Hepatic
glucose uptake (HGU) is critical for maintaining normal postprandial glucose
metabolism. Insulin is clearly a key regulator of HGU, but the physiologic mechanisms
by which it acts have yet to be established. This study sought to determine the
mechanisms by which insulin regulates liver glucose uptake under
postprandial-like conditions (hyperinsulinemia, hyperglycemia, and a positive
portal vein to arterial glucose gradient). Portal vein insulin infusion
increased hepatic insulin levels 5-fold in healthy dogs. In one group (n=7),
the physiologic response was allowed to fully occur, while in another (n=7),
insulin’s indirect hepatic effects, occurring secondary to its actions on adipose
tissue, pancreas, and brain, were blocked. This was accomplished by infusing
triglyceride (intravenous), glucagon (portal vein), and inhibitors of brain
insulin action (intracerebroventricular) to prevent decreases in plasma free
fatty acids or glucagon, while blocking increased hypothalamic insulin
signaling for 4h. In contrast to the indirect hepatic effects of insulin, which
were previously shown capable of independently generating a half-maximal stimulation
of HGU, direct hepatic insulin action was by itself able to fully stimulate
HGU. This suggests that under hyperinsulinemic/hyperglycemic conditions insulin’s
indirect effects are redundant to direct engagement of hepatocyte insulin
receptors.