EFFECTS OF A 7-DAY INFUSION OF GLUCOSE ON INSULIN-SECRETION IN-VIVO AND IN-VITRO IN VENTROMEDIAL HYPOTHALAMIC-LESIONED OBESE RATS

Excessive stimulation of insulin secretion may be one cause of the bet a-cell dysfunction induced by hyperglycemia. We investigated a possibl e link between the prior endogenous hypersecretion of insulin and this dysfunction by performing a 7-day glucose infusion (50% wt/vol, 1.2 m l/h) on ventromedial hypothalamic VMH-lesioned hyperinsulinemic rats. Intravenous glucose tolerance tests (IVGTT 1.0 g/kg) revealed that a 3 -day glucose infusion enhanced the insulin responses in both the sham- and VMH-lesioned rats compared with saline infusions. A similar 7-day glucose infusion enhanced the insulin response to glucose in sham-les ioned rats but not in VMH-lesioned rats. Batch-incubation of islets is olated from sham-lesioned rats showed an enhanced insulin response to glucose after 7 days of glucose treatment compared with the saline inf usions. Conversely, the glucose infusion in VMH-lesioned rats markedly suppressed the in vitro insulin response. In sham- and VMH-lesioned r ats. similar islet insulin contents were produced by saline and glucos e treatments. Electron microscopy revealed that glucose infusions impa ired the granule-releasing function of the beta-cells in VMH-lesioned rats, while insulin synthesis was accelerated in either group. These f indings support the notion that excessive secretion is partly responsi ble for the beta-cell dysfunction induced by hyperglycemia without sig ns of exhaustion.