Abstract: BackgroundMuscular insulin resistance is frequently characterized by blunted increases in glucose-6-phosphate (G-6-P) reflecting impaired glucose transport/phosphorylation. These abnormalities likely relate to excessive intramyocellular lipids and mitochondrial dysfunction. We hypothesized that alterations in insulin action and mitochondrial function should be present even in nonobese patients with well-controlled type 2 diabetes mellitus (T2DM).Methods and FindingsWe measured G-6-P, ATP synthetic flux (i.e., synthesis) and lipid contents of skeletal muscle with 31P/1H magnetic resonance spectroscopy in ten patients with T2DM and in two control groups: ten sex-, age-, and body mass-matched elderly people; and 11 younger healthy individuals. Although insulin sensitivity was lower in patients with T2DM, muscle lipid contents were comparable and hyperinsulinemia increased G-6-P by 50% (95% confidence interval [CI] 39%–99%) in all groups. Patients with diabetes had 27% lower fasting ATP synthetic flux compared to younger controls (p = 0.031). Insulin stimulation increased ATP synthetic flux only in controls (younger: 26%, 95% CI 13%–42%; older: 11%, 95% CI 2%–25%), but failed to increase even during hyperglycemic hyperinsulinemia in patients with T2DM. Fasting free fatty acids and waist-to-hip ratios explained 44% of basal ATP synthetic flux. Insulin sensitivity explained 30% of insulin-stimulated ATP synthetic flux.ConclusionsPatients with well-controlled T2DM feature slightly lower flux through muscle ATP synthesis, which occurs independently of glucose transport /phosphorylation and lipid deposition but is determined by lipid availability and insulin sensitivity. Furthermore, the reduction in insulin-stimulated glucose disposal despite normal glucose transport/phosphorylation suggests further abnormalities mainly in glycogen synthesis in these patients.

Partial Text: Skeletal muscle insulin resistance is characteristic in the elderly as well as in persons at increased risk of type 2 diabetes mellitus (T2DM) and those with overt T2DM. In these groups, the content of intramyocellular lipids (IMCL) is frequently increased and related to insulin resistance [1,2]. However, this relationship disappears during exercise training, which increases both IMCL and insulin sensitivity in parallel [3,4]. Rather than IMCL, intracellular metabolites of free fatty acids (FFAs), such as long-chain fatty acyl coenzyme A and diacylglycerol, inhibit insulin action by stimulating phosphorylation of serine residues of insulin receptor substrate-1 (IRS-1) [5]. This suggests that IMCL do not directly contribute to insulin resistance but accumulate as a consequence of increased lipid availability from augmented lipolysis and excess dietary fat supply and/or of impaired mitochondrial lipid oxidation [6].

Patients with well-controlled T2DM have impaired flux through muscle ATP synthesis occurring independently of glucose transport/phosphorylation and lipid deposition. Lipid availability primarily determines bfATP, whereas insulin sensitivity defines ifATP. Furthermore, the reduction in insulin-stimulated glucose disposal despite normal glucose transport/phosphorylation suggests further abnormalities, mainly in glycogen synthesis of these patients with T2DM.

Source:

http://doi.org/10.1371/journal.pmed.0040154

 

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