The liver is a major site of uptake, degradation, and biologic action of insulin. It is not known, however, whether all of the hormone extracted by that organ exerts a biological effect or whether extraction may be independent of any physiological action. In addition, the rate of hepatic extraction affects peripheral levels of the hormone. The effects of insulin on glucose utilization (peripheral effect) and suppression of glucose production (hepatic effect) are dose-related processes with different sensitivities and insulin saturating levels (1). On this basis we evaluated the effects ofdifferences in fractional hepatic extraction of insulin with its resulting change in the concentrations and relative distribution of the hormone between the portal vein (predominantly hepatic effect) and arterial (peripheral effect) blood compartments. Such alterations may produce different contributions by the liver and peripheral tissues to the ensuing hypoglycemia. Since hypoglycemia triggers counterregulatory hormone secretion, which increases glucose production (2-7), this may modify the effect of insulin on hepatic glucose production. To examine these questions we compared insulin and sulfated insulin, which has markedly lower hepatic extraction, on the mechanism of hypoglycemia. This involved measurements of their effects on glucose levels, appearance, disappearance, and clearance, and the counterregulatory responses ofglucagon. Their binding to liver plasma membranes and these various interrelationships were also examined.Our data indicate that the significantly lower hepatic extraction of sulfated insulin caused higher concentrations of the hormone and significantly different relative distribution between the portal vein and arterial blood compartments. This results in significantly different contributions by the liver and peripheral tissues to the same hypoglycemia and was associated with greater counterregulatory effect on glucose production.
Methods
Materials