Mitochondrial diabetes mellitus—glucose‐induced signaling defects and β‐cell loss

Japanese diabetic patients whose mothers were also diabetic were screened, using peripheral leukocytes, for an A to G transition at nucleotide pair 3243 of the mitochondrial gene, a tRNA^Leu(UUR) mutation. This mutation was identified in four pedigrees from among 300 unrelated patients. Diabetes mellitus cosegretated with the mutation, except in 1 young subject, and was maternally inherited. Long‐term follow‐up revealed that the underlying disorder in affected members is a progressive impairment of insulin secretion. In accord with this finding, this mutation was found to be highly prevalent in a subset of diabetes mellitus called slowly progressive IDDM; the mutation was identified in 3 of 27 Japanese patients enrolled in the prospective study of islet cell antibody (ICA)‐positive, initially non–insulin‐dependent diabetic patients, who are very likely to become insulin dependent in several years. The histologic characteristics of slowly progressive IDDM include loss, though incomplete, of pancreatic β‐cells. Mitochondrial gene defects in β‐cells could therefore cause glucose‐induced signaling defects as well as β‐cell loss, which explains the wide range of diabetic phenotypes, from NIDDM phenotype to IDDM, in patients with this mitochondrial gene mutation. © 1995 John Wiley & Sons, Inc.