The contribution of hyperglycaemia and hypoinsulinaemia to the insulin resistance of streptozotocin-diabetic rats

Summary The relative contribution of hyperglycaemia and hypoinsulinaemia was evaluated in rats made diabetic by streptozotocin administration. Four groups of rats were studied: untreated normal rats; streptozotocin-diabetic; streptozotocin-diabetic treated with phlorizin (0.4 mg/kg body weight per day); streptozotocin-diabetic mildly treated with insulin (0.7 IU/day). In all groups, insulin action (responsiveness) was assessed with the euglycaemic (5.3 mmol/l) hyperinsulinaemic (524 mU/l) clamp technique combined with ³H-2-deoxy-D-glucose method, enabling determination of the glucose utilization index in various tissues. Responsiveness of the overall glucose utilization process to insulin was reduced by 28% in streptozotocin-diabetic rats (12.0±1.2 vs 16.5±0.6 mg·kg^–1·min^–1, p<0.001). This was associated with a significant reduction (p<0.05) in the glucose utilization index in all muscles studied (average=17.0 vs 32.1 ng·mg of tissue^–1·min^–1), in the heart (19.6 vs 39.5 ng·mg^–1·min^–1), brown adipose tissue (98.9 vs 178.0 ng·mg^–1·min^–1), skin (6.4 vs 13.1 ng·mg^–1·min^–1). Phlorizin treatment normalized plasma glucose levels without affecting those of insulin, and restored overall glucose utilization to normal (16.6±1.0mg·kg^–1·min^–1). This normalization was accompanied by a normalization of the glucose utilization index in all muscle types studied (29.2 ng·mg^–1·min^–1), in the heart (50.0ng·mg^–1·min^–1), brown adipose tissue (157.2 ng·mg^–1·min^–1), and skin (10.0 ng·mg^–1·min^–1). White adipose tissue, brain and gut were not affected. Mild insulin treatment with persistent hyperglycaemia was not able to significantly ameliorate glucose disposal (14.5±0.9 mg·kg^–1·min^–1) or the glucose utilization index of most individual tissues (muscle=18.4; heart=36.2; brown adipose tissue=148.0; skin=7.7 ng· mg^–1· min^–1). These data show that correction of hyperglycaemia in streptozotocin-diabetic rats normalizes insulin action, while partial correction of the hypoinsulinaemia fails to do so.