Lower intrinsic ADP-stimulated mitochondrial respiration underlies in vivo mitochondrial dysfunction in muscle of male type 2 diabetic patients.
OBJECTIVE
A lower in vivo mitochondrial function has been reported in both type 2 diabetic patients and first-degree relatives of type 2 diabetic patients. 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 diabetic patients.


METHODS
Ten overweight diabetic patients, 12 first-degree relatives, and 16 control subjects, all men, matched for age and BMI, participated in this study. Insulin sensitivity was measured with a hyperinsulinemic-euglycemic 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 phosphocreatine recovery half-time after exercise using (31)P-magnetic resonance spectroscopy.


RESULTS
Insulin-stimulated glucose disposal was lower in diabetic patients compared with control subjects (11.2 +/- 2.8 vs. 28.9 +/- 3.7 micromol x kg(-1) fat-free mass x min(-1), respectively; P = 0.003), with intermediate values for first-degree relatives (22.1 +/- 3.4 micromol x kg(-1) fat-free mass x min(-1)). In vivo mitochondrial function was 25% lower in diabetic patients (P = 0.034) and 23% lower in first-degree relatives, but the latter did not reach statistical significance (P = 0.08). Interestingly, ADP-stimulated basal respiration was 35% lower in diabetic patients (P = 0.031), and fluoro-carbonyl cyanide phenylhydrazone-driven maximal mitochondrial respiratory capacity was 31% lower in diabetic patients (P = 0.05) compared with control subjects with intermediate values for first-degree relatives.


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.
Phielix
Esther
E
Department of Human Biology, Maastricht University, Maastricht, the Netherlands.
Schrauwen-Hinderling
Vera B
VB
Mensink
Marco
M
Lenaers
Ellen
E
Meex
Ruth
R
Hoeks
Joris
J
Kooi
Marianne Eline
ME
Moonen-Kornips
Esther
E
Sels
Jean-Pierre
JP
Hesselink
Matthijs K C
MK
Schrauwen
Patrick
P
D000244:Adenosine Diphosphate / Q000378:metabolism*; D050260:Carbohydrate Metabolism / Q000187:drug effects; D019069:Cell Respiration / Q000502:physiology*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000503:physiopathology*; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D050356:Lipid Metabolism / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D008931:Mitochondria, Muscle / Q000187:drug effects / Q000378:metabolism*
D007328:Insulin; D000244:Adenosine Diphosphate; D005947:Glucose