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Lower intrinsic ADP-stimulated mitochondrial respiration underlies in vivo mitochondrial dysfunction in muscle of male type 2 diabetic patients

Departments of Human Biology¹ and
Human Movement Sciences², Maastricht University, The Netherlands and
departments of Radiology³ and
Internal Medicine⁴, Maastricht University Hospital, The Netherlands

Objective: A lower in vivo mitochondrial function has been reported in (first-degree relatives (FDR) of) diabetic patients (T2DM). The nature of this reduction is unknown. Here we tested the hypothesis that a lower intrinsic mitochondrial respiratory capacity may underlie lower in vivo mitochondrial function observed in T2DM.

Research Design and Methods: Ten overweight T2DM, twelve FDR, and sixteen control subjects - all males - matched for age and BMI participated in this study. Insulin sensitivity was measured with a hyperinsulineamic euglyceamic clamp. Ex vivo intrinsic mitochondrial respiratory capacity was determined in permeabilized skinned muscle fibers using high-resolution respirometry and normalized for mitochondrial content. In vivo mitochondrial function was determined by measuring post-exercise PCr recovery half-time (PCr_t1/2) using ³¹Phosphorus Magnetic Resonance Spectroscopy.

Results: Insulin-stimulated glucose disposal (µ mol/kgFFM/min) was lower in T2DM compared to control subjects (11.2 ± 2.8 vs 28.9 ± 3.7, respectively; p=0.003), with intermediate values for FDR (22.1 ± 3.4). In vivo mitochondrial function was 25% lower in T2DM (p=0.034) and 23% lower in FDR, but the latter did not reach statistical significance (p=0.08). Interestingly, ADP-stimulated basal respiration was 35% lower in T2DM (p=0.031) and FCCP-driven maximal mitochondrial respiratory capacity was 31% lower in T2DM (p=0.05) compared to control subjects with intermediate values for FDR.

Conclusions: A reduced basal ADP-stimulated and maximal mitochondrial respiratory capacity underlies the reduction in in vivo mitochondrial function, independent of mitochondrial content. A reduced capacity at both the level of the electron transport chain and phosphorylation system underlies this impaired mitochondrial capacity.

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