Chang An Chu

Comparison of the direct and indirect effects of epinephrine on hepatic glucose production.

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 +/- 29 to 107 +/- 37 and 42 +/- 12 to 1,064 +/- 144 pg/ml, respectively. Hepatic sinusoidal EPI levels in EPI po and EPI pe were indistinguishable (561 +/- 84 and 568 +/- 75 pg/ml, respectively). During peripheral epinephrine infusion, GP increased from 2.2 +/- 0.1 to 5.1 +/- 0.2 mg/kg x 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 +/- 0.1 to 3.8 +/- 0.6 mg/kg x min. Peripheral EPI infusion increased the maximal gluconeogenic rate from 0.7 +/- 0.4 to 1.8 +/- 0.5 mg/ kg x min. Portal EPI infusion did not change the maximal gluconeogenic rate. The estimated initial increase in glycogenolysis was approximately 1.7 and 2.3 mg/kg x 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.

Effect of a selective rise in sinusoidal norepinephrine on HGP is due to an increase in glycogenolysis

To determine the effect of a selective rise in liver sinusoidal norepinephrine (NE) on hepatic glucose production (HGP), norepinephrine (50 ng.kg-1.min-1) was infused intraportally (Po-NE) for 3 h into five 18-h-fasted conscious dogs with a pancreatic clamp. In the control protocol, NE (0.2 ng.kg-1.min-1) and glucose were infused peripherally to match the arterial NE and blood glucose levels in the Po-NE group. Hepatic sinusoidal NE levels rose approximately 30-fold in the Po-NE group but did not change in the control group. The arterial NE levels did not change significantly in either group. During the portal NE infusion, HGP increased from 1.9 +/- 0.2 to 3.5 +/- 0.4 mg.kg-1.min-1 (15 min; P < 0.05) and then gradually fell to 2.4 +/- 0.4 mg.kg-1.min-1 by 3 h. HGP in the control group did not change (2.0 +/- 0.2 to 2.0 +/- 0.2 mg.kg-1.min-1) for 15 min but then gradually fell to 1.1 +/- 0.2 mg.kg-1.min-1 by the end of the study. Because the fall in HGP from 15 min on was parallel in the two groups, the effect of NE on HGP (the difference between HGP in the two groups) did not decline over time. Gluconeogenesis did not change significantly in either group. In conclusion, elevation in hepatic sinusoidal NE significantly increases HGP by selectively stimulating glycogenolysis. Compared with the previously determined effects of epinephrine or glucagon on HGP, the effect of NE is, on a molar basis, less potent but more sustained over time.To determine the effect of a selective rise in liver sinusoidal norepinephrine (NE) on hepatic glucose production (HGP), norepinephrine (50 ng ⋅ kg-1 ⋅ min-1) was infused intraportally (Po-NE) for 3 h into five 18-h-fasted conscious dogs with a pancreatic clamp. In the control protocol, NE (0.2 ng ⋅ kg-1 ⋅ min-1) and glucose were infused peripherally to match the arterial NE and blood glucose levels in the Po-NE group. Hepatic sinusoidal NE levels rose ∼30-fold in the Po-NE group but did not change in the control group. The arterial NE levels did not change significantly in either group. During the portal NE infusion, HGP increased from 1.9 ± 0.2 to 3.5 ± 0.4 mg ⋅ kg-1 ⋅ min-1(15 min; P < 0.05) and then gradually fell to 2.4 ± 0.4 mg ⋅ kg-1 ⋅ min-1by 3 h. HGP in the control group did not change (2.0 ± 0.2 to 2.0 ± 0.2 mg ⋅ kg-1 ⋅ min-1) for 15 min but then gradually fell to 1.1 ± 0.2 mg ⋅ kg-1 ⋅ min-1by the end of the study. Because the fall in HGP from 15 min on was parallel in the two groups, the effect of NE on HGP (the difference between HGP in the two groups) did not decline over time. Gluconeogenesis did not change significantly in either group. In conclusion, elevation in hepatic sinusoidal NE significantly increases HGP by selectively stimulating glycogenolysis. Compared with the previously determined effects of epinephrine or glucagon on HGP, the effect of NE is, on a molar basis, less potent but nore sustained over time.

