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We tested the hypothesis that the loss of hepatic nerves decreases peripheral insulin sensitivity. Surgical hepatic denervation (DN) was performed in 22 dogs approximately 16 days before study; 7 dogs (Sham-Sal) had a sham procedure. A euglycemic hyperinsulinemic (1 mU x kg(-1) x min(-1); arterial insulin 35 +/- 1 microU/ml in all dogs) clamp was performed in conscious dogs. From 0 to 90 min of the clamp, all dogs received the same treatment; then the DN dogs were divided into three groups. From 90 to 180 min, DN-PeA (n = 7) and DN-PoA (n = 7) groups received acetylcholine 2.5 microg x kg(-1) x min(-1) via peripheral or portal vein, respectively, and DN-Sal (n = 8) received no acetylcholine. During 150-180 min, the Sham-Sal, DN-Sal, DN-PeA, and DN-PoA groups exhibited glucose infusion rates of 12.4 +/- 0.8, 9.3 +/- 0.8 (P < 0.05 vs. Sham-Sal), 9.1 +/- 0.1 (P < 0.05 vs. Sham-Sal), and 12.7 +/- 1.6 mg. kg(-1) x min(-1); nonhepatic glucose uptakes of 11.5 +/- 0.9, 8.9 +/- 0.7 (P < 0.05 vs. Sham-Sal), 8.6 +/- 0.9 (P < 0.05 vs. Sham-Sal), and 11.9 +/- 1.7 mg. kg(-1). min(-1); net hindlimb glucose uptakes of 18.4 +/- 2.1, 13.7 +/- 1.1 (P < 0.05 vs. Sham-Sal), 17.5 +/- 1.9, and 16.7 +/- 3.2 mg/min; and glucose utilization rates of 14.4 +/- 1.4, 10.4 +/- 0.8 (P < 0.05 vs. Sham-Sal), 9.8 +/- 0.9 (P < 0.05 vs. Sham-Sal), and 13.6 +/- 1.8 mg. kg(-1) x min(-1), respectively. DN caused peripheral insulin resistance, and intraportal but not peripheral acetylcholine restored insulin sensitivity.

The glycemic and hormonal responses and net hepatic and nonhepatic glucose uptakes were quantified in conscious 42-h-fasted dogs during a 180-min infusion of glucose at 10 mg. kg(-1). min(-1) via a peripheral (Pe10, n = 5) or the portal (Po10, n = 6) vein. Arterial plasma insulin concentrations were not different during the glucose infusion in Pe10 and Po10 (37 +/- 6 and 43 +/- 12 microU/ml, respectively), and glucagon concentrations declined similarly throughout the two studies. Arterial blood glucose concentrations during glucose infusion were not different between groups (125 +/- 13 and 120 +/- 6 mg/dl in Pe10 and Po10, respectively). Portal glucose delivery made the hepatic glucose load significantly greater (36 +/- 3 vs. 46 +/- 5 mg. kg(-1). min(-1) in Pe10 vs. Po10, respectively, P < 0.05). Net hepatic glucose uptake (NHGU; 1.1 +/- 0. 4 vs. 3.1 +/- 0.4 mg. kg(-1). min(-1)) and fractional extraction (0. 03 +/- 0.01 vs. 0.07 +/- 0.01) were smaller (P < 0.05) in Pe10 than in Po10. Nonhepatic (primarily muscle) glucose uptake was correspondingly increased in Pe10 compared with Po10 (8.9 +/- 0.4 vs. 6.9 +/- 0.4 mg. kg(-1). min(-1), P < 0.05). Approximately one-half of the difference in NHGU between groups could be accounted for by the difference in hepatic glucose load, with the remainder attributable to the effect of the portal signal itself. Even in the absence of somatostatin and fixed hormone concentrations, the portal signal acts to alter partitioning of a glucose load among the tissues, stimulating NHGU and reducing peripheral glucose uptake.

