Improvement in glucose-induced insulin secretion in diabetic rats after long-term gliclazide treatment: A comparative study using different models of non-insulin-dependent diabetes mellitus induced by neonatal streptozotocin

Abstract

Understanding of the long-term action of sulfonylureas in humans with non-insulin-dependent diabetes mellitus (NIDDM) may be facilitated by studying the effect of long-term sulfonylurea administration to animal models of the disease. In this study two different versions of the neonatal streptozotocin-induced diabetes (STZ) rat model of NIDDM were used. The n5-STZ model (STZ on day 5 after birth), which is characterized by basal hyperglycemia, a marked reduction of pancreatic insulin stores, and insulin resistance, and the n0-STZ model (STZ on day of birth), which develops mild hyperglycemia, have an approximately 50% reduction in pancreatic insulin content, and no insulin resistance. The diabetic rats were given oral gliclazide (10 mg/kg/day) and compared with untreated diabetic rats and nondiabetic rats. Insulin secretion was studied the day after the last gliclazide dose using the isolated perfused pancreas preparation. In severely hyperglycemic n5-STZ rats (plasma glucose levels >16 mmol/L) the long-term gliclazide treatment did not lower the plasma glucose values, did not affect pancreatic insulin stores, and did not significantly modify in vitro insulin release in response to glucose or arginine. In moderately hyperglycemic n5-STZ rats (plasma glucose levels <16 mmol/L) the plasma glucose levels declined progressively and reached a mean of 8 mmol/L at the end of gliclazide therapy. The increase in pancreatic insulin stores in n5-STZ rats remained marginal. In the n0-STZ rats gliclazide treatment did not significantly modify the plasma glucose levels or the pancreatic insulin stores. After gliclazide therapy in both the n5-STZ gliclazide responder group and the n0-STZ group: (a) in vitro glucose-induced insulin secretion was increased three- to fivefold; (b) the response to arginine, which is increased in diabetic rats, was amplified by two- to threefold; (c) insulin release in response to gliclazide was unchanged. In conclusion, long-term gliclazide therapy augments stimulated insulin secretion in these two rat models of NIDDM and does not induce any refractoriness to short-term sulfonylurea administration. The improvement of β-cell function observed here was not related to the concomitant variations of hyperglycemia and/ or pancreatic insulin content.