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.
Highlights
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
We recently showed that shortterm elevation of plasma free fatty acid (FFA) profoundly inhibits insulinstimulated glucose transport/phosphorylation and mitochondrial function, reflected by diminished increase in intramyocellular glucose-6-phosphate (G-6-P) and ATP synthesis, independently of ectopic muscle fat contents [13]
Volunteers Thirty-one volunteers were included in this study: (i) patients with metabolically well-controlled T2DM, (ii) sex, age, body mass index (BMI)-matched older volunteers without diabetes (CONo), and (iii) younger individuals without diabetes (CONy)
Summary
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. Insulin resistant elderly people and first-degree relatives of patients with T2DM have impaired muscle ATP production and elevated IMCL [11,12] These studies raised the questions of (i) whether lipid accumulation in skeletal muscle and/or insulin resistance promotes mitochondrial dysfunction and, if so, (ii) whether insulin stimulation can overcome such alterations. In this context, we recently showed that shortterm elevation of plasma FFAs profoundly inhibits insulinstimulated glucose transport/phosphorylation and mitochondrial function, reflected by diminished increase in intramyocellular glucose-6-phosphate (G-6-P) and ATP synthesis, independently of ectopic muscle fat contents [13]. This hyperglycemia increases the risk of heart attacks, kidney failure, and other life-threatening complications
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