Stimulatory effect of vasoactive intestinal peptide on glycogenolysis and gluconeogenesis in isolated rat hepatocytes: antagonism by insulin.

We have studied the effect of Vasoactive Intestinal Peptide (VIP) on glycogenolysis and gluconeogenesis (as measured by the conversion of [U-14C]pyruvate into glucose) in hepatocytes isolated from fed rats. The influence of VIP on glycogen phosphorylase alpha and pyruvate kinase activities, as well as on cAMP levels, was also evaluated. In addition, the possible antagonism of insulin on these VIP-mediated effects was investigated. VIP enhanced both glycogenolysis and gluconeogenesis in a dose-dependent manner. At 10(-6) M VIP, both processes were increased 2-fold as compared to the basal values; the calculated half-maximal stimulatory concentrations were 2.5 x 10(-8) M and 4 x 10(-8) M, respectively. VIP also caused a dose-dependent activation of glycogen phosphorylase and inactivation of pyruvate kinase. At 10(-6) M VIP, glycogen phosphorylase a was increased 3-fold and pyruvate kinase activity was reduced by 46%. The addition of 10(-7) M VIP to the incubation medium caused a 2-fold increase of basal cAMP levels. All these VIP-mediated effects were markedly blocked by the presence of 10(-8) M insulin. As compared to glucagon (10(-7) M) the potency of an equimolar concentration of VIP, in terms of stimulation of gluconeogenesis, inactivation of pyruvate kinase, and activation of glycogen phosphorylase ranged from 35-45%. Our results indicate that VIP increases hepatic glucose output through the stimulation of both glycogenolysis and gluconeogenesis. These effects seem to be mediated by a cAMP-dependent mechanism.