Impact of chronic fructose infusion on hepatic metabolism during TPN administration

During chronic total parenteral nutrition (TPN), net hepatic glucose uptake (NHGU) is markedly elevated. However, NHGU is reduced by the presence of an infection. We recently demonstrated that a small, acute (3-h) intraportal fructose infusion can correct the infection-induced impairment in NHGU. The aim of this study was to determine whether the addition of fructose to the TPN persistently enhances NHGU in the presence of an infection. TPN was infused continuously into the inferior vena cava of chronically catheterized dogs for 5 days. On day 3, a bacterial clot was implanted in the peritoneal cavity, and either saline (CON, n = 5) or fructose (+FRUC, 1.0 mg. kg(-1). min(-1), n = 6) infusion was included with the TPN. Forty-two hours after the infection was induced, hepatic glucose metabolism was assessed in conscious dogs with arteriovenous and tracer methods. Arterial plasma glucose concentration was lower with chronic fructose infusion (120 +/- 4 vs. 131 +/- 3 mg/dl, +FRUC vs. CON, P < 0.05); however, NHGU was not enhanced (2.2 +/- 0.5 vs. 2.8 +/- 0.4 mg. kg(-1). min(-1)). Acute removal of the fructose infusion dramatically decreased NHGU (2.2 +/- 0.5 to -0.2 +/- 0.5 mg. kg(-1). min(-1)), and net hepatic lactate release also fell (1.6 +/- 0.3 to 0.5 +/- 0.3 mg. kg(-1). min(-1)). This led to an increase in the arterial plasma glucose (Delta13 +/- 3 mg/dl, P < 0.05) and insulin (Delta5 +/- 2 micro U/ml) concentrations and to a decrease in glucagon (Delta-11 +/- 3 pg/ml) concentration. In conclusion, the addition of chronic fructose infusion to TPN during infection does not lead to a persistent augmentation of NHGU.     

Hyperinsulinemia compensates for infection-induced impairment in net hepatic glucose uptake during TPN

In animals receiving total parenteral nutrition (TPN), infection impairs net hepatic glucose uptake (NHGU) by 40% and induces mild hyperinsulinemia. In the normal animal, the majority of the glucose taken up by the liver is diverted to lactate, but in the infected state, lactate release is curtailed. Because of the hyperinsulinemia and reduced NHGU, more glucose is utilized by peripheral tissues. Our aims were to determine the role of infection-induced hyperinsulinemia in 1) limiting the fall in NHGU and hepatic lactate release and 2) increasing the proportion of glucose disposed of by peripheral tissues. Chronically catheterized dogs received TPN for 5 days via the inferior vena cava. On day 3, a fibrin clot with a nonlethal dose of E. coli was placed into the peritoneal cavity; sham dogs received a sterile clot. On day 5, somatostatin was infused to prevent endogenous pancreatic hormone secretion, and insulin and glucagon were replaced at rates matching incoming hormone concentrations observed previously in sham or infected dogs. The TPN-derived glucose infusion was adjusted to maintain a constant arterial plasma glucose level of approximately 120 mg/dl. after a basal blood sampling period, the insulin infusion rate was either maintained constant (infected time control, Hi-Ins, n = 6; sham time control, Sham, n = 6) or decreased (infected + reduced insulin, Lo-Ins; n = 6) for 180 min to levels seen in noninfected dogs (from 23 +/- 2 to 12 +/- 1 microU/ml). Reduction of insulin to noninfected levels decreased NHGU by 1.4 +/- 0.5 mg x kg(-1) x min(-1) (P < 0.05) and nonhepatic glucose utilization by 4.8 +/- 0.8 mg x kg(-1) x min(-1) (P < 0.01). The fall in NHGU was caused by a decline in HGU (Delta-0.6 +/- 0.4 mg x kg(-1) x min(-1)) and a concomitant increase in hepatic glucose production (HGP, Delta0.8 +/- 0.5 mg x kg(-1) x min(-1)); net hepatic lactate release was not altered. Hyperinsulinemia that accompanies infection 1) primarily diverts glucose carbon to peripheral tissues, 2) limits the fall in NHGU by enhancing HGU and suppressing HGP, and 3) does not enhance hepatic lactate release, thus favoring hepatic glucose storage. Compensatory hyperinsulinemia plays a critical role in facilitating hepatic and peripheral glucose disposal during an infection.     

