ELECTROPHYSIOLOGICAL AND METABOLIC CHARACTERIZATION OF SINGLE BETA-CELLS AND ISLETS FROM DIABETIC GK RATS

We have used the whole-cell recording technique to determine whether A TP-sensitive potassium (K-ATP) currents, voltage-dependent Ca2+ curren ts, and exocytosis are different in single beta-cells from pancreatic islets of Goto-Kakizaki (GK) rats, a novel model of NIDDM, and normal rats. In addition, we have also measured the insulin secretory respons es, ATP content, and the rate of glucose metabolism in intact islets. Although the glucose sensitivity of the K-ATP current was similar betw een GK rats and controls, in the absence of glucose, K-ATP current den sity was larger in GK rats, which resulted in a more hyperpolarized me mbrane potential. Whole-cell Ca2+ currents were similar. By monitoring the cell capacitance with a fixed intracellular solution, no differen ce was detected in the exocytotic responses of beta-cells from normal and GK rats. In islets from GK rats, the rates of glucose utilization ([H-3]H2O production from 5-[H-3]glucose) and oxidation ([C-14]CO2 pro duction from U-[C-14]glucose) were not significantly different from co ntrols. Insulin secretion, however, was impaired (by 50%), and this wa s paralleled by a smaller increase in ATP content in response to stimu lation by 10 mmol/l glucose in islets from GK rats when compared with controls. Under conditions in which K-ATP channels were held open and the effects of glucose were independent of membrane potential, insulin release was still significantly lower in GK rat islets than in contro ls. These findings suggest that the impaired insulin secretion in isle ts from GK rats does not simply result from a failure to close K-ATP c hannels, nor does it result from an impairment in calcium secretion co upling.