AUTOREGULATION OF HEPATIC GLUCOSE-PRODUCTION

In vitro evidence indicates that the liver responds directly to change s in circulating glucose concentrations with reciprocal changes in glu cose production and that this autoregulation plays a role in maintenan ce of normoglycemia. Under in vivo conditions it is difficult to separ ate the effects of glucose on neural regulation mediated by the centra l nervous system from its direct effect on the liver. Nevertheless, it is clear that nonhormonal mechanisms can cause significant changes in net hepatic glucose balance. In response to hyperglycemia, net hepati c glucose output can be decreased by as much as 60-90% by nonhormonal mechanisms. Under conditions in which hepatic glycogen stores are high (i.e. the overnight-fasted state), a decrease in the glycogenolytic r ate and an increase in the rate of glucose cycling within the liver ap pear to be the explanation for the decrease in hepatic glucose output seen in response to hyperglycemia. During more prolonged fasting, when glycogen levels are reduced, a decrease in gluconeogenesis may occur as a part of the nonhormonal response to hyperglycemia. A substantial role for hepatic autoregulation in the response to insulin-induced hyp oglycemia is most clearly evident in severe hypoglycemia (less than or equal to 2.8 mmol/l). The nonhormonal response to hypoglycemia appare ntly involves enhancement of both gluconeogenesis and glycogenolysis a nd is capable of supplying enough glucose to meet at least half of the requirement of the brain. The nonhormonal response can include neural signaling, as well as autoregulation. However, even in the absence of the ability to secrete counterregulatory hormones (glucocorticoids, c atecholamines, and glucagon), dogs with denervated livers (to interrup t neural pathways between the liver and brain) were able to respond to hypoglycemia with increases in net hepatic glucose output. Thus, even though the endocrine system provides the primary response to changes in glycemia, autoregulation plays an important adjunctive role.