Infection impairs insulin-dependent hepatic glucose uptake during total parenteral nutrition

Total parenteral nutrition (TPN) markedly augments net hepatic glucose uptake (NHGU) and hepatic glycolysis in the presence of mild hyperglycemia and hyperinsulinemia. This increase is impaired by an infection. We determined whether the adaptation to TPN alters the responsiveness of the liver to insulin and whether infection impairs that response. Chronically catheterized dogs received TPN for 5 days. On day 3 of TPN, either a nonlethal hypermetabolic infection was induced (INF, n = 5) or a sham surgery was performed (SHAM, n = 5). Forty-two hours after clot implantation, somatostatin and glucagon (34 +/- 3 vs. 84 +/- 11 pg/ml in artery, SHAM vs. INF) were infused, and a three-step (120 min each) isoglycemic (approximately 120 mg/dl) hyperinsulinemic (approximately 12, 25, and 50 microU/ml) clamp was performed to simulate levels seen in normal, infected, and exogenous insulin treatment states. In SHAM, NHGU (3.5 +/- 0.2 to 4.2 +/- 0.4 to 4.6 +/- 0.5 mg x kg(-1) x min(-1)) modestly increased. In INF, NHGU was consistently lower at each insulin step (1.1 +/- 0.5 to 2.6 +/- 0.5 to 2.8 +/- 0.7 mg x kg(-1) x min(-1)). Although NHGU increased from the first to the second step in INF, it did not increase further with the highest dose of insulin. Despite increases in NHGU, net hepatic lactate release did not increase in SHAM and fell in INF. In summary, in the TPN-adapted state, liver glucose uptake is unresponsive to increases in insulin above the basal level. Although the infection-induced increase in insulin sustains NHGU, further increments in insulin enhance neither NHGU nor glycolysis.     

Impact of infection on glucose-dependent liver glucose uptake during TPN: interaction with insulin

Chronic total parenteral nutrition (TPN) markedly augments net hepatic glucose uptake (NHGU). This adaptive increase is impaired by an infection despite accompanying hyperinsulinemia. In the nonadapted state, NHGU is dependent on the prevailing glucose levels. Our aims were to determine whether the adaptation to TPN alters the glucose dependence of NHGU, whether infection impairs this dependence, and whether insulin modulates the glucose dependence of NHGU during infection. Chronically catheterized dogs received TPN for 5 days. On day 3 of TPN, dogs received either a bacterial fibrin clot to induce a nonlethal infection (INF, n = 9) or a sterile fibrin clot (Sham, n = 6). Forty-two hours after clot implantation, somatostatin was infused. In Sham, insulin and glucagon were infused to match the level seen in Sham (9 +/- 1 microU/ml and 23 +/- 4 pg/ml, respectively). In infected animals, either insulin and glucagon were infused to match the levels seen in infection (25 +/- 2 microU/ml and 101 +/- 15 pg/ml; INF-HI; n = 5) or insulin was replaced to match the lower levels seen in Sham (13 +/- 2 microU/ml), whereas glucagon was kept elevated (97 +/- 9 pg/ml; INF-LO; n = 4). Then a four-step (90 min each) hyperglycemic (120, 150, 200, or 250 mg/dl) clamp was performed. NHGU increased at each glucose step in Sham (from 3.6 +/- 0.6 to 5.4 +/- 0.7 to 8.9 +/- 0.9 to 12.1 +/- 1.1 mg.kg(-1).min(-1)); the slope of the relationship between glucose levels and NHGU (i.e., glucose dependence) was higher than that seen in nonadapted animals. Infection impaired glucose-dependent NHGU in both INF-HI (1.3 +/- 0.4 to 2.9 +/- 0.5 to 5.5 +/- 1.0 to 7.7 +/- 1.6 mg.kg(-1).min(-1)) and INF-LO (0.5 +/- 0.7 to 2.2 +/- 0.6 to 4.2 +/- 1.0 to 5.8 +/- 0.8 mg.kg(-1).min(-1)). In summary, TPN augments glucose-dependent NHGU, the presence of infection decreases glucose-dependent NHGU, and the accompanying hyperinsulinemia associated with infection does not sustain the glucose dependence of NHGU.     

