INSULIN-RESISTANCE ASSOCIATED WITH MATERNALLY INHERITED DIABETES AND DEAFNESS

Maternally inherited diabetes and deafness (MIDD) is a form of diabete s associated with mutation of mitochondrial DNA (mtDNA) that occurs in 1% to 2% of individuals with diabetes. Understanding the clinical cou rse and abnormalities in insulin secretion and action in affected indi viduals should allow better understanding of how this genetic defect a lters glucose metabolism. We report the clinical course of three indiv iduals with mtDNA mutations and deafness. Subjects no. 1 and 2 had dia betes not yet requiring insulin therapy, and subject no. 3, the son of subject no. 2, had normal glucose tolerance. Defective oxidative phos phorylation (OXPHOS) based on OXPHOS enzymology of skeletal muscle bio psy of subjects no. 1 and 2 showed activity of less than 5% of the tol erance level in complex III for subject no. 1 and in complexes I, I III, and IV for subject no. 2. Assessing insulin secretion using insul in response to intravenous glucose and insulin sensitivity based on mi nimal model analysis of an insulin-modified frequently sampled intrave nous glucose tolerance test (FSIGT), first-phase insulin secretion was abnormal in subjects no. 1 and 2 and normal in subject no. 3 (AUG, 57 , 93, and 1,235 pmol/mL, respectively). In contrast, all three subject s had low insulin sensitivity indices (0.04, 0.14, and 0.27 x 10(-4) x min/pmol/L, respectively). Subject no. 2, who underwent three FSIGT s tudies over a 16-month interval, showed transient improvement in insul in release in response to modification of diet and exercise (first-pha se insulin AUC, 57 pmol/min v 287 pmol/min 10 months later; fasting in sulin, 97 pmol/Lv237 pmol/L 10 months later), but by 16 months, first- phase insulin release and fasting insulin had decreased (AUG, 64 and 1 36 pmol/L, respectively) despite higher fasting glucose. We conclude t hat in our subjects with MIDD, insulin resistance is present and appea rs to precede defects in insulin release. (C) 1996 by W.B. Saunders Co mpany