Muscle mitochondrial ATP synthesis and glucose transport/phosphorylation in type 2 diabetes

Background Muscular insulin resistance is frequently characterized by blunted increases in glucose- 6phosphate ( 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 Findings We measured G-6-P, ATP synthetic flux ( i. e., synthesis) and lipid contents of skeletal muscle with P-31/H-1 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. Conclusions Patients 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.