We clinically characterized 18 diabetic patients in 7 families with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) and mitochondrial DNA mutations of tRNALEU(UUR) (3243), 5 diabetics in a family with myoclonic epilepsy and ragged red fiber (MERRF) and tRNALYS (8344) mutation and 11 diabetics in a family with chronic external ophthalmoplegia (CPEO) and multiple deletions. Insulin secretory capacities were significantly reduced in the mutant relatives, as compared with the non-mutant members. It is speculated that the mutation-induced OPHOS defects in the pancreatic beta- cells might result in insulin secretory defects.