The long-term objectives of this proposal are to elucidate the regulation of fractional hepatic extraction of insulin, glucagon and somatostatin and their role in regulation of hepatic carbohydrate metabolism. Conscious dogs with sampling catheters in the portal and hepatic veins and femoral artery and Doppler flow probes on the portal vein and hepatic artery will be studied. The role of the parasympathetic and sympathetic nervous system on the increased fractional hepatic extraction of insulin after oral glucose will be assessed. Since peripheral glucose infusion, in contrast to oral glucose, does not augment fractional hepatic extraction of insulin, gastric inhibitory polypeptide (GIP) will be infused into the portal system or mannitol given orally with peripherally infused glucose to determine whether fractional hepatic extraction of insulin can be increased to mimick that observed after oral glucose. We previously demonstrated that increased fractional hepatic extraction of insulin is not essential for the greater hepatic uptake of glucose after oral compared to peripheral infusion of glucose. The role of the fractional hepatic extraction of insulin and glucagon on glucose appearance, glucose disappearance and glucose clearance will be measured in the atropine, Alpha-and beta-adrenergic blocker experiments utilizing infusion of H3-3-glucose. The fractional hepatic extraction of insulin and several of its analogues and glucagon will be correlated with these parameters of carbohydrate metabolism. The role of hormone counterregulation, especially glucagon, in response to insulin-induced hypoglycemia in masking the hepatic effect of insulin will be investigated. This will be evaluated by infusing variable doses of insulin and analogues to cause graded amounts of hypoglycemia and counterregulation. The relationship between fractional hepatic extraction of insulin and glucagon and hepatic uptake of glucose after oral glucose will be examined in dogs in which endogenous insulin and glucagon secretion will be inhibited by somatostatin and graded amounts of the two hormones infused into the portal system. The validity of measurements of peripheral C-peptide to insulin molar ratio to assess hepatic extraction of insulin will be evaluated by comparing results obtained with this ratio and those from direct measurements.
