CLINICAL PHENOTYPES, INSULIN-SECRETION, AND INSULIN SENSITIVITY IN KINDREDS WITH MATERNALLY INHERITED DIABETES AND DEAFNESS DUE TO MITOCHONDRIAL TRNA(LEU(UUR)) GENE MUTATION

An A-to-G transition in the mitochondrial tRNA(Leu(UUR)) gene at base pair 3243 has been shown to be associated with the maternally transmit ted clinical phenotype of NIDDM and sensorineural hearing loss in whit e and Japanese pedigrees. We have detected this mutation in 25 of 50 t ested members of five white French pedigrees. Affected (mutation-posit ive) family members presented variable clinical features, ranging from normal glucose tolerance (NGT) to insulin-requiring diabetes. The pre sent report describes the clinical phenotypes of affected members and detailed evaluations of insulin secretion and insulin sensitivity in s even mutation-positive individuals who have a range of glucose toleran ce from normal (n = 3) to impaired (n = 1) to NIDDM (n = 3). Insulin s ecretion was evaluated during two experimental protocols: the first in volved the measurement of insulin secretory responses during intraveno us glucose tolerance test, hyperglycemic damp, and intravenous injecti on of arginine. The second consisted of the administration of graded f end oscillatory infusions of glucose and studies to define C-peptide k inetics. This protocol was aimed at assessing two sensitive measures o f beta-cell dysfunction: the priming effect of glucose on the glucose- insulin secretion rate (ISR) dose-response curve and the ability of os cillatory glucose infusion to entrain insulin secretory oscillations. Insulin sensitivity was assessed by euglycemic-hyperinsulinemic clamp. Evaluation of insulin secretion demonstrated a large degree of betwee n- and within-subject variability. However, all subjects, including th ose with NGT, demonstrated abnormal insulin secretion on at least one of the tests. In the four subjects with normal or impaired glucose tol erance, glucose failed to prime the ISR response, entrainment of ultra dian insulin secretory oscillations was abnormal, or both defects were present. The response to arginine was always preserved, including in subjects with NIDDM. Insulin resistance was observed only in the subje cts with overt diabetes. In conclusion, the pathophysiological mechani sms responsible for the development of NIDDM and insulin-requiring dia betes in this syndrome are complex and might include defects in insuli n production, glucose toxicity, and insulin resistance. However, our d ata suggest that a defect of glucose-regulated insulin secretion is an early possible primary abnormality in carriers of the mutation. This defect might result from the progressive reduction of oxidative phosph orylation and implicate the glucose-sensing mechanism of beta-cells.