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 a 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 × 10^-8 M and 4 × 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.