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

Abstract

BACKGROUND:

Muscular 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 FINDINGS:

We measured G-6-P, ATP synthetic flux (i.e., synthesis) and lipid contents of skeletal muscle with (31)P/(1)H 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.

• Authors: Julia Szendroedi, Albrecht I Schmid, Marek Chmelik, Christian Toth, Attila Brehm, Martin Krssak, Peter Nowotny, Michael Wolzt, Werner Waldhausl, Michael Roden
• Journal: PLoS medicine (PLoS Med) Vol. 4 Issue 5 Pg. e154 (May 2007) ISSN: 1549-1676 [Electronic] United States
• PMID: 17472434 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Blood Glucose
• Fatty Acids, Nonesterified
• Glucose-6-Phosphate
• Adenosine Triphosphate

Topics

• Adenosine Triphosphate (biosynthesis)
• Adipose Tissue (metabolism, physiology)
• Adult
• Aged
• Blood Glucose (metabolism)
• Diabetes Mellitus, Type 2 (metabolism)
• Fatty Acids, Nonesterified (metabolism)
• Female
• Glucose Clamp Technique
• Glucose-6-Phosphate (blood)
• Humans
• Insulin Resistance (physiology)
• Magnetic Resonance Spectroscopy
• Male
• Middle Aged
• Mitochondria, Muscle (metabolism)
• Obesity (metabolism, physiopathology)
• Phosphorylation