scholarly journals Interaction of equal increments in arterial and portal vein insulin on hepatic glucose production in the dog

1997 ◽  
Vol 273 (5) ◽  
pp. E972-E980 ◽  
Author(s):  
Dana K. Sindelar ◽  
Chang A. Chu ◽  
Doss W. Neal ◽  
Alan D. Cherrington
Keyword(s):  
Portal Vein ◽  
Endocrine Pancreas ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Experimental Period ◽  
Hepatic Glucose ◽  
Glucose Output ◽  
Hepatic Glucose Uptake ◽  
Selective Increase ◽  
Arteriovenous Difference

We have previously shown that a selective increase of 84 pmol/l in either arterial or portal vein insulin (independent of a change in insulin in the other vessel) can suppress tracer-determined glucose production (TDGP) and net hepatic glucose output (NHGO) by ∼50%. In the present study we investigated the interaction between equal increments in arterial and portal vein insulin in the suppression of TDGP and NHGO. Isotopic ([3-3H]glucose) and arteriovenous difference methods were used in conscious overnight fasted dogs. A pancreatic clamp was used to control the endocrine pancreas. A 40-min basal period was followed by a 180-min test period, during which arterial and portal vein insulin levels were simultaneously and equally increased 102 pmol/l. Hepatic sinusoidal glucagon levels remained unchanged, and euglycemia was maintained by peripheral glucose infusion. TDGP was suppressed ∼60% by the last 30 min of the experimental period. In contrast, NHGO was suppressed 100% by that time. Coincidentally, hepatic glucose uptake (net hepatic [3H]glucose balance) increased significantly (∼4 μmol ⋅ kg−1⋅ min−1). The effects of simultaneous equal increases in peripheral and portal venous insulin were not additive in the suppression of TDGP. However, they were additive in decreasing NHGO as a result of an increase in the uptake of glucose by the liver.

Effect of a selective rise in hepatic artery insulin on hepatic glucose production in the conscious dog

1999 ◽  
Vol 276 (4) ◽  
pp. E806-E813
Author(s):  
Dana K. Sindelar ◽  
Kayano Igawa ◽  
Chang A. Chu ◽  
Jim H. Balcom ◽  
Doss W. Neal ◽  
...  
Keyword(s):  
Portal Vein ◽  
Hepatic Artery ◽  
Insulin Infusion ◽  
Hepatic Glucose Production ◽  
Control Period ◽  
Glucose Production ◽  
Insulin Level ◽  
Hepatic Glucose ◽  
Glucose Output ◽  
Selective Increase

In the present study we compared the hepatic effects of a selective increase in hepatic sinusoidal insulin brought about by insulin infusion into the hepatic artery with those resulting from insulin infusion into the portal vein. A pancreatic clamp was used to control the endocrine pancreas in conscious overnight-fasted dogs. In the control period, insulin was infused via peripheral vein and the portal vein. After the 40-min basal period, there was a 180-min test period during which the peripheral insulin infusion was stopped and an additional 1.2 pmol ⋅ kg−1⋅ min−1of insulin was infused into the hepatic artery (HART, n = 5) or the portal vein (PORT, n = 5, data published previously). In the HART group, the calculated hepatic sinusoidal insulin level increased from 99 ± 20 (basal) to 165 ± 21 pmol/l (last 30 min). The calculated hepatic artery insulin concentration rose from 50 ± 8 (basal) to 289 ± 19 pmol/l (last 30 min). However, the overall arterial (50 ± 8 pmol/l) and portal vein insulin levels (118 ± 24 pmol/l) did not change over the course of the experiment. In the PORT group, the calculated hepatic sinusoidal insulin level increased from 94 ± 30 (basal) to 156 ± 33 pmol/l (last 30 min). The portal insulin rose from 108 ± 42 (basal) to 192 ± 42 pmol/l (last 30 min), whereas the overall arterial insulin (54 ± 6 pmol/l) was unaltered during the study. In both groups hepatic sinusoidal glucagon levels remained unchanged, and euglycemia was maintained by peripheral glucose infusion. In the HART group, net hepatic glucose output (NHGO) was suppressed from 9.6 ± 2.1 μmol ⋅ kg−1⋅ min−1(basal) to 4.6 ± 1.0 μmol ⋅ kg−1⋅ min−1(15 min) and eventually fell to 3.5 ± 0.8 μmol ⋅ kg−1⋅ min−1(last 30 min, P < 0.05). In the PORT group, NHGO dropped quickly ( P < 0.05) from 10.0 ± 0.9 (basal) to 7.8 ± 1.6 (15 min) and eventually reached 3.1 ± 1.1 μmol ⋅ kg−1⋅ min−1(last 30 min). Thus NHGO decreases in response to a selective increase in hepatic sinusoidal insulin, regardless of whether it comes about because of hyperinsulinemia in the hepatic artery or portal vein.

