Diazoxide-Induced Hyperglycemia In Rats Is Regulated By Modulation Of Calcium Receptor Activity

The mechanism of insulin secretion by pancreatic beta-cells includes closure of the K-ATP channels, depolarization of plasma membrane and stimulation of the Cat - influx. The increase of intracellular Camay also be induced by activation of the phospholipase C (PLC)- coupled calcium receptor (CaR) that is present in pancreatic islets. Diazoxide increases blood glucose concentration by inhibiting pancreatic insulin secretion. The mechanism of action of diazoxide involves opening of K-ATP channels, cell membrane hyperpolarization, and inhibition of Ca2+ influx into the cells. The present study was designated to determine the in vivo effects of CaR activation by R-568 and CaR inhibition by NPS 2143 on plasma glucose and insulin levels in the presence of diazoxide. Wistar rats, after 14 h fasting, were anesthetized with inactin and loaded ip with diazoxide 40 mg/kg b.w.. R-568 and NPS2143 were given iv in doses 1 and 2 mg/kg b.w., respectively. Blood glucose, Ca2+ and insulin levels were determined in selected time points while blood pressure was continuously monitored during the experiment. Diazoxide significantly increased blood glucose level in all tested groups. However, as compared to the rats receiving diazoxide alone, glucose concentration was lower in diazoxide/R-568 group, whereas markedly higher in diazoxide/NPS2143 group. Adversely, insulin level was higher in diazoxide/R-568 and lower in diazoxide/NPS2143 rats, than in animals given diazoxide alone. These results highlight the importance of CaR activity in diazoxide-induced hyperglycemia and hypoinsulinemia.