Development of hyperglycaemia 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 litter-mates (+/+ 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 micrograms/kg) than in the db/db (100 micrograms/kg) mice and the maximum response which was obtained at 320-1000 micrograms/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 non-treated db/db mice, but was still considerably depressed when compared with that in +/+ mice.(ABSTRACT TRUNCATED AT 250 WORDS)