To determine the extent to which the effect of a physiologic increment in epinephrine (EPI) on glucose production (GP) arises indirectly from its action on peripheral tissues (muscle and adipose tissue), epinephrine was infused intraportally (EPI po) or peripherally (EPI pe) into 18-h-fasted conscious dogs maintained on a pancreatic clamp. Arterial EPI levels in EPI po and EPI pe groups rose from 97 Ϯ 29 to 107 Ϯ 37 and 42 Ϯ 12 to 1,064 Ϯ 144 pg/ml, respectively. Hepatic sinusoidal EPI levels in EPI po and EPI pe were indistinguishable (561 Ϯ 84 and 568 Ϯ 75 pg/ml, respectively). During peripheral epinephrine infusion, GP increased from 2.2 Ϯ 0.1 to 5.1 Ϯ 0.2 mg/kg·min (10 min). In the presence of the same rise in sinusoidal EPI, but with no rise in arterial EPI (during portal EPI infusion), GP increased from 2.1 Ϯ 0.1 to 3.8 Ϯ 0.6 mg/kg·min. Peripheral EPI infusion increased the maximal gluconeogenic rate from 0.7 Ϯ 0.4 to 1.8 Ϯ 0.5 mg/ kg·min. Portal EPI infusion did not change the maximal gluconeogenic rate. The estimated initial increase in glycogenolysis was ഠ 1.7 and 2.3 mg/kg·min in the EPI pe and EPI po groups, respectively. Gluconeogenesis was responsible for 60% of the overall increase in glucose production stimulated by the increase in plasma epinephrine (EPI pe). Elevation of sinusoidal EPI per se had no direct gluconeogenic effect on the liver, thus its effect on glucose production was solely attributable to an increase in glycogenolysis. Lastly, the gluconeogenic effects of EPI markedly decreased (60-80%) its overall glycogenolytic action on the liver. ( J.

Hypoglycemia limits optimal glycemic control in type 1 diabetes mellitus (T1DM), making novel strategies to mitigate it desirable. We hypothesized that portal (Po) vein insulin delivery would lessen hypoglycemia. In the conscious dog, insulin was infused into the hepatic Po vein or a peripheral (Pe) vein at a rate four times of basal. In protocol 1, a full counterregulatory response was allowed, whereas in protocol 2, glucagon was fixed at basal, mimicking the diminished α-cell response to hypoglycemia seen in T1DM. In protocol 1, glucose fell faster with Pe insulin than with Po insulin, reaching 56 ± 3 vs. 70 ± 6 mg/dL (P = 0.04) at 60 min. The change in area under the curve (ΔAUC) for glucagon was similar between Pe and Po, but the peak occurred earlier in Pe. The ΔAUC for epinephrine was greater with Pe than with Po (67 ± 17 vs. 36 ± 14 ng/mL/180 min). In protocol 2, glucose also fell more rapidly than in protocol 1 and fell faster in Pe than in Po, reaching 41 ± 3 vs. 67 ± 2 mg/dL (P < 0.01) by 60 min. Without a rise in glucagon, the epinephrine responses were much larger (ΔAUC of 204 ± 22 for Pe vs. 96 ± 29 ng/mL/180 min for Po). In summary, Pe insulin delivery exacerbates hypoglycemia, particularly in the presence of a diminished glucagon response. Po vein insulin delivery, or strategies that mimic it (i.e., liver-preferential insulin analogs), should therefore lessen hypoglycemia.

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...

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This study assessed the effectiveness of surgical sympathetic denervation of the common hepatic artery (CHADN) in improving glucose tolerance. CHADN eliminated norepinephrine content in the liver and partially decreased it in the pancreas and the upper gut. We assessed oral glucose tolerance at baseline and after 4 weeks of high-fat high-fructose (HFHF) feeding. Dogs were then randomized to sham surgery (SHAM) (n = 9) or CHADN surgery (n = 11) and retested 2.5 or 3.5 weeks later while still on the HFHF diet. CHADN improved glucose tolerance by ∼60% in part because of enhanced insulin secretion, as indicated by an increase in the insulinogenic index. In a subset of dogs (SHAM, n = 5; CHADN, n = 6), a hyperinsulinemic-hyperglycemic clamp was used to assess whether CHADN could improve hepatic glucose metabolism independent of a change in insulin release. CHADN reduced the diet-induced defect in net hepatic glucose balance by 37%. In another subset of dogs (SHAM, n = 4; CHADN, n = 5) the HFHF diet was continued for 3 months postsurgery and the improvement in glucose tolerance caused by CHADN continued. In conclusion, CHADN has the potential to enhance postprandial glucose clearance in states of diet-induced glucose intolerance.