Role of the hepatic sympathetic nerves in the regulation of net hepatic glucose uptake and the mediation of the portal glucose signal

Abstract

Role of the hepatic sympathetic nerves in the regulation of net hepatic glucose uptake and the mediation of the portal glucose signal. Am J Physiol Endocrinol Metab 290: E9 -E16, 2006. First published August 16, 2005 doi:10.1152/ajpendo.00184.2005.-Portal glucose delivery enhances net hepatic glucose uptake (NHGU) relative to peripheral glucose delivery. We hypothesize that the sympathetic nervous system normally restrains NHGU, and portal glucose delivery relieves the inhibition. Two groups of 42-h-fasted conscious dogs were studied using arteriovenous difference techniques. Denervated dogs (DEN; n ϭ 10) underwent selective sympathetic denervation by cutting the nerves at the celiac nerve bundle near the common hepatic artery; control dogs (CON; n ϭ 10) underwent a sham procedure. After a 140-min basal period, somatostatin was given along with basal intraportal infusions of insulin and glucagon. Glucose was infused peripherally to double the hepatic glucose load (HGL) for 90 min (P1). In P2, glucose was infused intraportally (3-4 mg ⅐ kg Ϫ1 ⅐ min Ϫ1 ), and the peripheral glucose infusion was reduced to maintain the HGL for 90 min. This was followed by 90 min (P3) in which portal glucose infusion was terminated and peripheral glucose infusion was increased to maintain the HGL. P1 and P3 were averaged as the peripheral glucose infusion period (PE). The average HGLs (mg ⅐ kg Ϫ1 ⅐ min Ϫ1 ) in CON and DEN were 55 Ϯ 3 and 54 Ϯ 4 in the peripheral periods and 55 Ϯ 3 and 55 Ϯ 4 in P2, respectively. The arterial insulin and glucagon levels remained basal in both groups. NHGU (mg ⅐ kg Ϫ1 ⅐ min Ϫ1 ) in CON averaged 1.7 Ϯ 0.3 during PE and increased to 2.9 Ϯ 0.3 during P2. NHGU (mg ⅐ kg Ϫ1 ⅐ min Ϫ1 ) was greater in DEN than CON (P Ͻ 0.05) during PE (2.9 Ϯ 0.4) and failed to increase significantly (3.2 Ϯ 0.2) during P2 (not significant vs. CON). Selective sympathetic denervation increased NHGU during hyperglycemia but significantly blunted the response to portal glucose delivery.autonomic nervous system; liver; canine POSTPRANDIAL HYPERGLYCEMIA is a concern for individuals with type 2 diabetes. The ability of the liver and peripheral tissues to increase their uptake of glucose after food injestion is therefore an area of interest. There are three major determinants of net hepatic glucose uptake (NHGU): the levels of insulin and glucagon in the blood, the glucose load reaching the liver, and the route of glucose delivery. NHGU increases with an increase in insulin concentration (31) and decreases with an elevation of glucagon (17). Likewise, hepatic glucose uptake is positively correlated with the glucose load. Finally, it has been shown that, when the glucose level is higher in the portal vein than in the hepatic artery, NHGU is augmented (2).The stimulus for this response has been termed the portal glucose signal. Previous studies carried out in our laboratory have shown that activation of the portal signal not only increases NHGU but also reduces glucose uptake by muscle (2, 18, 33).In the 1960s, Shimazu et al. (43,44) s...

New ways in which GLP-1 can regulate glucose homeostasis

“…The effect of a portal vein-arterial glucose gradient to promote glucose storage in the liver has been termed the portal signal. The portal signal has also been shown to stimulate pancreatic insulin secretion (15) and suppress skeletal muscle glucose uptake (16), and the responses stimulated by hepatoportal hyperglycemia have recently been linked to sympathetic nervous system activity (17). It is interesting to note that the current data indicate a similar role for GLP-1 signaling, making it possible that the CNS GLP-1 system acts in parallel with or mediates the portal signal.…”

Hepatic glycogen can regulate hypoglycemic counterregulation via a liver-brain axis

“…Despite hepatic denervation (verified by average liver norepinephrine levels of 5 ± 3 ng/g liver in denervated dogs versus 658 ± 68 ng/g liver in nondenervated animals; ref. 21), NHGU during the glycogen-manipulation period was increased by fructose infusion ( Figure 2C), leading to hepatic glycogen levels that were indistinguishable from those in the Gly++ group (79 ± 5 vs 80 ± 4 mg/g liver; Figure 2D). In this case, the counterregulatory hormone responses to insulin-induced hypoglycemia were similar to those that occurred in the Gly group rather than the Gly++ group ( Figure 4).…”

Weighted Effects of Bromocriptine Treatment on Glucose Homeostasis during Hyperglycemic versus Euglycemic Clamp Conditions in Insulin Resistant Hamsters: Bromocriptine as a Unique Postprandial Insulin Sensitizer

“…Bromocriptine treatment attenuates this inappropriate overactive hypothalamic drive for increased sympathetic tone to liver in glucose intolerant animals [2,15,20,22] which is a main stimulus for increased HGO and may block hepatic glucose disposal during the postprandial state [24,25]. In insulin resistant states, bromocriptine also removes the hypothalamic inhibition of mechanisms known to induce [26][27][28] vagal stimulation of hepatic insulin sensitivity during the postmeal period [15,[21][22][23]29].…”