OBJECTIVE: Impaired muscular mitochondrial function is related to common insulin resistance in type 2 diabetes. Mitochondrial diseases frequently lead to diabetes, which is mostly attributed to defective beta-cell mitochondria and secretion. RESEARCH DESIGN AND METHODS: We assessed muscular mitochondrial function and lipid deposition in liver (hepatocellular lipids [HCLs]) and muscle (intramyocellular lipids [IMCLs]) using (31)P/(1)H magnetic resonance spectroscopy and insulin sensitivity and endogenous glucose production (EGP) using hyperinsulinemic-euglycemic clamps combined with isotopic tracer dilution in one female patient suffering from MELAS (myopathy, encephalopathy, lactic acidosis, and stroke-like episodes) syndrome and in six control subjects. RESULTS: The MELAS patient showed impaired insulin sensitivity (4.3 vs. 8.6 +/- 0.5 mg x kg(-1) x min(-1)) and suppression of EGP (69 vs. 94 +/- 1%), and her baseline and insulin-stimulated ATP synthesis were reduced (7.3 and 8.9 vs. 10.6 +/- 1.0 and 12.8 +/- 1.3 micromol x l(-1) x min(-1)) compared with those of the control subjects. HCLs and IMCLs were comparable between the MELAS patient and control subjects. CONCLUSIONS: Impairment of muscle mitochondrial fitness promotes insulin resistance and could thereby contribute to the development of diabetes in some patients with the MELAS syndrome.