The aim of this study was to determine whether the elimination of the hepatic arterial-portal (A-P) venous glucose gradient would alter the effects of portal glucose delivery on hepatic or peripheral glucose uptake. Three groups of 42-h-fasted conscious dogs (n = 7/group) were studied. After a 40-min basal period, somatostatin was infused peripherally along with intraportal insulin (7.2 pmol x kg(-1) x min(-1)) and glucagon (0.65 ng x kg(-1) x min(-1)). In test period 1 (90 min), glucose was infused into a peripheral vein to double the hepatic glucose load (HGL) in all groups. In test period 2 (90 min) of the control group (CONT), saline was infused intraportally; in the other two groups, glucose was infused intraportally (22.2 micromol x kg(-1) x min(-1)). In the second group (PD), saline was simultaneously infused into the hepatic artery; in the third group (PD+HAD), glucose was infused into the hepatic artery to eliminate the negative hepatic A-P glucose gradient. HGL was twofold basal in each test period. Net hepatic glucose uptake (NHGU) was 10.1 +/- 2.2 and 12.8 +/- 2.1 vs. 11.5 +/- 1.6 and 23.8 +/- 3.3* vs. 9.0 +/- 2.4 and 13.8 +/- 4.2 micromol x kg(-1) x min(-1) in the two periods of CONT, PD, and PD+HAD, respectively (* P < 0.05 vs. same test period in PD and PD+HAD). NHGU was 28.9 +/- 1.2 and 39.5 +/- 4.3 vs. 26.3 +/- 3.7 and 24.5 +/- 3.7* vs. 36.1 +/- 3.8 and 53.3 +/- 8.5 micromol x kg(-1) x min(-1) in the first and second periods of CONT, PD, and PD+HAD, respectively (* P < 0.05 vs. same test period in PD and PD+HAD). Thus the increment in NHGU and decrement in extrahepatic glucose uptake caused by the portal signal were significantly reduced by hepatic arterial glucose infusion. These results suggest that the hepatic arterial glucose level plays an important role in generation of the effect of portal glucose delivery on glucose uptake by liver and muscle.

Experiments were performed on twelve 42-h-fasted, conscious dogs to determine whether the head arterial glucose level is used as a reference standard for comparison with the portal glucose level in bringing about the stimulatory effect of portal glucose delivery on net hepatic glucose uptake (NHGU). Each experiment consisted of an 80-min equilibration, a 40-min control, and two 90-min test periods. After the control period, somatostatin was given along with insulin (7.2 pmol. kg(-1). min(-1); 3.5-fold increase) and glucagon (0.6 ng. kg(-1). min(-1); basal) intraportally. Glucose was infused intraportally (22.2 micromol. kg(-1). min(-1)) and peripherally as needed to double the hepatic glucose load. In one test period, glucose was infused into both vertebral and carotid arteries (HEAD(G); 22.2 +/- 0.8 micromol. kg(-1). min(-1)); in the other test period, saline was infused into the head arteries (HEAD(S)). One-half of the dogs received HEAD(G) first. When all dogs are considered, the blood arterial-portal glucose gradients (-0.52 +/- 0.07 vs. -0.49 +/- 0.03 mM) and the hepatic glucose loads (339 +/- 14 vs. 334 +/- 20 micromol. kg(-1). min(-1)) were similar in HEAD(G) and HEAD(S). NHGU was 24.1 +/- 3.8 and 25.1 +/- 4.6 micromol. kg(-1). min(-1), and nonhepatic glucose uptake was 46.1 +/- 4.2 and 48.8 +/- 7.0 micromol. kg(-1). min(-1) in HEAD(G) and HEAD(S), respectively. The head arterial glucose level is not the reference standard used for comparison with the portal glucose level in the generation of the portal signal.

Experiments were performed on two groups of 42-h-fasted conscious dogs (n = 6/group). Somatostatin was given peripherally with insulin (4-fold basal) and glucagon (basal) intraportally. In the first experimental period, glucose was infused peripherally to double the hepatic glucose load (HGL) in both groups. In the second experimental period, glucose (21.8 micromol. kg-1. min-1) was infused intraportally and the peripheral glucose infusion rate (PeGIR) was reduced to maintain the precreating HGL in the portal signal (PO) group, whereas saline was given intraportally in the control (CON) group and PeGIR was not changed. In the third period, the portal glucose infusion was stopped in the PO group and PeGIR was increased to sustain HGL. PeGIR was continued in the CON group. The glucose loads to the liver did not differ in the CON and PO groups. Net hepatic glucose uptake was 9.6 +/- 2.5, 11.6 +/- 2.6, and 15.5 +/- 3.2 vs. 10.8 +/- 1.8, 23.7 +/- 3.0, and 15.5 +/- 1.1 micromol. kg-1. min-1, and nonhepatic glucose uptake (non-HGU) was 29.8 +/- 1.1, 40.1 +/- 4.5, and 49.5 +/- 4.0 vs. 26.6 +/- 4.3, 23.2 +/- 4.0, and 40.4 +/- 3.1 micromol. kg-1. min-1 in the CON and PO groups during the three periods, respectively. Cessation of the portal signal shifted NHGU and non-HGU to rates similar to those evident in the CON group within 10 min. These results indicate that even under hyperinsulinemic conditions the effects of the portal signal on hepatic and peripheral glucose uptake are rapidly reversible.

