Mitochondrial diabetes is associated with insulin resistance in subcutaneous adipose tissue but not with increased...

We recently showed that patients with mitochondrial diabetes are insulin resistant in skeletal muscle before the decline in insulin secretion is observed. In this study, we further evaluate whether insulin resistance is associated with increased ectopic fat accumulation and altered adipose and hepatic tissue insulin sensitivity. We studied 15 nonobese patients with the m.3243A > G mutation. Five were without diabetes (group 1), three had newly diagnosed diabetes (group 2), and seven had previously diagnosed diabetes (group 3). Thirteen healthy volunteers of similar age and body mass index (BMI) served as controls. Insulin-stimulated glucose uptake was measured with positron emission tomography using 2- [(18)F]-fluoro-2-deoxyglucose during euglycemic hyperinsulinemia. Fat masses and liver fat content were measured with magnetic resonance imaging and spectroscopy. Compared with controls, insulin-stimulated glucose uptake in adipose tissue was decreased by ∼50% in all groups with the m.3243A > G mutation. In addition, fat masses were not different, but insulin-mediated suppression of lipolysis and adiponectin metabolism were blunted in patients with the m.3243A > G mutation. Hepatic fat content was normal (<5.6%) in 80% of patients and significantly elevated in one case only. Hepatic glucose metabolism in patients with m.3243A > G did not differ from that of controls. In conclusion, m.3243A > G mutation affects subcutaneous adipose tissue metabolism. This seems to occur before aberrant liver metabolism, if any, can be observed or before beta-cell failure results in mitochondrial diabetes.