BETA-CELL LOSS AND GLUCOSE-INDUCED SIGNALING DEFECTS IN DIABETES-MELLITUS CAUSED BY MITOCHONDRIAL TRNA(LEU)(UUR) GENE MUTATION

Japanese diabetic patients with diabetic mothers were screened, using peripheral leukocytes, for an A to G transition at nucleotide pair 324 3, a tRNA(Leu(UUR)) mutation of the mitochondrial gene. This mutation was identified in four pedigrees from among 300 unrelated patients. Di abetes mellitus cosegregated with the mutation, except in one young su bject, and was maternally inherited. Long-term follow-up revealed that the underlying disorder, in affected individuals, is a progressive im pairment of insulin secretion. In accordance with this finding, the mu tation was found to be highly prevalent in a diabetes mellitus subset termed slowly progressive IDDM; the mutation was identified in 3 out o f 27 subjects enrolled in the prospective study of islet cell antibody (ICA)-positive, initially non-insulin-dependent diabetic Japanese pat ients, who are at high risk of progressing to insulin dependence over several years. The histologic characteristics of slowly progressive in sulin-dependent diabetes mellitus include substantial loss, though inc omplete, of pancreatic beta-cells. Mitochondrial gene defects in beta- cells could therefore cause glucose-induced signalling defects as well as beta-cell loss. This would explain the wide range of diabetic phen otypes, from NIDDM to IDDM, in patients with this mitochondrial gene m utation.