Phenobarbital treatment enhances insulin-mediated glucose metabolism and improves lipid metabolism in the diabetic rat

Abstract

Previous studies with healthy volunteers and non-insulin-dependent diabetic (NIDDM) patients have shown a strong association between overall glucose metabolism and hepatic microsomal enzyme activity. In this study, the effects of 10-day oral administration of phenobarbital (PB), a potent inducer of the hepatic microsomal mixed-function oxidase system, on carbohydrate and lipid metabolism in the basal state and on glucose kinetics during submaximal hyperinsulinemic (5 mU · kg −1 · min −1 insulin) clamps were investigated in nondiabetic rats and in rats made diabetic by the intravenous (IV) administration of either low-dose (40 mg/kg) or high-dose (55 mg/kg) streptozocin (STZ). In control rats receiving PB in drinking water (0.5 mg/mL), serum insulin and triglyceride levels were diminished without any change in glucose and cholesterol concentrations in the fed state. Administration of PB in drinking water (0.25 mg/mL) to both groups of diabetic rats decreased their water intake and serum triglyceride levels in the absence of an effect on glucose, insulin, and cholesterol concentrations in the fed state. However, fasting serum glucose levels and basal glucose turnover rates were lower in both groups of diabetic rats receiving PB. PB treatment increased the heparin-releasable lipoprotein lipase (LPL) activity of epididymal fat in both control and low-dose diabetic groups; this was not assessed in the high-dose diabetic group. Neither peripheral glucose utilization nor hepatic glucose production during submaximal insulin clamps was modified by PB treatment in nondiabetic rats. In contrast, PB administration enhanced insulin-mediated peripheral glucose utilization, as well as suppression of hepatic glucose production, in both low-dose and high-dose diabetic groups. The stimulatory effect of PB on insulin-mediated glucose utilization in low-dose diabetic rats was confirmed by increased incorporation of (3- 3H)glucose into glycogen in the rectus muscle measured at the end of the clamp. In conclusion, (1) PB administration decreased fasting serum glucose levels and augmented insulin-mediated glucose metabolism in insulin-deficient diabetic rats, and (2) the triglyceride-lowering effect of PB in both nondiabetic and diabetic rats may be in part due to increased clearance by adipose tissue LPL.