Parallel Reduction of Pancreas Insulin Content and Insulin Secretion in 48-h Tolbutamide-Infused Normoglycemic Rats

Abstract

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 x kg(-1) x 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 mmol/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.

Prenatal tolbutamide treatment alters plasma glucose and insulin concentrations and negatively affects the postnatal performance of chickens

“…Ball et al [39,40] and McClenaghan et al [41] demonstrated that chronic in vitro exposure of rat pancreatic b-cells to tolbutamide for 18 to 144 h led to a decline in their insulinotrophic activity because of a direct desensitization of pancreatic b-cells and a declined insulin secretion and pancreatic insulin content. Similar findings were also reported in rats after in vivo treatment of tolbutamide [42,43]. As higher insulin levels and lower plasma glucose concentrations in tolbutamidetreated embryos were observed 8 and 24 h after each tolbutamide injection, desensitization of b-cells in broiler embryos did not seem to occur or the dose of tolbutamide was high enough to continue the stimulation of insulin secretion.…”

Diethyldithiocarbamate-mediated zinc ion chelation reveals role of Cav2.3 channels in glucagon secretion

“…Rather, our study suggests a causative role for excessive insulin release and depleted insulin stores, akin to β-cell exhaustion in rodent models of T2DM, where loss of GSIS is often preceded by excessive insulin secretion [55,56]. In this context, it is particular intriguing that transiently (48 h) upregulating insulin secretion in non-diabetic rats sufficiently to lower β-cell insulin content has been shown to selectively reduce the second phase insulin response by 50% [57]. In any event, our findings suggest that Ca v 2.3 channel dysfunction per se is associated with basal hyperinsulinemia and possibly increased glucose sensitivity but normal glucose responsiveness of islet insulin secretion.…”

Dynamics of insulin sensitivity, β-cell function, and β-cell mass during the development of diabetes in fa/fa rats

“…Glucose infusion and partial pancreatectomy studies have clearly demonstrated acute adaptation of ␤-cell function in response to increased insulin demand (15,27). However, the concept of ␤-cell exhaustion would suggest that ␤-cell hypersecretion may not be sustainable in the long run (11,13). Studies of function in obese Zucker rats have also generated mixed results.…”

“…Chronic glucose infusion and partial pancreatectomy studies have clearly shown ␤-cell function to be plastic and responsive to acute changes (15,27). However, other studies have shown chronic hypersecretion to be unsustainable, termed ␤-cell exhaustion (11). Overall, the relative contributions of ␤ m and function to the hyperinsulinemia of obesity remain unresolved.…”