scholarly journals Role of hepatic α- and β-adrenergic receptor stimulation on hepatic glucose production during heavy exercise

1997 ◽  
Vol 273 (5) ◽  
pp. E831-E838 ◽  
Author(s):  
Robert H. Coker ◽  
Mahesh G. Krishna ◽  
D. Brooks Lacy ◽  
Deanna P. Bracy ◽  
David H. Wasserman
Keyword(s):  
Portal Vein ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Test Period ◽  
Saline Control ◽  
Adrenergic Blockade ◽  
Heavy Exercise ◽  
Hepatic Glucose ◽  
Glucose Output

The role of catecholamines in the control of hepatic glucose production was studied during heavy exercise in dogs, using a technique to selectively block hepatic α- and β-adrenergic receptors. Surgery was done >16 days before the study, at which time catheters were implanted in the carotid artery, portal vein, and hepatic vein for sampling and the portal vein and vena cava for infusions. In addition, flow probes were implanted on the portal vein and hepatic artery. Each study consisted of a 100-min equilibration, a 30-min basal, a 20-min heavy exercise (∼85% of maximum heart rate), a 30-min recovery, and a 30-min adrenergic blockade test period. Either saline (control; n= 7) or α (phentolamine)- and β (propranolol)-adrenergic blockers (Blk; n = 6) were infused in the portal vein. In both groups, epinephrine (Epi) and norepinephrine (NE) were infused in the portal vein during the blockade test period to create supraphysiological levels at the liver. Isotope ([3-3H]glucose) dilution and arteriovenous differences were used to assess hepatic function. Arterial Epi, NE, glucagon, and insulin levels were similar during exercise in both groups. Endogenous glucose production (Ra) rose similarly during exercise to 7.9 ± 1.2 and 7.5 ± 2.0 mg ⋅ kg−1⋅ min−1in control and Blk groups at time = 20 min. Net hepatic glucose output also rose to a similar rate in control and Blk groups with exercise. During the blockade test period, arterial plasma glucose and Rarose to 164 ± 5 mg/dl and 12.0 ± 1.4 mg ⋅ kg−1⋅ min−1, respectively, but were essentially unchanged in Blk. The attenuated response to catecholamine infusion in Blk substantiates the effectiveness of the hepatic adrenergic blockade. In conclusion, these results show that direct hepatic adrenergic stimulation does not participate in the increase in Ra, even during the exaggerated sympathetic response to heavy exercise.

