There is abundant evidence that the autonomic nervous system is involved in regulation of hepatic substrate balance and metabolism. In 1963, Russek postulated the presence of glucoreceptors in the hepatoportal region which communicated information about glycemia to feeding centers in the brain via the vagus nerve.’Numerous investigations since that time have provided direct evidence of reciprocal control of hepatic glycogen and substrate metabolism by the sympathetic and parasympathetic nervous systems. This work has been reviewed in detailZ3 Briefly, stimulation of the sympathetic nervous system, whether at the level of the hepatic hilus, the subdiaphragmatic hepatic branch of the splanchnic nerve, or the ventromedial hypothalamus (VMH), increases glycogenolysis and. hepatic glucose production. VMH stimulation also increases the activity of hepatic phosphoenolpyruvate carboxykinase (PEPCK), which catalyzes the rate-limiting step in gluconeogenesis. 2* 3 Parasympathetic stimulation, either by stimulation of the hepatic branch of the vagus nerve or the lateral hypothalamus (LH), is followed by increased hepatic glucose uptake and glycogen storage. LH stimulation reduces PEPCK activity in the liver. 2S3 Moreover, the introduction of glucose into the portal via intestinal absorption or intraportal injection results in a decrease in the firing rate of afferent fibers in the hepatic branch of the vagus nerve and of glucose-sensitive neurons in the LH, 4S” with the firing rate being inversely proportional to the portal vein glucose leveL4 Decreases in the afferent firing rate in the vagus have been demonstrated to be accompanied by increases in the efferent firing rate in the pancreatic branch of the vagus, thus contributing to an increase in insulin secretion? For three decades evidence has accumulated that administration of glucose either enterally or directly into the portal vein results in enhancement of net hepatic (or splanchnic) glucose uptake (NHGU), in comparison with NHGU observed during peripheral intravenous glucose delivery.*-” In early studies, it was not clear how much of this enhancement was due to the increased insulin secretion occurring in response to enteral or intraportal glucose delivery, and how much was due to an independent mechanism. Consequently our laboratory carried out a series of experiments in the conscious dog in which NHGU was measured during peripheral and intraportal glucose delivery,. with somatostatin being administered in order to suppress pancreatic endocrine secretion and insulin and glucagon being infused intraportally. Under conditions of basal insulinemia and glucagonemia, no NHGU occurred during hyperglycemia (mean arterial and portal plasma glucose concentrations 217 and 213 mg/dL, respectively) induced by peripheral glucose infusion.‘* On the other hand, portal glucose infusion to create the same hepatic glucose load, or mass of glucose reaching the liver,(with arterial and portal plasma glucose levels of 200 and 220 mg/dL, respectively) in the presence of basal insulin and glucagon levels resulted in significant NHGU (1.4 mg~ kg-1~ min-‘).‘6 When hyperinsulinemia (3-to 4-fold basal) was combined with hyperglycemia of peripheral origin (raising the hepatic glucose load 2-to 4-fold), NHGU did occur, but in all instances it was 2.5 to 3-fold less than during studies in which similar conditions existed but where some of the glucose was administered via the portal vein. 13-15 Only with intraportal glucose delivery did rates of NHGU reach the levels observed in response to oral glucose ingestion. 13 The difference in NHGU was not due simply to differences in portal vein glucose levels; at any …