Route-dependent effect of nutritional support on liver glucose uptake

The liver is a major site of glucose disposal during chronic (5 day) total parenteral (TPN) and enteral (TEN) nutrition. Net hepatic glucose uptake (NHGU) is dependent on the route of delivery when only glucose is delivered acutely; however, the hepatic response to chronic TPN and TEN is very similar. We aimed to determine whether the route of nutrient delivery altered the acute (first 8 h) response of the liver and whether chronic enteral delivery of glucose alone could augment the adaptive response to TPN. Chronically catheterized conscious dogs received either TPN or TEN containing glucose, Intralipid, and Travasol for either 8 h or 5 days. Another group received TPN for 5 days, but approximately 50% of the glucose in the nutrition was given via the enteral route (TPN+EG). Hepatic metabolism was assessed with tracer and arteriovenous difference techniques. In the presence of similar arterial plasma glucose levels (approximately 6 mM), NHGU and net hepatic lactate release increased approximately twofold between 8 h and 5 days in TPN and TEN. NHGU (26 +/- 1 vs. 23 +/- 3 micromol.kg(-1).min(-1)) and net hepatic lactate release (44 +/- 1 vs. 34 +/- 6 micromol.kg(-1).min(-1)) in TPN+EG were similar to results for TPN, despite lower insulin levels (96 +/- 6 vs. 58 +/- 16 pM, TPN vs. TPN+EG). TEN does not acutely enhance NHGU or disposition above that seen with TPN. However, partial delivery of enteral glucose is effective in decreasing the insulin requirement during chronic TPN.     

Portal 5-hydroxytryptophan infusion enhances glucose disposal in conscious dogs

Intraportal serotonin infusion enhances net hepatic glucose uptake (NHGU) during glucose infusion but blunts nonhepatic glucose uptake and can cause gastrointestinal discomfort and diarrhea at high doses. Whether the serotonin precursor 5-hydroxytryptophan (5-HTP) could enhance NHGU without gastrointestinal side effects during glucose infusion was examined in conscious 42-h-fasted dogs, using arteriovenous difference and tracer ([3-3H]glucose) techniques. Experiments consisted of equilibration (-120 to -30 min), basal (-30 to 0 min), and experimental (EXP; 0-270 min) periods. During EXP, somatostatin, fourfold basal intraportal insulin, basal intraportal glucagon, and peripheral glucose (to double the hepatic glucose load) were infused. In one group of dogs (HTP, n = 6), saline was infused intraportally from 0 to 90 min (P1), and 5-HTP was infused intraportally at 10, 20, and 40 microg x kg(-1) x min(-1) from 90 to 150 (P2), 150 to 210 (P3), and 210 to 270 (P4) min, respectively. In the other group (SAL, n = 7), saline was infused intraportally from 0 to 270 min. NHGU in SAL was 14.8 +/- 1.9, 18.5 +/- 2.3, 16.3 +/- 1.4, and 19.7 +/- 1.6 micromol x kg(-1) x min(-1) in P1-P4, whereas NHGU in 5-HTP averaged 16.4 +/- 2.6, 18.5 +/- 1.4, 20.8 +/- 2.0, and 27.6 +/- 2.6 micromol x kg(-1) x min(-1) (P < 0.05 vs. SAL). Nonhepatic glucose uptake (micromol x kg(-1) x min(-1)) in SAL was 30.2 +/- 4.3, 36.8 +/- 5.8, 44.3 +/- 5.8, and 54.6 +/- 11.8 during P1-P4, respectively, whereas in HTP the corresponding values were 26.3 +/- 6.8, 44.9 +/- 10.1, 47.5 +/- 11.7, and 51.4 +/- 13.2 (not significant between groups). Intraportal 5-HTP enhances NHGU without significantly altering nonhepatic glucose uptake or causing gastrointestinal side effects, raising the possibility that a related agent might have a role in reducing postprandial hyperglycemia.     

Time course of the hepatic adaptation to TPN: interaction with glycogen depletion

In response to chronic (5 days) TPN, the liver becomes a major site of glucose disposal, removing approximately 45% (4.5 mg.kg(-1).min(-1)) of exogenous glucose. Moreover, approximately 70% of glucose is not stored but released as lactate. We aimed to determine in chronically catheterized conscious dogs the time course of adaptation to TPN and the glycogen depletion impact on early time course. After an 18-h (n = 5) fast, TPN was infused into the inferior vena cava for 8 (n = 5) or 24 h (n = 6). A third group, of 42-h-fasted animals (n = 6), was infused with TPN for 8 h. TPN was infused at a rate designed to match the dog's calculated basal energy and nitrogen requirements. NHGU (-2.3 +/- 0.1 to 2.2 +/- 0.7 to 3.9 +/- 0.6 vs. -1.7 +/- 0.3 to 1.1 +/- 0.5 to 2.9 +/- 0.4 mg.kg(-1).min(-1), basal to 4 to 8 h, 18 vs. 42 h) and net hepatic lactate release (0.7 +/- 0.3 to 0.6 +/- 0.1 to 1.4 +/- 0.2 vs. -0.6 +/- 0.1 to 0.1 +/- 0.1 to 0.8 +/- 0.1 mg.kg(-1).min(-1), basal to 4 to 8 h) increased progressively. Net hepatic glycogen repletion and tracer determined that glycogen syntheses were similar. After 24 h of TPN, NHGU (5.4 +/- 0.6 mg.kg(-1).min(-1)) and net hepatic lactate release (2.6 +/- 0.4 mg.kg(-1).min(-1)) increased further. In summary, 1) most hepatic adaptation to TPN occurs within 24 h after initiation of TPN, and 2) prior glycogen depletion does not augment hepatic adaptation rate.     

