beta-cell glucotoxicity in the Psammomys obesus model of type 2 diabetes

Deficient insulin secretion and relative hyperproinsulinemia are characteri stic features of type 2 diabetes. The gerbil Psammomys obesus appears to be an ideal natural model of the human disease because it shows increased ten dency to develop diet-induced diabetes, which is associated with moderate o besity. The disease is characterized by initial hyperinsulinemia, progressi ng to hypoinsulinemia associated with depleted pancreatic insulin stores an d an increased proportion of insulin precursor molecules in the blood and i slets. Although the proinsulin translational efficacy was found to be incre ased in hyperglycemic animals, insulin mRNA levels were not augmented and e xhibited a gradual decrease with disease progression. The development of hy perglycemia was associated with a transient increase in beta -cell prolifer ative activity, as opposed to a prolonged increase in the rate of beta -cel l death, culminating in disruption of islet architecture. The hypothesis th at glucotoxicity is responsible in part for these in vivo changes was inves tigated in vitro in primary islet cultures. Islets from diabetes-prone P. o besus cultured at high glucose concentrations displayed changes in beta -ce ll function that mimic those observed in diabetic animals. These changes in clude deficient insulin secretion, depleted insulin content, an increased p roportion of insulin precursor molecules, a progressive increase of DNA fra gmentation, and a transient proliferative response. Furthermore, insulin mR NA was not increased by short-term exposure of P. obesus islets to elevated glucose in vitro. It is proposed that beta -cell glucotoxicity in P. obesu s results from the inability of proinsulin biosynthesis to keep pace with c hronic insulin hypersecretion, The resulting depletion of the insulin store s may be related to deficient glucose-regulated insulin gene transcription, possibly due to defective PDX-1 (pancreatic duodenal homeobox factor-1) ex pression in the adult P. obesus. An additional glucotoxic effect involves t he loss of beta -cell mass in hyperglycemic P. obesus as a result of progre ssive beta -cell death without an adequate increase in the rate of beta -ce ll proliferation.