The relative contributions of impaired insulin secretion and of tissue insensitivity to
insulin to the
carbohydrate intolerance of
uremia were investigated in 10 chronically uremic subjects. Two types of
glucose-clamp experiments were performed in each patient before and after 10 wk of thrice weekly
hemodialysis. In both types the
blood glucose concentration was maintained at a constant level by the periodic adjustment of a variable
glucose infusion with a negative feedback formula.Hyperglycemic clamp. The
blood glucose concentration was acutely raised and maintained 125 mg/dl above basal levels for 2 h. Since the
glucose concentration was held constant, the
glucose infusion rate is an index of
glucose metabolism (M). After dialysis M increased in all patients from an average of 4.23 to 6.30 mg/kg body wt per min (P < 0.001). The plasma
insulin responses (I) both pre- and postdialysis were biphasic with an early burst within the first 2-5 min, followed by a phase of gradually increasing
insulin concentration. After dialysis the plasma
insulin response diminished slightly. Consequently, the M/I ratio, an index of tissue sensitivity to endogenous
insulin, increased postdialysis in all subjects by an average of 92% (P < 0.01). Euglycemic clamp. The plasma
insulin concentration was acutely raised and maintained by a primecontinuous
insulin infusion. The
blood glucose concentration was held constant at the basal level by a variable
glucose infusion as above. M/I again is a measure of tissue sensitivity to
insulin (exogenous) and increased in all patients postdialysis by an average of 57% (P < 0.01). In two patients hepatic
glucose production was measured with tritiated
glucose during the euglycemic clamp and declined by 84% predialysis. A similar decrease (82%) was observed postdialysis. Thus, both the hyperglycemic and euglycemic clamp techniques demonstrated tissue insensitivity to
insulin to be the dominant
carbohydrate defect in
uremia. The surprising apparent lack of consistency in the change in beta cell response postdialysis is explained by the strong inverse correlation between beta cell sensitivity to
glucose and tissue sensitivity to
insulin (r = -0.920; P < 0.001). Those individuals who showed the most striking improvement in tissue sensitivity to
insulin actually decreased their serum
insulin response to
hyperglycemia; those whose improvement in tissue sensitivity was more modest showed increases in beta cell responses.