The purpose of this study was to determine the role of pancreatic innervation in mediating exercise-induced changes in pancreatic hormone secretion and glucose kinetics. Dogs underwent surgery >16 days before an experiment, at which time flow probes were implanted on the portal vein and the hepatic artery, and Silastic catheters were inserted in the carotid artery, portal vein, and hepatic vein for sampling. In one group of dogs (DP) all nerves and plexuses to the pancreas were sectioned during surgery. A second group of dogs underwent sham denervation (SHAM). Pancreatic tissue norepinephrine was reduced by >98% in DP dogs. Each study consisted of basal (30 to 0 min) and moderate exercise (0 to 150 min, 100 m/min, 12% grade) periods. Isotope ([3-³H]glucose) dilution and arteriovenous differences were used to assess hepatic function. Arterial and portal vein glucagon and insulin concentrations and the rate of net extrahepatic splanchnic glucagon release (NESGR) were similar in DP and SHAM during the basal period. Arterial and portal vein glucagon and NESGR increased similarly in DP and SHAM during exercise. Arterial and portal vein insulin were similar during exercise. Arterial glucose, tracer-determined endogenous glucose production, and net hepatic glucose output were similar in DP and SHAM during the basal and exercise periods. These results demonstrate that pancreatic nerves are not essential to pancreatic hormone secretion or glucose homeostasis during rest or moderate exercise.