Interaction of a selective serotonin reuptake inhibitor with insulin in the control of hepatic glucose uptake in conscious dogs

Whether hyperinsulinemia is required for stimulation of net hepatic glucose uptake (NHGU) by a selective serotonin reuptake inhibitor (SSRI) was examined in four groups of conscious 42-h-fasted dogs, using arteriovenous difference and tracer ([3-3H]glucose) techniques. Experiments consisted of equilibration (-120 to -30 min), basal (-30 to 0 min), and experimental periods (Exp; 0-240 min). During Exp, somatostatin, intraportal insulin [at basal (Ins groups) or 4-fold basal rates (INS groups)], basal intraportal glucagon, and peripheral glucose (to double hepatic glucose load) were infused. In the Fluv-Ins (n = 7) and Fluv-INS groups (n = 6), saline was infused intraportally from 0 to 90 min (P1), and fluvoxamine was infused intraportally at 2 microg x kg(-1) x min(-1) from 90 to 240 min (P2). Sal-Ins (n = 9) and Sal-INS (n = 8) received intraportal saline in P1 and P2. NHGU during P2 was 8.4 +/- 1.4 and 6.9 +/- 2.3 micromol x kg(-1) x min(-1) in Sal-Ins and Fluv-Ins, respectively (not significant), and 13.3 +/- 2.2 and 20.9 +/- 3.1 micromol x kg(-1) x min(-1) (P < 0.05) in Sal-INS and Fluv-INS. Unidirectional (tracer-determined) hepatic glucose uptake was twofold greater (P < 0.05) in Fluv-INS than Sal-INS. Net hepatic carbon retention during P2 was significantly greater in Fluv-INS than Sal-INS (18.5 +/- 2.7 vs. 12.2 +/- 1.9 micromol x kg(-1) x min(-1)). Nonhepatic glucose uptake was reduced in Fluv-INS vs. Sal-INS (20.0 +/- 1.3 vs. 38.4 +/- 5.4 micromol x kg(-1) x min(-1), P < 0.05). Intraportal fluvoxamine enhanced NHGU and net hepatic carbon retention in the presence of hyperinsulinemia but not euinsulinemia, suggesting that hepatocyte-targeted SSRIs may reduce postprandial hyperglycemia.     

Importance of the hepatic arterial glucose level in generation of the portal signal in conscious dogs

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.     

Inclusion of low amounts of fructose with an intraportal glucose load increases net hepatic glucose uptake in the presence of relative insulin deficiency in dog

The effect of small amounts of fructose on net hepatic glucose uptake (NHGU) during hyperglycemia was examined in the presence of insulinopenia in conscious 42-h fasted dogs. During the study, somatostatin (0.8 microg.kg(-1).min(-1)) was given along with basal insulin (1.8 pmol.kg(-1).min(-1)) and glucagon (0.5 ng.kg(-1).min(-1)). After a control period, glucose (36.1 micromol.kg(-1).min(-1)) was continuously given intraportally for 4 h with (2.2 micromol.kg(-1).min(-1)) or without fructose. In the fructose group, the sinusoidal blood fructose level (nmol/ml) rose from <16 to 176 +/- 11. The infusion of glucose alone (the control group) elevated arterial blood glucose (micromol/ml) from 4.3 +/- 0.3 to 11.2 +/- 0.6 during the first 2 h after which it remained at 11.6 +/- 0.8. In the presence of fructose, glucose infusion elevated arterial blood glucose (micromol/ml) from 4.3 +/- 0.2 to 7.4 +/- 0.6 during the first 1 h after which it decreased to 6.1 +/- 0.4 by 180 min. With glucose infusion, net hepatic glucose balance (micromol.kg(-1).min(-1)) switched from output (8.9 +/- 1.7 and 13.3 +/- 2.8) to uptake (12.2 +/- 4.4 and 29.4 +/- 6.7) in the control and fructose groups, respectively. Average NHGU (micromol.kg(-1).min(-1)) and fractional glucose extraction (%) during last 3 h of the test period were higher in the fructose group (30.6 +/- 3.3 and 14.5 +/- 1.4) than in the control group (15.0 +/- 4.4 and 5.9 +/- 1.8). Glucose 6-phosphate and glycogen content (micromol glucose/g) in the liver and glucose incorporation into hepatic glycogen (micromol glucose/g) were higher in the fructose (218 +/- 2, 283 +/- 25, and 109 +/- 26, respectively) than in the control group (80 +/- 8, 220 +/- 31, and 41 +/- 5, respectively). In conclusion, small amounts of fructose can markedly reduce hyperglycemia during intraportal glucose infusion by increasing NHGU even when insulin secretion is compromised.     

