Inhibition of central GABA_A receptors enhances hepatic glucose production and peripheral glucose uptake

Previous studies have demonstrated that intracerebroventricular (ICV) injection of bicuculline methiodide (BMI), a gamma-amkrobutyric acid receptor antagonist, increases plasma glucose concentrations. The purpose of the present study was to determine whether the hyperglycemic response was due to an increased rate of hepatic glucose production (HGP) or a change in the rate of glucose utilization. In vivo glucose flux was assessed in catheterized, conscious overnight fasted rats using [3-³H]glucose. ICV injection of BMI (10 nmol) increased glucose levels 60% after 30 min. This hyperglycemia resulted from a rapid increase in HGP that exceeded an increased rate of glucose utilization. No alteration in the glucose metabolic clearance rate, an index of the avidity of the body's tissues for glucose, was detected in BMI-Injected rats. BMI enhanced both hepatic gluconeogermals and glycogenolysis, since the reduction in War glycogen (19 μmol/g liver) could not totally account for all of the increased HGP. These metabolic alterations were associated with sustained increases in circulating concentrations of corticosterone, giucagon and catecholamines. Prior adrenalectomy completely abolished the BMI-induced increase in glucose flux and the reduction in tissue glycogen, despite the persistent hyperglucagonemia. These data indicate that, in the fasted condition, the hyperglycemia produced by central administration of BMI results from an increased rate of HGP (both gluconeogenesis and glycogenolysis) and not a reduction in the ability of tissues to use glucose. The concomitant elevation in glucose disposal was the result of an increased mass action effect. The enhanced glucose metabolic response to BMI appears mediated exclusively by an increased secretion of epinephrine from the adrenal medulla.