Interaction between genetic and dietary factors determines beta-cell function in Psammomys obesus, an animal model of type 2 diabetes

The gerbil Psammomys obesus develops nutrition-dependent diabetes. We studi ed the interaction between diet and diabetic predisposition for beta-cell f unction. A 4-day high-energy (HE) diet induced a 3-, 4-, and 1.5-fold incre ase in serum glucose, insulin, and triglycerides, respectively, in diabetes -prone (DP) but not diabetes-resistant (DR) P, obesus, Hyperglycemia and co ncurrent 90% depletion of islet immunoreactive insulin stores were partiall y corrected by an 18-h fast. In vitro early insulin response to glucose was blunted in both DR and DP perifused islets, The HE diet augmented early an d late insulin response in DR islets, whereas in DP islets, secretion progr essively declined. Dose-response studies showed a species-related increase in islet glucose sensitivity, further augmented in DP P, obesus by a HE die t, concomitant with a decreased threshold for glucose and a 55% reduction i n maximal response. These changes were associated with a fourfold increase in glucose phosphorylation capacity in DP islets, There were no differences in islet glucokinase (GK) and hexokinase (HK) K-m; however, GK V-max was 3 .7- to 4.6-fold higher in DP islets, and HK V-max was augmented 3.7-fold by the HE diet in DP islets, We conclude that the insulin-resistant P, obesus has an inherent deficiency in insulin release. In the genetically predispo sed P, obesus (DP), augmented islet glucose phosphorylation ability and die t-induced reduction of the glucose threshold for secretion may lead to inad equate insulin secretion and depletion of insulin stores In the presence of caloric abundance. Thus, genetic predisposition and beta-cell maladaptatio n to nutritional load seem to determine together the progression to overt d iabetes in this species. It is hypothesized that similar events may occur i n obese type 2 diabetic patients.