Rescue of beta-cell exhaustion by diazoxide after the development of diabetes mellitus in rats with streptozotocin-induced diabetes.

In this study, we attempted to demonstrate the possibility of rescuing beta-cell exhaustion by chronic intervention with an ATP-sensitive K(+) channel opener, diazoxide, which reduces the stress of insulin secretion, using rats with streptozotocin-induced diabetes. Three groups of male Wistar rats: (i) controls (n = 7), (ii) streptozotocin (30 mg/kg i.v.)-induced diabetic rats (n = 10), and (iii) streptozotocin-induced diabetic rats treated with diazoxide 30 mg/kg for 6 weeks (n = 10), were studied. Intraperitoneal 2-g glucose tolerance testing was performed every 2 weeks, and pancreatic tissue was examined after 6 weeks of treatment with diazoxide. The insulin concentration in diabetic rats treated with diazoxide was significantly higher than in diabetic rats without diazoxide (6.6 +/- 1.6 vs. 2.4 +/- 1.0 ng/ml, P < 0.05). The islet size and its cell number were reduced in diabetic rats compared to those in normal control rats. In normal control rats, 88% of pancreatic islet cells were insulin-positive, while 50% or less were positive in diabetic rats. However, islet size and its cell size appeared to be well preserved by diazoxide treatment. The average mass of islets in diazoxide-treated rats was significantly larger than that in untreated control animals. In addition, the degree of immunostaining for insulin was obviously higher in rats treated with diazoxide than in rats without diazoxide. Pancreatic proinsulin mRNA was restored in rats treated with diazoxide. The present study demonstrated that diazoxide protected from further damage the pancreatic beta-cells both functionally and morphologically in streptozotocin-induced diabetic rats by suppression of excessive insulin secretion. Our results strongly suggest the possibility that chronic intervention with an ATP-sensitive K(+) channel opener prevents the progress of deranged beta-cell function even after the development of diabetes mellitus.