GLUCAGON-STIMULATED GLYCOGENOLYSIS - TIME-DEPENDENT SENSITIVITY TO INSULIN

The effects of physiological increments in portal vein glucagon and insulin on net hepatic glucose production (NHGP) were studied in isolated [dog] liver that was cross-perfused with whole blood. The preparation was designed such that counterregulatory responses to intraportal hormone infusion were minimized, thus presumably revealing the responses of the liver alone. Basal hepatic glucose production was 5.9 .+-. 0.9 SE mg/min per 100 g liver. A stepwise increase in portal glucagon (100 pg/ml) induced the following pattern of glucose production by the liver: NHGP tripled within 15 min and declined thereafter, reaching a production at 60 min that was twice the prestimulation glucose production rate. During the 2nd h of constant glucagon stimulation, production declined at a slow rate (by 1.2 mg/min per 100 g each 30 min) and was still significantly above the preglucagon production rate at 2 h. Termination of glucagon caused NHGP to fall to the prestimulation value within 20 min. Tracer studies indicated that gluconeogenesis followed a dynamic pattern similar to that of total net glucose production. When portal glucagon was increased by 100 pg/ml for 2 h, and insulin was infused intraportally along with glucagon during the 2nd h only (elevating portal insulin 200 .mu.U[units]/ml), insulin completely reversed the stimulatory effect of increased glucagon on production. Administering the same dose of insulin before and during a glucagon stimulus did not prevent at least the initial glucagon-stimulated peak in NHGP. Insulin appeared to accelerate the decline in production that followed the initial peak. Apparently in the absence of counterregulatory responses the hepatic response to a physiological glucagon stimulus is only slowly evanescent, and the potency of insulin in inhibiting glucagon-stimulated glucose production depends not only on the insulin-to-glucagon ratio, but also on the order of hormone administration. The complex nature of the interaction between insulin and glucagon in regulating hepatic glucose production was emphasized.