Effect of a mixed meal on hepatic lactate and gluconeogenic precursor metabolism in dogs

1984 ◽  
Vol 247 (3) ◽  
pp. E362-E369 ◽  
Author(s):  
M. A. Davis ◽  
P. E. Williams ◽  
A. D. Cherrington
Keyword(s):  
Hepatic Glucose Production ◽  
Lactate Production ◽  
Glucose Production ◽  
Hepatic Uptake ◽  
Mixed Meal ◽  
Arterial Lactate ◽  
Hepatic Glucose ◽  
Hepatic Glucose Uptake ◽  
Arterial Glucose ◽  
Arterial Lactate Level

The present experiments were undertaken to assess lactate and gluconeogenic precursor metabolism in the 30 h following consumption of a mixed meal by the overnight-fasted, conscious dog. The arterial glucose level rose by a maximum of 13 mg/dl 4 h after the meal and had returned to control levels by 12 h. Hepatic glucose production was suppressed for 12 h after feeding, but net hepatic glucose uptake did not occur. The arterial lactate level rose from 0.55 +/- 0.10 to 1.28 +/- 0.14 mM within 1 h of feeding and remained elevated for 12 h. Net hepatic lactate production, measured with an A-V difference technique, rose from 3.5 +/- 2.8 to 19.4 +/- 3.1 mumol X kg-1 X min-1 h after the meal and declined slowly over the next 22 h. The liver then began to consume lactate so that at 30 h net hepatic uptake was 5.7 +/- 0.5 mumol X kg-1 X min-1. The total hepatic uptake of the gluconeogenic amino acids (alanine, glycine, serine, threonine) increased from 5.3 +/- 0.8 to 11.5 +/- 2.5 mumol X kg-1 X min-1 at 1 h and remained elevated for 4 h. The arterial alanine level rose from 0.36 +/- 0.03 to 0.51 +/- 0.04 mM at 2 h and remained elevated for 18 h. Insulin increased from 11 +/- 2 microU/ml to a maximum of 44 +/- 5 4 h after the meal, and the glucagon level rose from 59 +/- 8 pg/ml to a maximum of 150 +/- 22 1 h after feeding.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Coordinated changes in hepatic amino acid metabolism and endocrine signals support hepatic glucose production during fetal hypoglycemia

2015 ◽  
Vol 308 (4) ◽  
pp. E306-E314 ◽  
Author(s):  
Satya S. Houin ◽  
Paul J. Rozance ◽  
Laura D. Brown ◽  
William W. Hay ◽  
Randall B. Wilkening ◽  
...  
Keyword(s):  
Fetal Liver ◽  
Hepatic Glucose Production ◽  
Plasma Concentrations ◽  
Glucose Production ◽  
Late Gestation ◽  
Fetal Sheep ◽  
Fetal Plasma ◽  
Hepatic Glucose ◽  
Molar Percent ◽  
Glucose Output

Reduced fetal glucose supply, induced experimentally or as a result of placental insufficiency, produces an early activation of fetal glucose production. The mechanisms and substrates used to fuel this increased glucose production rate remain unknown. We hypothesized that in response to hypoglycemia, induced experimentally with maternal insulin infusion, the fetal liver would increase uptake of lactate and amino acids (AA), which would combine with hormonal signals to support hepatic glucose production. To test this hypothesis, metabolic studies were done in six late gestation fetal sheep to measure hepatic glucose and substrate flux before (basal) and after [days (d)1 and 4] the start of hypoglycemia. Maternal and fetal glucose concentrations decreased by 50% on d1 and d4 ( P < 0.05). The liver transitioned from net glucose uptake (basal, 5.1 ± 1.5 μmol/min) to output by d4 (2.8 ± 1.4 μmol/min; P < 0.05 vs. basal). The [U-13C]glucose tracer molar percent excess ratio across the liver decreased over the same period (basal: 0.98 ± 0.01, vs. d4: 0.89 ± 0.01, P < 0.05). Total hepatic AA uptake, but not lactate or pyruvate uptake, increased by threefold on d1 ( P < 0.05) and remained elevated throughout the study. This AA uptake was driven largely by decreased glutamate output and increased glycine uptake. Fetal plasma concentrations of insulin were 50% lower, while cortisol and glucagon concentrations increased 56 and 86% during hypoglycemia ( P < 0.05 for basal vs. d4). Thus increased hepatic AA uptake, rather than pyruvate or lactate uptake, and decreased fetal plasma insulin and increased cortisol and glucagon concentrations occur simultaneously with increased fetal hepatic glucose output in response to fetal hypoglycemia.