Chronic hepatic artery ligation does not prevent liver from differentiating portal vs. peripheral glucose delivery

Infusion of glucose into the hepatic artery blocks the stimulatory effect of the "portal signal" on net hepatic glucose uptake (NHGU) during portal glucose delivery. We hypothesized that hepatic artery ligation (HAL) would result in enhanced NHGU during peripheral glucose infusion because the arterial glucose concentration would be perceived as lower than that in the portal vein. Fourteen dogs underwent HAL approximately 16 days before study. Conscious 42-h-fasted dogs received somatostatin, intraportal insulin, and glucagon infusions at fourfold basal and at basal rates, respectively, and peripheral glucose infusion to create hyperglycemia. After 90 min (period 1), seven dogs (HALpo) received intraportal glucose (3.8 mg. kg-1. min-1) and seven (HALpe) continued to receive only peripheral glucose for 90 min (period 2). These two groups were compared with nine non-HAL control dogs (control) treated as were HALpe. During period 2, the arterial plasma insulin concentrations (24 +/- 3, 20 +/- 1, and 24 +/- 2 microU/ml) and hepatic glucose loads (39.1 +/- 2.5, 43.8 +/- 2.9, and 37.7 +/- 3.7 mg. kg-1. min-1) were not different in HALpe, HALpo, and control, respectively. HALpo exhibited greater (P < 0.05) NHGU than HALpe and control (3.1 +/- 0.3, 2.0 +/- 0.4, and 2.0 +/- 0.1 mg. kg-1. min-1, respectively). Net hepatic carbon retention was approximately twofold greater (P < 0.05) in HALpo than in HALpe and control. NHGU and net hepatic glycogen synthesis during peripheral glucose infusion were not enhanced by HAL. Even though there exists an intrahepatic arterial reference site for the portal vein glucose concentration, the failure of HAL to result in enhanced NHGU during peripheral glucose infusion suggests the existence of one or more comparison sites outside the liver.     

Vagal cooling and concomitant portal norepinephrine infusion do not reduce net hepatic glucose uptake in conscious dogs

We examined the role of efferent neural signaling in regulation of net hepatic glucose uptake (NHGU) in two groups of conscious dogs with hollow perfusable coils around their vagus nerves, using tracer and arteriovenous difference techniques. Somatostatin, intraportal insulin and glucagon at fourfold basal and basal rates, and intraportal glucose at 3.8 mg.kg(-1).min(-1) were infused continuously. From 0 to 90 min [period 1 (P1)], the coils were perfused with a 37 degrees C solution. During period 2 [P2; 90-150 min in group 1 (n = 3); 90-180 min in group 2 (n = 6)], the coils were perfused with -15 degrees C solution to eliminate vagal signaling, and the coils were subsequently perfused with 37 degrees C solution during period 3 (P3). In addition, group 2 received an intraportal infusion of norepinephrine at 16 ng.kg(-1).min(-1) during P2. The effectiveness of vagal suppression was demonstrated by the increase in heart rate during P2 (111 +/- 17, 167 +/- 16, and 105 +/- 13 beats/min in group 1 and 71 +/- 6, 200 +/- 11, and 76 +/- 6 beats/min in group 2 during P1-P3, respectively) and by prolapse of the third eyelid during P2. Arterial plasma glucose, insulin, and glucagon concentrations; hepatic blood flow; and hepatic glucose load did not change significantly during P1-P3. NHGU during P1-P3 was 2.7 +/- 0.4, 4.1 +/- 0.6, and 4.0 +/- 1.2 mg.kg(-1).min(-1) in group 1 and 5.0 +/- 0.9, 5.6 +/- 0.7, and 6.1 +/- 0.9 mg.kg(-1).min(-1) in group 2 (not significant among periods). Interruption of vagal signaling with or without intraportal infusion of norepinephrine to augment sympathetic tone did not suppress NHGU during portal glucose delivery, suggesting the portal signal stimulates NHGU independently of vagal efferent flow.     