Concomitant portal infusion of gluconeogenic amino acids (GNGAA) and glucose significantly reduces net hepatic glucose uptake (NHGU), in comparison with NHGU during portal infusion of glucose alone. To determine whether this effect on NHGU is specific to the portal route of GNGAA delivery, somatostatin, intraportal insulin (3-fold basal) and glucagon (basal), and intraportal glucose (to increase the hepatic glucose load by approximately 50%) were infused for 240 min. GNGAA were infused peripherally into a group of dogs (PeAA), at a rate to match the hepatic GNGAA load in a group of dogs that were given the same GNGAA mixture intraportally (PoAA) at 7.6 micromol. kg-1. min-1 (9). The arterial blood glucose concentrations and hepatic glucose loads were the same in the two groups, but NHGU (-0. 9 +/- 0.2 PoAA and -2.1 +/- 0.5 mg. kg-1. min-1 in PeAA, P < 0.05) and net hepatic fractional extraction of glucose (2.6 +/- 0.7% in PoAA vs. 5.9 +/- 1.4% in PeAA, P < 0.05) differed. Neither the hepatic loads nor the net hepatic uptakes of GNGAA were significantly different in the two groups. Net hepatic glycogen synthesis was approximately 2.5-fold greater in PeAA than PoAA (P < 0.05). Intraportal, but not peripheral, amino acid infusion suppresses NHGU and net hepatic glycogen synthesis in response to intraportal glucose infusion.

The aim of this study was to assess the decay of the effect of the portal signal on net hepatic glucose uptake (NHGU). Experiments were performed on five 42-h-fasted conscious dogs. After the 40-min basal period, somatostatin was given peripherally along with insulin (1.8 pmol. kg-1. min-1) and glucagon (0.65 ng. kg-1. min-1) intraportally. In the first experimental period (Pe-GLU-1; 90 min), glucose was infused into a peripheral vein to double the glucose load to the liver (HGL). In the second experimental period (Po-GLU; 90 min), glucose (20.1 micromol. kg-1. min-1) was infused intraportally and the peripheral glucose infusion was reduced to maintain the same HGL. In the third period (Pe-GLU-2; 120 min), the portal glucose infusion was stopped and the peripheral glucose infusion was increased to again sustain HGL. Arterial insulin levels (42 +/- 3, 47 +/- 3, 43 +/- 3 pmol/l) were basal and similar in the Pe-GLU-1, Po-GLU, and Pe-GLU-2 periods, respectively. Arterial glucagon levels were also basal and similar (51 +/- 3, 49 +/- 2, 46 +/- 2 ng/l) in the three experimental periods. The glucose loads to the liver were 251 +/- 11, 274 +/- 14, and 276 +/- 12 micromol. kg-1. min-1, respectively. NHGU was 6.3 +/- 2.4, 19.1 +/- 2.8, and 9.2 +/- 1.2 micromol. kg-1. min-1, and nonhepatic glucose uptake (non-HGU) was 23.6 +/- 3.0, 5.3 +/- 1.8, and 25.5 +/- 3.7 micromol. kg-1. min-1 in the three periods, respectively. Cessation of the portal signal for only 10 min shifted NHGU and non-HGU to 9.4 +/- 2.2 and 25.0 +/- 2.8 micromol. kg-1. min-1, respectively; thus the effect of the portal signal was rapidly reversed both at the liver and peripheral tissues.

The effect of concomitant intraportal infusion of glucose and gluconeogenic amino acids (AA) on net hepatic glucose uptake (NHGU) and glycogen synthesis was examined in 42-h-fasted dogs. After a basal period, there was a 240-min experimental period during which somatostatin was infused continuously into a peripheral vein and insulin and glucagon (at 3-fold basal and basal rates, respectively) and glucose (18.3 mumol.kg-1.min-1) were infused intraportally. One group (PoAA, n = 7) received an AA mixture intraportally at 7.6 mumol.kg-1.min-1, whereas the other group (NoAA, n = 6) did not receive AA. Arterial blood glucose concentrations and hepatic glucose loads were the same in the two groups. NHGU averaged 4.8 +/- 2.0 (PoAA) and 9.4 +/- 2.0 (NoAA) mumol.kg-1.min-1 (P < 0.05), and tracer-determined hepatic glucose uptake was 4.6 +/- 1.6 (PoAA) and 10.0 +/- 1.7 (NoAA) mumol.kg-1.min-1 (P < 0.05). AA data for PoAA and NoAA, respectively, were as follows: arterial blood concentrations, 1,578 +/- 133 vs. 1,147 +/- 86 microM (P < 0.01); hepatic loads, 56 +/- 3 vs. 32 +/- 4 mumol.kg-1.min-1 (P < 0.01); and net hepatic uptakes, 14.1 +/- 1.4 vs. 5.6 +/- 0.4 mumol.kg-1.min-1 (P < 0.01). The rate of net hepatic glycogen synthesis was 7.5 +/- 1.9 (PoAA) vs. 10.7 +/- 2.3 (NoAA) mumol.kg-1.min-1 (P = 0.1). In a net sense, intraportal gluconeogenic amino acid delivery directed glucose carbon away from the liver. Despite this, net hepatic carbon uptake was equivalent in the presence and absence of amino acid infusion.