Involvement of the vagus nerves in the regulation of basal hepatic glucose production in conscious dogs

2002 ◽  
Vol 283 (5) ◽  
pp. E958-E964 ◽  
Author(s):  
Sylvain Cardin ◽  
Konstantin Walmsley ◽  
Doss W. Neal ◽  
Phillip E. Williams ◽  
Alan D. Cherrington
Keyword(s):  
Hepatic Glucose Production ◽  
Control Period ◽  
Glucose Production ◽  
Heart Rate Change ◽  
Vagus Nerves ◽  
Hepatic Glucose Metabolism ◽  
Vagal Blockade ◽  
Hepatic Glucose ◽  
Cooling Coils ◽  
Glucose Output

We determined if blocking transmission in the fibers of the vagus nerves would affect basal hepatic glucose metabolism in the 18-h-fasted conscious dog. A pancreatic clamp (somatostatin, basal portal insulin, and glucagon) was employed. A 40-min control period was followed by a 90-min test period. In one group, stainless steel cooling coils (Sham, n = 5) were perfused with a 37°C solution, while in the other (Cool, n = 6), the coils were perfused with −20°C solution. Vagal blockade was verified by heart rate change (80 ± 9 to 84 ± 14 beats/min in Sham; 98 ± 12 to 193 ± 22 beats/min in Cool). The arterial glucose level was kept euglycemic by glucose infusion. No change in tracer-determined glucose production occurred in Sham, whereas in Cool it dropped significantly (2.4 ± 0.4 to 1.9 ± 0.4 mg · kg−1· min−1). Net hepatic glucose output did not change in Sham but decreased from 1.9 ± 0.3 to 1.3 ± 0.3 mg · kg−1· min−1in the Cool group. Hepatic gluconeogenesis did not change in either group. These data suggest that vagal blockade acutely modulates hepatic glucose production by inhibiting glycogenolysis.

scholarly journals Arrestin domain-containing 3 (Arrdc3) modulates insulin action and glucose metabolism in liver

2020 ◽  
Vol 117 (12) ◽  
pp. 6733-6740 ◽  
Author(s):  
Thiago M. Batista ◽  
Sezin Dagdeviren ◽  
Shannon H. Carroll ◽  
Weikang Cai ◽  
Veronika Y. Melnik ◽  
...  
Keyword(s):  
Messenger Rna ◽  
Insulin Action ◽  
Hepatic Glucose Production ◽  
Glycogen Synthesis ◽  
Glucose Production ◽  
Hepatic Glycogen ◽  
Glycogen Accumulation ◽  
Hepatic Glucose ◽  
Glucose Output

Insulin action in the liver is critical for glucose homeostasis through regulation of glycogen synthesis and glucose output. Arrestin domain-containing 3 (Arrdc3) is a member of the α-arrestin family previously linked to human obesity. Here, we show thatArrdc3is differentially regulated by insulin in vivo in mice undergoing euglycemic-hyperinsulinemic clamps, being highly up-regulated in liver and down-regulated in muscle and fat. Mice with liver-specific knockout (KO) of the insulin receptor (IR) have a 50% reduction inArrdc3messenger RNA, while, conversely, mice with liver-specific KO ofArrdc3(L-Arrdc3KO) have increased IR protein in plasma membrane. This leads to increased hepatic insulin sensitivity with increased phosphorylation of FOXO1, reduced expression of PEPCK, and increased glucokinase expression resulting in reduced hepatic glucose production and increased hepatic glycogen accumulation. These effects are due to interaction of ARRDC3 with IR resulting in phosphorylation of ARRDC3 on a conserved tyrosine (Y382) in the carboxyl-terminal domain. Thus,Arrdc3is an insulin target gene, and ARRDC3 protein directly interacts with IR to serve as a feedback regulator of insulin action in control of liver metabolism.