Hepatic and Gut Clearance of Catecholamines in the Conscious Dog

Our aim was to assess hepatic and gut catecholamine clearance under normal and simulated stress conditions. Following a 90-minute saline infusion period, epinephrine ([EPI] 180 ng/kg x min) and norepinephrine ([NE] 500 ng/kg x min) were infused peripherally for 90 minutes into five 18-hour fasted, conscious dogs undergoing a pancreatic clamp (somatostatin plus basal insulin and glucagon). Arterial plasma levels of EPI and NE increased from 44 +/- 9 to 2,961 +/- 445 and 96 +/- 6 to 6,467 +/- 571 pg/mL, respectively (both P < .05). Portal vein plasma levels of EPI and NE increased from 23 +/- 8 to 1,311 +/- 173 and 79 +/- 10 to 3,477 +/- 380 pg/mL, respectively (both P < .05). Hepatic vein plasma levels of EPI and NE increased from 5 +/- 2 to 117 +/- 33 and 48 +/- 10 to 448 +/- 59 pg/mL, respectively (both P < .05). Net hepatic and gut EPI uptake increased from 0.5 +/- 0.1 to 30.0 +/- 3.0 and 0.4 +/- 0.1 to 26.3 +/- 4.0 ng/kg x min, respectively (both P < .05). Net hepatic and gut NE uptake increased from 1.5 +/- 0.4 to 74.7 +/- 8.4 and 0.8 +/- 0.2 to 57.9 +/- 7.6 ng/kg x min, respectively (both P < .05). Neither the net hepatic (0.86 +/- 0.05 to 0.93 +/- 0.02) nor gut (0.45 +/- 0.10 to 0.55 +/- 0.04) fractional extraction of EPI changed significantly during the simulated stress condition. Net hepatic and gut spillover of NE increased from 0.8 +/- 0.2 to 3.5 +/- 1.3 and 0.6 +/- 0.2 to 8.8 +/- 2.0 ng/kg x min, respectively, during catecholamine infusion (both P < .05). These results indicate that (1) approximately 30% of circulating catecholamines are cleared by the splanchnic bed (16% and 14% by the liver and gut, respectively); (2) the liver and gut remove a large proportion (approximately 86% to 93% and 45% to 55%, respectively) of the catecholamines delivered to them on first pass; and (3) high levels of plasma catecholamines increase NE spillover from both the liver and gut, suggesting that the percentage of NE released from the presynaptic neuron that escapes the synaptic cleft is increased in the presence of high circulating catecholamine levels.

Portal adrenergic blockade does not inhibit the gluconeogenic effects of circulating catecholamines on the liver

This study was undertaken to determine the impact of portal adrenergic blockade on the gluconeogenic effects of epinephrine (EPI) and norepinephrine (NE). Experiments were performed on 18-hour fasted conscious dogs and consisted of a 100-minute equilibration, a 40-minute basal, and two 90-minute test periods. A pancreatic clamp was used to fix insulin and glucagon levels at basal values. Propranolol (1 microgram/kg.min) and phentolamine (2 micrograms/kg.min) were infused intraportally during both test periods. Portal infusion of alpha- and beta-adrenergic blockers alone (first test period) slightly increased hepatic glucose production from 2.4 +/- 0.4 to 2.8 +/- 0.5 mg/kg.min (nonsignificant [NS]) NE (500 ng/kg.min) and EPI (180 ng/kg.min) were infused peripherally during the second test period. Arterial NE and EPI increased from 186 +/- 63 to 6,725 +/- 913 pg/mL and 76 +/- 25 to 2,674 +/- 344 pg/mL, respectively. Portal NE and EPI increased from 135 +/- 32 to 4,082 +/- 747 pg/mL and 28 +/- 8 to 1,114 +/- 174 pg/mL, respectively. Hepatic glucose production, the maximal gluconeogenic rate, and gluconeogenic efficiency increased from 2.8 +/- 0.5 to 3.8 +/- 0.4 mg/kg.min (P < .05), 0.7 +/- 0.3 to 2.1 +/- 0.6 mg/kg.min (P < .05), and 21% +/- 8% to 60% +/- 13% (P < .05), respectively, in response to catecholamine infusion. Net hepatic lactate balance changed from output (1.5 +/- 3.3 mumol/kg.min) to uptake (-11.0 +/- 3.8 mumol/kg.min, P < .05). Net hepatic glycerol uptake increased from -1.5 +/- 0.7 to -5.5 +/- 2.0 mumol/kg.min (P < .05). Net hepatic uptake of gluconeogenic amino acids did not change significantly. Similarly, hepatic glycogenolysis did not increase during catecholamine infusion. In conclusion, portal delivery of adrenergic blockers selectively inhibits the glycogenolytic effects of EPI and NE on the liver, but allows a marked gluconeogenic response to the catecholamines.