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

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=10) underwent selective sympathetic denervation by cutting the nerves at the celiac nerve bundle near the common hepatic artery; control dogs (CON; n=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.kg(-1).min(-1)), 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.kg(-1).min(-1)) in CON and DEN were 55+/-3 and 54+/-4 in the peripheral periods and 55+/-3 and 55+/-4 in P2, respectively. The arterial insulin and glucagon levels remained basal in both groups. NHGU (mg.kg(-1).min(-1)) in CON averaged 1.7+/-0.3 during PE and increased to 2.9+/-0.3 during P2. NHGU (mg.kg(-1).min(-1)) was greater in DEN than CON (P<0.05) during PE (2.9+/-0.4) and failed to increase significantly (3.2+/-0.2) during P2 (not significant vs. CON). Selective sympathetic denervation increased NHGU during hyperglycemia but significantly blunted the response to portal glucose delivery.     

Portal infusion of a selective serotonin reuptake inhibitor enhances hepatic glucose disposal in conscious dogs

Intraportal delivery of serotonin enhanced net hepatic glucose uptake (NHGU) during a hyperinsulinemic hyperglycemic clamp, but serotonin elevated catecholamines and can cause gastrointestinal distress. We hypothesized that the selective serotonin reuptake inhibitor (SSRI) fluvoxamine would enhance NHGU without side effects. Arteriovenous difference and tracer ([3-(3)H]glucose) techniques were used in conscious 42-h-fasted dogs. Experiments consisted of equilibration (-120 to -30 min), basal (-30 to 0 min), and experimental (EXP; 0-270 min) periods. During EXP, somatostatin, fourfold basal intraportal insulin, basal intraportal glucagon, and peripheral glucose (to double the hepatic glucose load) were infused. Saline (SAL) was infused intraportally during 0-90 min (P1), and fluvoxamine was infused intraportally at 0.5, 1, and 2 mug.kg(-1).min(-1) from 90 to 150 (P2), 150 to 210 (P3), and 210 to 270 (P4) min, respectively, in the FLUV group (n = 8). The SAL group (n = 9) received intraportal saline during 0-270 min. NHGU in SAL was 13.9 +/- 1.7 and 17.0 +/- 2.0 mumol.kg(-1).min(-1) in P3-P4, respectively, while NHGU in FLUV averaged 19.7 +/- 2.8 and 26.6 +/- 3.0 mumol.kg(-1).min(-1) (P < 0.05 vs. SAL). Net hepatic carbon retention was greater (P < 0.05) in FLUV than in SAL (17.6 +/- 2.6 vs. 13.9 +/- 2.7 and 23.8 +/- 3.0 vs. 14.4 +/- 3.3 mumol.kg(-1).min(-1) in P3-P4, respectively), and final hepatic glycogen concentrations were 50% greater in FLUV (P < 0.005). Nonhepatic glucose uptake was greater in SAL than in FLUV at 270 min (P < 0.05). Catecholamine concentrations remained basal, and the animals evidenced no distress. Thus fluvoxamine enhanced NHGU and hepatic carbon storage without raising circulating serotonin concentrations or causing stress, suggesting that hepatic-targeted SSRIs might be effective in reducing postprandial hyperglycemia in individuals with diabetes or impaired glucose tolerance.     

Hepatic glucose metabolism during intraduodenal glucose infusion: impact of infection

