Effect of gliclazide treatment on insulin secretion and beta-cell mass in non-insulin dependent diabetic Goto-Kakisaki rats

The Goto-Kakisaki rat is a genetic non-overweight model of non-insulin-depe ndent diabetes mellitus. Adult Goto-Kakisaki rats exhibit a mild basal hype rglycaemia (11 mmol/l) with impaired glucose tolerance, elevated basal plas ma insulin level, a failure of insulin release in response to glucose toget her with a 50% depletion of the total pancreatic beta-cell mass and insulin stores. We have examined the effects of long-term (4 weeks) gliclazide tre atment on the severity of diabetes in adult male Goto-Kakisaki rats (10-12 weeks of age). Gliclazide was administered orally (10 mg/kg per day). Glicl azide-treated Goto-Kakisaki rats were evaluated against Wistar and untreate d Goto-Kakisaki rats. In the gliclazide-treated Goto-Kakisaki rats, basal p lasma glucose levels declined progressively reaching 8 mmol/l as a mean at the end of treatment, and their basal insulin levels decreased to values si milar to those in non-diabetic Wistar rats. Despite their total pancreatic beta-cell remaining unaffected, their pancreatic insulin stores were twice increased, with a similar improvement of the insulin content per individual beta-cell. Furthermore, the glucose-stimulated insulin release as evaluate d in vivo during an intravenous glucose tolerance-test was significantly im proved (twice increased) in the gliclazide-treated Goto-Kakisaki rats. This was correlated with a modest but significant enhancement of the early phas e of insulin release in vitro (isolated perfused pancreas), in response to glucose. However, the overall insulin response in vitro remained clearly de fective with no reappearance of the late phase of insulin release. The in v itro response to arginine (which was basically amplified in the Goto-Kakisa ki model) or to gliclazide were kept unchanged after the gliclazide treatme nt. In conclusion, chronic gliclazide does not exert any beta-cytotrophic e ffect, but improves beta-cell function in the adult Goto-Kakisaki rat as fa r as it lowers basal insulin release, increases beta-cell insulin stores, a nd increases the glucose-induced insulin release. (C) 1998 Elsevier Science B.V. All rights reserved.