In vitro evidence indicates that the liver responds directly to changes in circulating glucose concentrations with reciprocal changes in glucose production and that this autoregulation plays a role in maintenance of normoglycemia. Under in vivo conditions it is dif®cult to separate the effects of glucose on neural regulation mediated by the central nervous system from its direct effect on the liver. Nevertheless, it is clear that nonhormonal mechanisms can cause signi®cant changes in net hepatic glucose balance. In response to hyperglycemia, net hepatic 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 rate and an increase in the rate of glucose cycling within the liver appear 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 hypoglycemia is most clearly evident in severe hypoglycemia (#2.8 mmol/l). The nonhormonal response to hypoglycemia apparently involves enhancement of both gluconeogenesis and glycogenolysis and 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, catecholamines, and glucagon), dogs with denervated livers (to interrupt 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. European Journal of Endocrinology 138 240±248

The effects of increases in plasma epinephrine from 78 +/- 32 to 447 +/- 75, 1,812 +/- 97, or 2,495 +/- 427 pg/ml on glucose production, including gluconeogenesis, were determined in the conscious, overnight-fasted dog, using a combination of tracer [( 3-3H]glucose and [U-14C]alanine) and arteriovenous difference techniques. Insulin and glucagon were fixed at basal levels using a pancreatic clamp. Plasma glucose levels rose during the 180-min epinephrine infusion by 47 +/- 7, 42 +/- 22, and 74 +/- 25 mg/dl, respectively, in association with increases in hepatic glucose output of 1.04 +/- 0.22, 1.87 +/- 0.23, and 3.70 +/- 0.83 mg.kg-1.min-1 (at 15 min). Blood lactate levels rose by 1.52 +/- 0.24, 4.29 +/- 0.49, and 4.60 +/- 0.45 mmol/l, respectively, by 180 min, despite increases in hepatic uptake of lactate of 3.47 +/- 5.73, 12.83 +/- 3.46, and 37.00 +/- 4.20 mumol.kg-1.min-1. The intrahepatic gluconeogenic efficiency with which the liver converted the incoming alanine to glucose had risen by 84 +/- 40, 77 +/- 24, and 136 +/- 34% at 180 min, respectively. The latter effect plus the effect on net hepatic lactate uptake point to an intrahepatic action of high levels of the hormone in vivo. In conclusion, epinephrine produces dose-dependent increments in overall glucose production, which involve a progressive stimulation of both glycogenolysis (as assessed by glucose production at 15 min) and gluconeogenesis (assessed in the last 30 min of the study). The latter involves a peripheral action of the catecholamine to increase gluconeogenic substrate supply to the liver and may also involve a hepatic effect when high epinephrine levels are present.

Net hepatic glucose uptake (NHGU) is much greater during oral or intraportal glucose loading than during peripheral intravenous glucose delivery even when similar glucose loads and hormone levels reaching the liver are maintained. To determine whether this difference is influenced by the hepatic nerves, nine conscious 42-h-fasted dogs in which a surgical denervation of the liver (liver norepinephrine levels postdenervation averaged 2.4% of normal) had been performed were subjected to a 40-min control period and two randomized 90-min test periods during which somatostatin (0.8 microgram.kg-1.min-1), intraportal insulin (1.2 mU.kg-1.min-1), and intraportal glucagon (0.5 ng.kg-1.min-1) were infused. The glucose load to the liver was increased twofold by infusing glucose into a peripheral vein (Pe) or the portal vein (Po). Arterial insulin and glucagon concentrations were 39 +/- 2 and 39 +/- 3 microU/ml and 55 +/- 5 and 54 +/- 7 pg/ml during Pe and Po, respectively. The hepatic glucose loads were 50.3 +/- 4.4 and 51.4 +/- 5.8 mg.kg-1.min-1 while NHGU was 2.1 +/- 0.5 and 2.2 +/- 0.7 mg.kg-1.min-1 during Pe and Po, respectively. Similar hormone levels and glucose loads reaching the liver in dogs with intact hepatic nerve supplies were previously shown to be associated with NHGU of 1.4 +/- 0.7 and 3.5 +/- 0.8 mg.kg-1.min-1 in the presence of peripheral and portal glucose delivery, respectively. In conclusion, an intact nerve supply to the liver appears to be vital for the normal response of the liver to intraportal glucose delivery.

We assessed basal glucose metabolism in 16 female nonpregnant (NP) and 16 late-pregnant (P) conscious, 18-h-fasted dogs that had catheters inserted into the hepatic and portal veins and femoral artery approximately 17 days before the experiment. Pregnancy resulted in lower arterial plasma insulin (11 +/- 1 and 4 +/- 1 microU/ml in NP and P, respectively, P < 0.05), but plasma glucose (5.9 +/- 0.1 and 5.6 +/- 0.1 mg/dl in NP and P, respectively) and glucagon (39 +/- 3 and 36 +/- 2 pg/ml in NP and P, respectively) were not different. Net hepatic glucose output was greater in pregnancy (42.1 +/- 3.1 and 56.7 +/- 4.0 micromol. 100 g liver(-1).min(-1) in NP and P, respectively, P < 0.05). Total net hepatic gluconeogenic substrate uptake (lactate, alanine, glycerol, and amino acids), a close estimate of the gluconeogenic rate, was not different between the groups (20.6 +/- 2.8 and 21.2 +/- 1.8 micromol. 100 g liver(-1). min(-1) in NP and P, respectively), indicating that the increment in net hepatic glucose output resulted from an increase in the contribution of glycogenolytically derived glucose. However, total glycogenolysis was not altered in pregnancy. Ketogenesis was enhanced nearly threefold by pregnancy (6.9 +/- 1.2 and 18.2 +/- 3.4 micromol. 100 g liver(-1).min(-1) in NP and P, respectively), despite equivalent net hepatic nonesterified fatty acid uptake. Thus late pregnancy in the dog is not accompanied by changes in the absolute rates of gluconeogenesis or glycogenolysis. Rather, repartitioning of the glucose released from glycogen is responsible for the increase in hepatic glucose production.

The effects of norepinephrine (NE) at levels present in the circulation and synaptic cleft during stress on glucose metabolism were examined in overnight-fasted conscious dogs with fixed basal levels of insulin and glucagon. Plasma NE rose from 132 +/- 14 to 442 +/- 85 pg/ml and 100 +/- 20 to 3,244 +/- 807 pg/ml during 3 h of low (n = 6) and high (n = 5) NE infusion, respectively. Plasma glucose and glucose production rose only with high NE infusion (from 108 +/- 4 to 159 +/- 15 mg/dl and 2.78 +/- 0.24 to 3.41 +/- 0.38 mg.kg-1.min-1, respectively). NE infusion caused dose-dependent net hepatic lactate consumption, but net hepatic alanine uptake fell only with high NE infusion (31%). Alanine conversion to glucose rose by 67 +/- 13, 136 +/- 20, and 412 +/- 104%, and intrahepatic gluconeogenic efficiency rose by 42 +/- 27, 299 +/- 144, and 212 +/- 21% with saline and with low and high NE infusion, respectively. In conclusion, NE enhances gluconeogenesis by stimulating peripheral precursor release, by increasing substrate movement into the hepatocyte, and by increasing intrahepatic gluconeogenic efficiency. However, only the higher NE levels affected glucose metabolism profoundly enough to stimulate glucose production and to elevate the glucose level.