We previously reported that infection decreases hepatic glucose uptake when glucose is given as a constant peripheral glucose infusion (8 mg. kg(-1) x min(-1)). This impairment persisted despite greater hyperinsulinemia in the infected group. In a normal setting, hepatic glucose uptake can be further enhanced if glucose is given gastrointestinally. Thus the aim of this study was to determine whether hepatic glucose uptake is impaired during an infection when glucose is given gastrointestinally. Thirty-six hours before study, a sham (SH, n = 7) or Escherichia coli-containing (2 x 10(9) organisms/kg; INF; n = 7) fibrin clot was placed in the peritoneal cavity of chronically catheterized dogs. After the 36 h, a glucose bolus (150 mg/kg) followed by a continuous infusion (8 mg. kg(-1). min(-1)) of glucose was given intraduodenally to conscious dogs for 240 min. Tracer ([3-(3)H]glucose and [U-(14)C]glucose) and arterial-venous difference techniques were used to assess hepatic and intestinal glucose metabolism. Infection increased hepatic blood flow (35 +/- 5 vs. 47+/-3 ml x g(-1) x min(-1); SH vs. INF) and basal glucose rate of appearance (2.1+/-0.2 vs. 3.3+/-0.1 mg x kg(-1) x min(-1)). Arterial insulin concentrations increased similarly in SH and INF during the last hour of glucose infusion (38+/-8 vs. 46+/-20 microU/ml), and arterial glucagon concentrations fell (62+/-14 to 30+/-3 vs. 624+/-191 to 208+/-97 pg/ml). Net intestinal glucose absorption was decreased in INF, attenuating the increase in blood glucose caused by the glucose load. Despite this, net hepatic glucose uptake (1.6+/-0.8 vs. 2.4+/- 0.9 mg x kg(-1) x min(-1); SH vs. INF) and consequently tracer-determined glycogen synthesis (1.3+/-0.3 vs. 1.0+/-0.3 mg. kg(-1) x min(-1)) were similar between groups. In summary, infection impairs net glucose absorption, but not net hepatic glucose uptake or glycogen deposition, when glucose is given intraduodenally.     

Nonhepatic response to portal glucose delivery in conscious dogs

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.     

Impact of continuous and pulsatile insulin delivery on net hepatic glucose uptake

The pancreas releases insulin in a pulsatile manner; however, studies assessing the liver's response to insulin have used constant infusion rates. Our aims were to determine whether the secretion pattern of insulin [continuous (CON) vs. pulsatile] in the presence of hyperglycemia 1) influences net hepatic glucose uptake (NHGU) and 2) entrains NHGU. Chronically catheterized conscious dogs fasted for 42 h received infusions including peripheral somatostatin, portal insulin (0.25 mU x kg(-1) x min(-1)), peripheral glucagon (0.9 ng x kg(-1) x min(-1)), and peripheral glucose at a rate double the glucose load to the liver. After the basal period, insulin was infused for 210 min at either four times the basal rate (1 mU x kg(-1) x min(-1)) or an identical amount in pulses of 1 and 4 min duration, followed by intervals of 11 and 8 min (CON, 1/11, and 4/8, respectively) in which insulin was not infused. A variable peripheral glucose infusion containing [3H]glucose clamped glucose levels at twice the basal level ( approximately 200 mg/dl) throughout each study. Hepatic metabolism was assessed by combining tracer and arteriovenous difference techniques. Arterial plasma insulin (microU/ml) either increased from basal levels of 6 +/- 1 to a constant level of 22 +/- 4 in CON or oscillated from 5 +/- 1 to 416 +/- 79 and from 6 +/- 1 to 123 +/- 43 in 1/11 and 4/8, respectively. NHGU (-0.8 +/- 0.3, 0.4 +/- 0.2, and -0.9 +/- 0.4 mg x kg(-1) x min(-1)) and net hepatic fractional extraction of glucose (0.04 +/- 0.01, 0.04 +/- 0.01, and 0.05 +/- 0.01 mg x kg(-1) x min(-1)) were similar during the experimental period. Spectral analysis was performed to assess whether a correlation existed between the insulin secretion pattern and NHGU. NHGU was not augmented by pulsatile insulin delivery, and there is no evidence of entrainment in hepatic glucose metabolism. Thus the loss of insulin pulsatility per se likely has little or no impact on the effectiveness of insulin in regulating liver glucose uptake.     

Intraportal administration of neuropeptide Y and hepatic glucose metabolism

We examined whether intraportal delivery of neuropeptide Y (NPY) affects glucose metabolism in 42-h-fasted conscious dogs using arteriovenous difference methodology. The experimental period was divided into three subperiods (P1, P2, and P3). During all subperiods, the dogs received infusions of somatostatin, intraportal insulin (threefold basal), intraportal glucagon (basal), and peripheral intravenous glucose to increase the hepatic glucose load twofold basal. Following P1, in the NPY group (n = 7), NPY was infused intraportally at 0.2 and 5.1 pmol.kg(-1).min(-1) during P2 and P3, respectively. The control group (n = 7) received intraportal saline infusion without NPY. There were no significant changes in hepatic blood flow in NPY vs. control. The lower infusion rate of NPY (P2) did not enhance net hepatic glucose uptake. During P3, the increment in net hepatic glucose uptake (compared with P1) was 4 +/- 1 and 10 +/- 2 micromol.kg(-1).min(-1) in control and NPY, respectively (P < 0.05). The increment in net hepatic fractional glucose extraction during P3 was 0.015 +/- 0.005 and 0.039 +/- 0.008 in control and NPY, respectively (P < 0.05). Net hepatic carbon retention was enhanced in NPY vs. control (22 +/- 2 vs. 14 +/- 2 micromol.kg(-1).min(-1), P < 0.05). There were no significant differences between groups in the total glucose infusion rate. Thus, intraportal NPY stimulates net hepatic glucose uptake without significantly altering whole body glucose disposal in dogs.     

