Chronic suppression of insulin by diazoxide alters the activities of key enzymes regulating hepatic gluconeogenesis in Zucker rats

Objectives: Chronic attenuation of hyperinsulinemia by diazoxide (DZ), an inhibitor of glucose-mediated insulin secretion, improved insulin sensitivity and glucose tolerance and caused down-regulation of lipid metabolizing enzymes in adipose tissue and decreased the rate of weight gain in mildly hyperglycemic obese Zucker rats. Since the liver plays a central role in glucose homeostasis, we studied the effect of chronic insulin suppression on key insulin-sensitive enzymes regulating hepatic gluconeogenesis. Methods: DZ (150 mg/kg per day) or vehicle (control) was administered to 7-week-old female obese and lean Zucker rats for a period of 4 weeks. Results: DZ-treated animals showed lower fasting plasma insulin levels (P < 0.001) than their controls. Plasma glucose levels were lower in DZ obese rats than in controls (P < 0.001), without a significant change in DZ lean animals. DZ had no effect on glucose transporter 2 protein expression in either strain. DZ treatment resulted in lower hepatic glucokinase (P < 0.001) and glucose-6-phosphatase (P < 0.0001) and phosphoenolpyruvate carboxykinase (PEPCK) activities only in obese rats compared with controls (P < 0.001). However, DZ-treated lean rats demonstrated higher PEPCK activity than controls (P < 0.002). DZ-treated animals demonstrated enhanced hepatic glucose-6-phosphate content (P < 0.01), glycogen synthase activity (P < 0.0001) and glycogen content (P < 0.02) compared with their controls despite increased hepatic glycogen phosphorylase a activity in these animals (P < 0.02). Conclusions: Chronic suppression of hyperinsulinemia in obese Zucker rats by DZ decreased the activities of key enzymes regulating hepatic gluconeogenesis, implying that attenuation of the hyperinsulinemic state by DZ may be therapeutically beneficial.