FUNCTIONAL AND METABOLIC PERTURBATIONS IN ISOLATED PANCREATIC-ISLETS FROM THE GK RAT, A GENETIC MODEL OF NONINSULIN-DEPENDENT DIABETES

Spontaneously diabetic nonobese GK rats exhibit high basal plasma glucose and insulin levels and a poor insulin secretory response to glucose. We studied insulin biosynthesis, insulin release, and glucose metabolism in freshly isolated islets from GK rats and control Wistar rats. In GK rats, islet insulin content was decreased when expressed per islet but normal when related to DNA content. In the presence of a low concentration (2.8 mm) of glucose both (pro)insulin and total protein biosynthesis was doubled in islets from GK rats. As judged from the (pro)insulin/total protein synthesis ratio, (pro)insulin biosynthesis was normally stimulated by 16.7 mm glucose. In islets from diabetic rats both basal and glucose-stimulated insulin release were dramatically decreased. A reduced secretory response to 10 mm leucine or 10 mm leucine plus 10 mm glutamine and a lack of response to 10 mm monomethylsuccinate were observed. By contrast the insulinotropic capacity of nonnutrient secretagogues such as 62 muM gliclazide or the combination of 2 mM Ba2+ and 1.4 mm theophylline in the absence of extracellular Ca2+ remained normal. Glucose oxidation (estimated as the production Of (CO2)-C-14 from D-[6-C-14]glucose) was severely impaired, whereas no major alteration of glycolytic flux (as judged from the conversion Of D-[5-H-3]glucose to (H2O)-H-3) could be detected. Accordingly, the D-[6-C-14]glucose Oxidation/D-[5-H-3]glucose use ratio was less markedly increased in response to a rise in glucose concentration in islets from GK rats than in islets from control rats. Thus, in islets from diabetic GK rats, glucose-induced insulin release but not insulin biosynthesis was impaired. This defect is associated with, and probably at least in part due to, a deficient oxidative metabolism of glucose in islet mitochondria.