Coupling of β-Cell Desensitization by Hyperglycemia to Excessive Stimulation and Circulating Insulin in Glucose-Infused Rats

Abstract

Nondiabetic rats were infused with glucose for 48 h to maintain moderate or marked hyperglycemia (mean blood glucose 13.2 +/- 0.7 or 22.8 +/- 0.3 mM, respectively). The two levels of hyperglycemia increased plasma insulin levels severalfold but decreased the insulin response to 27 mM glucose by 19 and 95%, respectively, versus saline infusion. Diazoxide (5 mg.kg-1.h-1), when continuously infused during the hyperglycemia protocols, completely inhibited the glucose-induced rise in plasma insulin levels. Diazoxide transformed beta-cell insensitivity to stimulation: glucose-induced insulin release was thus increased 318% after moderate hyperglycemia and 707% after marked hyperglycemia. These stimulatory effects of diazoxide were reversed by exogenous insulin infusion (8 or 2 U/24 h) in a dose-dependent manner. It is concluded that excessive beta-cell stimulation rather than glucotoxicity underlies hyperglycemia-induced beta-cell insensitivity. Effects of hyperinsulinemia can form part of the mechanisms whereby excessive stimulation affects beta-cell secretion.

Chronic Exposure to Excess Nutrients Left-shifts the Concentration Dependence of Glucose-stimulated Insulin Secretion in Pancreatic β-Cells

“…Further research is needed to clarify this distinction and to determine the relationship between insulin content and secretion in vivo. Interestingly, a previous study showed that DZ administration during sustained glucose infusion preserved insulin content and enhanced GSIS from isolated islets ex vivo (50).…”

Glucose-induced [Ca2+]i abnormalities in human pancreatic islets: important role of overstimulation.

“…Our experiments with diazoxide served to probe the importance of overstimulation for the desensitized insulin response to glucose and the [Ca 2+ ] i abnormalities seen after high-glucose culture. The choice of diazoxide was motivated by its inhibitory effect on glucose-induced insulin secretion, the swift reversibility thereof after 48 h of exposure time in vivo in rats (19) and after 20-22 h of culture of rat pancreatic islets (15), and the low toxicity in clinical settings (39).…”

“…Using animal models of diabetes, we (15,19) and others (20) have demonstrated that overstimulation exerts a profound desensitizing influence on insulin responses to glucose. These studies used diazoxide as a probe for avoiding overstimulation.…”

Too much of a good thing: why it is bad to stimulate the beta cell to secrete insulin

“…Treatment with the insulin secretion inhibitor diazoxide prevents impairment of beta cell function in rats administered a 48 h glucose infusion [22], in 90% pancreatectomised diabetic rats [23] and in streptozotocintreated rats [24]. Furthermore, treatment of patients with type 2 diabetes with diazoxide or somatostatin resulted in improved glucagon-and tolbutamide-induced insulin secretion [25] and restored insulin pulsatility and the insulin/ proinsulin ratio in vitro [26].…”