Parallel reduction of pancreas insulin content and insulin secretion in 48-h tolbutamide-infused normoglycemic rats

The overworked-beta-cell hypothesis proposes that lowered glucose-potentiated insulin secretory responses in diabetes are secondary to hyperstimulated insulin secretion and depletion of the beta-cell insulin stores. We tested this hypothesis in normal rats using a 48-h infusion of 200 mg.kg(-1).day(-1) tolbutamide in 20% glucose. Insulin secretion was measured by in vitro pancreas perfusion. Twice daily blood glucose values were equal in the tolbutamide-infused and control rats. Pancreas insulin content was 47 +/- 7% that of the controls (P < 0.004). Insulin responses to 16.7 nmol/l glucose, 16.7 mmol/l glucose/10 mmol/l arginine, and 5.5 mmol/l glucose/10 mmol/l arginine were reduced in parallel, except for the first phase response to 16.7 mmol/l glucose/arginine. Pancreas amylin content was unchanged in the tolbutamide-infused rats as was amylin secretion, resulting in higher than normal stored and secreted amylin-to-insulin molar ratios. Importantly, a raised amylin-to-insulin ratio and a relatively unimpaired first versus second phase insulin response for high glucose/arginine both occur in diabetic rats. Thus, our results support the overworked-beta-cell hypothesis by showing chronic beta-cell stimulation without hyperglycemia replicates part of the beta-cell dysfunction found with diabetes.