Combined intraportal infusion of acetylcholine and adrenergic blockers augments net hepatic glucose uptake

Portal glucose delivery in the conscious dog augments net hepatic glucose uptake (NHGU). To investigate the possible role of altered autonomic nervous activity in the effect of portal glucose delivery, the effects of adrenergic blockade and acetylcholine (ACh) on hepatic glucose metabolism were examined in 42-h-fasted conscious dogs. Each study consisted of an equilibration (-120 to -20 min), a control (-20 to 0 min), and a hyperglycemic-hyperinsulinemic period (0 to 300 min). During the last period, somatostatin (0.8 microg. kg(-1). min(-1)) was infused along with intraportal insulin (1.2 mU. kg(-1). min(-1)) and glucagon (0.5 ng. kg(-1). min(-1)). Hepatic sinusoidal insulin was four times basal (73 +/- 7 microU/ml) and glucagon was basal (55 +/- 7 pg/ml). Glucose was infused peripherally (0-300 min) to create hyperglycemia (220 mg/dl). In test protocol, phentolamine and propranolol were infused intraportally at 0.2 microg and 0.1 microg. kg(-1). min(-1) from 120 min on. ACh was infused intraportally at 3 microg. kg(-1). min(-1) from 210 min on. In control protocol, saline was given in place of the blockers and ACh. Hyperglycemia-hyperinsulinemia switched the net hepatic glucose balance (mg. kg(-1). min(-1)) from output (2.1 +/- 0.3 and 1.1 +/- 0.2) to uptake (2.8 +/- 0.9 and 2.6 +/- 0.6) and lactate balance (micromol. kg(-1). min(-1)) from uptake (7.5 +/- 2.2 and 6.7 +/- 1.6) to output (3.7 +/- 2.6 and 3.9 +/- 1.6) by 120 min in the control and test protocols, respectively. Thereafter, in the control protocol, NHGU tended to increase slightly (3.0 +/- 0.6 mg. kg(-1). min(-1) by 300 min). In the test protocol, adrenergic blockade did not alter NHGU, but ACh infusion increased it to 4.4 +/- 0.6 and 4.6 +/- 0.6 mg. kg(-1). min(-1) by 220 and 300 min, respectively. These data are consistent with the hypothesis that alterations in nerve activity contribute to the increase in NHGU seen after portal glucose delivery.     

Unlike mice, dogs exhibit effective glucoregulation during low-dose portal and peripheral glucose infusion

Portal infusion of glucose in the mouse at a rate equivalent to basal endogenous glucose production causes hypoglycemia, whereas peripheral infusion at the same rate causes significant hyperglycemia. We used tracer and arteriovenous difference techniques in conscious 42-h-fasted dogs to determine their response to the same treatments. The studies consisted of three periods: equilibration (100 min), basal (40 min), and experimental (180 min), during which glucose was infused at 13.7 micromol.kg(-1).min(-1) into a peripheral vein (p.e., n = 5) or the hepatic portal (p.o., n = 5) vein. Arterial blood glucose increased approximately 0.8 mmol/l in both groups. Arterial and hepatic sinusoidal insulin concentrations were not significantly different between groups. p.e. exhibited an increase in nonhepatic glucose uptake (non-HGU; Delta8.6 +/- 1.2 micromol.kg(-1).min(-1)) within 30 min, whereas p.o. showed a slight suppression (Delta-3.7 +/- 3.1 micromol.kg(-1).min(-1)). p.o. shifted from net hepatic glucose output (NHGO) to uptake (NHGU; 2.5 +/- 2.8 micromol.kg-1.min-1) within 30 min, but p.e. still exhibited NHGO (6.0 +/- 1.9 micromol.kg(-1).min(-1)) at that time and did not initiate NHGU until after 90 min. Glucose rates of appearance and disappearance did not differ between groups. The response to the two infusion routes was markedly different. Peripheral infusion caused a rapid enhancement of non-HGU, whereas portal delivery quickly activated NHGU. As a result, both groups maintained near-euglycemia. The dog glucoregulates more rigorously than the mouse in response to both portal and peripheral glucose delivery.