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OBJECTIVE-To study insulin sensitivity and perfusion in skeletal muscle together with the β-cell function in subjects with the m.3243A>G mutation in mitochondrial DNA, the most common cause of mitochondrial diabetes.
RESEARCH DESIGN AND METHODS-We measured skeletal muscle glucose uptake and perfusion using positron emission tomography and 2-[^sup 18^F]fluoro-2-deoxyglucose and [^sup 15^O]H2O during euglycemic hyperinsulinemia in 15 patients with m.3243A>G. These patients included five subjects with no diabetes as defined by the oral glucose tolerance test (OGTT) (group 1), three with GHb <6.1% and newly found diabetes by OGTT (group 2), and seven with a previously diagnosed diabetes (group 3). Control subjects consisted of 13 healthy individuals who were similar to the carriers of m.3243A>G with respect to age and physical activity. β-Cell function was assessed using the OGTT and subsequent mathematical modeling.
RESULTS-Skeletal muscle glucose uptake was significantly lower in groups 1, 2, and 3 than in the control subjects. The glucose sensitivity of β-cells in group 1 patients was similar to that of the control subjects, whereas in group 2 and 3 patients, the glucose sensitivity was significantly lower. The insulin secretion parameters correlated strongly with the proportion of m.3243A>G mutation in muscle.
CONCLUSIONS-Our findings show that subjects with m.3243A >G are insulin resistant in skeletal muscle even when ß-cell function is not markedly impaired or glucose control compromised. We suggest that both the skeletal muscle insulin sensitivity and the β-cell function are affected before the onset of the mitochondrial diabetes caused by the m.3243A>G mutation. Diabetes 58:543-549, 2009
Impaired insulin sensitivity characterizes adult-onset diabetes and has been attributed to decreased insulin-stimulated glucose uptake in major metabolic tissues such as skeletal muscle, liver, and adipose tissue (1,2). It predicts diabetes strongly in subjects with high hereditary risk (3). Decreased glucose uptake in skeletal muscle is the major determinant of impaired insulin sensitivity, because skeletal muscle is the tissue that accounts for the majority of insulin-stimulated glucose uptake in diabetes and in nondiabetic subjects (4). Impaired insulin sensitivity has been correlated with decreased mitochondrial function and with decreased expression of genes involved in mitochondrial oxidative phosphorylation in skeletal muscle (5,6). Interestingly, similar findings in oxidative phosphorylation have recently been made in healthy insulin-resistant subjects with high hereditary predisposition for diabetes (T).
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