DEVELOPMENT OF HYPERGLYCEMIA AND INSULIN-RESISTANCE IN CONSCIOUS GENETICALLY DIABETIC (C57BL/KSJ DB/DB) MICE

A bolus injection of insulin dose-dependently reduced plasma glucose levels in genetically diabetic (db/db) mice and their normoglycaemic littermates (+/+ mice) aged 5, 8 and 12 weeks. Compared between the groups, the dose-response curves showed that insulin resistance was already present in the 5-week-old db/db mice when they were still normoglycaemic. The minimum effective dose of insulin was lower in the +/+ (32 mu g/kg) than in the db/db (100 mu g/kg) mice and the maximum response which was obtained at 320-1000 mu g/kg of the hormone was higher in the former (about 80 %) than in the latter (about 55 %). Although the basal plasma glucose levels in the db/db mice were significantly increased with age as compared with those in the +/+ mice, the insulin response curves were identical in the db/db mice from 5 to 12 weeks of age. The number of insulin binding sites were significantly decreased by 22-50 % (5-12-week-old) in the liver plasma membrane from the db/db mice compared with that from the +/+ mice, while its affinity was not significantly changed between the groups. Streptozotocin (100 mg/kg, i.p.) treatment increased the number of insulin receptors in the db/db mice to a number comparable with those in the +/+ mice. Coinciding with the change, the hypoglycaemic action of insulin was slightly enhanced in the streptozotocin-treated db/db mice compared with that in nontreated dbidb mice, but was still considerably depressed when compared with that in +/+ mice. It is concluded that a simple dose-response study using a bolus injection of insulin can detect insulin resistance in db/db mice which occurred before the manifestation of hyperglycaemia and remained constant during the course of developing hyperglycaemia. Down-regulation of insulin receptors due to the hyperinsulinaemia may play only a part in the insulin resistance.