Effects of Insulin on Hepatic Glucose Metabolism and Glucose Utilization by Tissues

Abstract

The effects of administered insulin and of endogenous insulin secreted in response to a glucose load were studied in unanesthetized dogs, utilizing C-14 glucose to measure glu-cose production and uptake, and the incorporation of the carbon atoms of circulating glucose into the cellular constituents of the liver. In accord with earlier studies, it was found that administered insulin in-creases the rate of total glucose uptake during the development of hypoglycemia, during periods in which the continued infusion of insulin maintains a hypoglycemic state and also during periods of insulin infusion wherein hypoglycemia is prevented by the simultaneous intravenous infusion of glucose. This effect of insulin on utilization occurs independently of whether the animal has been maintained on a mixed diet (38% carbohydrate) or a high (78%) carbohydrate diet, or has been fasted for more than eight days, or has been treated with phlorizin. Increased glucose uptake continues during the period of restoration of the blood sugar level which occurs after termination of the insulin infusion. Increased glucose utilization occurs also during endogenous insulin secretion evoked by a glucose load, and even during infusion of glucose at a modest rate, where the blood sugar level is only slightly elevated. Under several conditions insulin has been found to inhibit glucose production by the liver. As reported in earlier studies, there is an initial effect of insulin, discernible before marked hypoglycemia has developed, to lower hepatic glucose production below its pre-insulin level. Also as described previously, hepatic glucose production during a hypoglycemia induced by a continuous insulin infusion is restrained by the insulin, inasmuch as hepatic glucose production (which may have equaled or exceeded the pre-insulin rate during the infusion) undergoes a further increase when insulin infusion is stopped. In the present studies a new manifestation of this action of insulin has been demonstrated, utilizing the animal maintained on a high (78%) carbohydrate diet. In this animal insulin infused together with enough glucose to prevent hypoglycemia reduces hepatic glucose production below the pre-insulin level over prolonged periods of time. Moreover, a prolonged, slowly increasing infusion of glucose which evokes endogenous insulin secretion and avoids the development of a marked hyperglycemia also reduces the rate of hepatic glucose production. More studies are required to determine the influence of dietary regimen on these findings. Under certain conditions the inhibiting effect of insulin on hepatic glucose production is not seen. The restraining action of continued insulin infusion is absent during insulin-induced hypo-glycemia in the animal whose liver glycogen stores have been depleted by prolonged fasting or by fasting together with phlorizinization; how-ever, in the acutely phlorizinized animal, when active glycogenolysis is proceeding, insulin often reduces the elevated rate of hepatic glucose production. Thus it appears that insulin restrains or decreases glu-cose production at a time when hepatic glycogenolysis is taking place. Endogenous insulin evoked by a slow prolonged glucose infusion in the absence of marked hyperglycemia increased the portion of the glucose carbon incorporated into liver constituents out of proportion to the simultaneous increase in over-all glucose uptake. The increased incorporation of C-14 was particularly evident in the liver glycogen fraction.