WHICH IS THE PRIMARY ETIOLOGIC EVENT IN OTSUKA LONG-EVANS TOKUSHIMA FATTY RATS, A MODEL OF SPONTANEOUS NON-INSULIN-DEPENDENT DIABETES-MELLITUS, INSULIN-RESISTANCE, OR IMPAIRED INSULIN-SECRETION

To identify the primary disorder causing diabetes mellitus in a model rat (Otsuka Long-Evans Tokushima Fatty [OLETF]) with non-insulin-dependent diabetes mellitus (NIDDM), we studied the temporal relationship between insulin resistance and impairment of pancreatic beta-cell function. Groups of 28 male OLETF rats and male nondiabetic control Long-Evans Tokushima Otsuka (LETO) rats were given an intravenous (IV) glucose and glucagon tolerance test (IVGTT) and hyperinsulinemic euglycemic cramp tests at 10, 16, 24, and 40 weeks of age. After the euglycemic clamp test, abdominal fat was measured and the pancreas was examined histologically. At 16 weeks of age, insulin-mediated whole-body glucose uptake as measured by the hyperinsulinemic euglycemic clamp technique was significantly reduced in OLETF rats (glucose infusion rate [GIR], 40.9 +/- 4.2 mu mol/kg . min) as compared with LETO rats (78.4 +/- 6.9). On the other hand, plasma insulin responses to glucose and glucagon in OLETF rats were higher than those in LETO rats at 16 and 24 weeks of age, but clearly decreased at 40 weeks of age (Sigma immunoreactive insulin [IRI] to glucagon, 8.81 +/- 1.81 v 27.32 +/- 4.59 nmol . min in OLETF and LETO rats. respectively, P < .01). Abdominal fat deposition was significantly greater in OLETF rats than in LETO rats at all ages tested except 10 weeks. Pancreatic islets of OLETF rats became enlarged and fibrotic. These results demonstrated that insulin resistance preceded impairment of pancreatic beta-cell function in OLETF rats, and that insulin resistance seemed closely related to fat deposition in the abdominal cavity. Copyright (C) 1995 by W.B. Saunders Company