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

• Published in: European journal of pharmacology Vol. 361; no. 2; pp. 243 - 251
• Main Authors: Dachicourt, Nathalie, Bailbé, Danielle, Gangnerau, Marie-Noelle, Serradas, Patricia, Ravel, Denis, Portha, Bernard
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 20.11.1998; Elsevier
• Subjects: Administration, Oral; Animals; Biological and medical sciences; Blood Glucose - drug effects; Diabetes Mellitus, Type 2 - metabolism; General and cellular metabolism. Vitamins; Gliclazide; Gliclazide - pharmacology; Glucose Tolerance Test; Goto–Kakisaki rat; Hypoglycemic Agents - pharmacology; Insulin - metabolism; Insulin release; Insulin Secretion; Islets of Langerhans - drug effects; Islets of Langerhans - metabolism; Male; Medical sciences; Non-insulin dependent diabetes; Pharmacology. Drug treatments; Rats; Sulfonylurea; β-cell mass; Gliclazide; Goto–Kakisaki rat; β-cell mass; Insulin release; Non-insulin dependent diabetes; Sulfonylurea; Endocrinopathy; Endocrine gland; Rat; Treatment efficiency; Rodentia; Oral administration; Strain specificity; Non insulin dependent diabetes; In vitro; Insulin; Long term; Biological activity; Endocrine secretion; In vivo; Vertebrata; Chemotherapy; Hypoglycemic agent; Mammalia; Animal; Sulfonylureas; Genetics; Endocrine pancreas
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/S0014-2999(98)00718-3

The Goto–Kakisaki rat is a genetic non-overweight model of non-insulin-dependent diabetes mellitus. Adult Goto–Kakisaki rats exhibit a mild basal hyperglycaemia (11 mmol/l) with impaired glucose tolerance, elevated basal plasma insulin level, a failure of insulin release in response to glucose together with a 50% depletion of the total pancreatic β-cell mass and insulin stores. We have examined the effects of long-term (4 weeks) gliclazide treatment 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). Gliclazide-treated Goto–Kakisaki rats were evaluated against Wistar and untreated Goto–Kakisaki rats. In the gliclazide-treated Goto–Kakisaki rats, basal plasma glucose levels declined progressively reaching 8 mmol/l as a mean at the end of treatment, and their basal insulin levels decreased to values similar to those in non-diabetic Wistar rats. Despite their total pancreatic β-cell remaining unaffected, their pancreatic insulin stores were twice increased, with a similar improvement of the insulin content per individual β-cell. Furthermore, the glucose-stimulated insulin release as evaluated in vivo during an intravenous glucose tolerance-test was significantly improved (twice increased) in the gliclazide-treated Goto–Kakisaki rats. This was correlated with a modest but significant enhancement of the early phase of insulin release in vitro (isolated perfused pancreas), in response to glucose. However, the overall insulin response in vitro remained clearly defective with no reappearance of the late phase of insulin release. The in vitro response to arginine (which was basically amplified in the Goto–Kakisaki model) or to gliclazide were kept unchanged after the gliclazide treatment. In conclusion, chronic gliclazide does not exert any β-cytotrophic effect, but improves β-cell function in the adult Goto–Kakisaki rat as far as it lowers basal insulin release, increases β-cell insulin stores, and increases the glucose-induced insulin release.