scholarly journals P0950EFFECT OF THYROID HORMONE TREATMENT ON RENAL REABSORPTION OF GLUCOSE IN ALLOXAN-INDUCED DIABETIC RATS

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Gireesh Dayma
Keyword(s):  
Blood Glucose ◽  
Thyroid Hormone ◽  
Glucose Homeostasis ◽  
Hepatic Glucose Production ◽  
Liver Perfusion ◽  
Glucose Production ◽  
Diabetic Rats ◽  
Hepatic Glucose ◽  
Glucose Output ◽  
Renal Expression

Abstract Background and Aims The thyroid hormone (TH) plays an important role in glucose metabolism. Recently, we showed that the TH improves glycemia control by decreasing cytokines expression in the adipose tissue and skeletal muscle of alloxan-induced diabetic rats, which were also shown to present primary hypothyroidism. In this context, this study aims to investigate whether the chronic treatment of diabetic rats with T3 could affect other tissues that are involved in the control of glucose homeostasis, as the liver and kidney. Method Adult male Wistar rats were divided into nondiabetic, diabetic, and diabetic treated with T3 (1.5 ?g/100 g BW for 4 weeks). Diabetes was induced by alloxan monohydrate (150 mg/kg, BW, i.p.). Animals showing fasting blood glucose levels greater than 250 mg/dL were selected for the study. Results After treatment, we measured the blood glucose, serum T3, T4, TSH, and insulin concentration, hepatic glucose production by liver perfusion, liver PEPCK, GAPDH, and pAKT expression, as well as urine glucose concentration and renal expression of SGLT2 and GLUT2. T3 reduced blood glucose, hepatic glucose production, liver PEPCK, GAPDH, and pAKT content and the renal expression of SGLT2 and increased glycosuria. Conclusion Results suggest that the decreased hepatic glucose output and increased glucose excretion induced by T3 treatment are important mechanisms that contribute to reduce serum concentration of glucose, accounting for the improvement of glucose homeostasis control in diabetic rats.

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

2004 ◽  
Vol 286 (2) ◽  
pp. E226-E233 ◽  
Author(s):  
Mary Courtney Moore ◽  
Sylvain Cardin ◽  
Dale S. Edgerton ◽  
Ben Farmer ◽  
Doss W. Neal ◽  
...  
Keyword(s):  
Low Dose ◽  
Glucose Production ◽  
Endogenous Glucose Production ◽  
Hepatic Glucose Output ◽  
Arterial Blood ◽  
Hepatic Glucose ◽  
Arterial Blood Glucose ◽  
Hepatic Portal ◽  
Glucose Output ◽  
Arteriovenous Difference

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 μmol· kg–1·min–1 into a peripheral vein (PE, n = 5) or the hepatic portal (PO, n = 5) vein. Arterial blood glucose increased ∼0.8 mmol/l in both groups. Arterial and hepatic sinusoidal insulin concentrations were not significantly different between groups. PE exhibited an increase in nonhepatic glucose uptake (non-HGU; Δ8.6 ± 1.2 μmol·kg–1·min–1) within 30 min, whereas PO showed a slight suppression (Δ–3.7 ± 3.1 μmol·kg–1·min–1). PO shifted from net hepatic glucose output (NHGO) to uptake (NHGU; 2.5 ± 2.8 μmol·kg–1·min–1) within 30 min, but PE still exhibited NHGO (6.0 ± 1.9 μmol·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.

The direct effects of catecholamines on hepatic glucose production occur via α1- and β2-receptors in the dog

2000 ◽  
Vol 279 (2) ◽  
pp. E463-E473 ◽  
Author(s):  
Chang An Chu ◽  
Dana K. Sindelar ◽  
Kayano Igawa ◽  
Stephanie Sherck ◽  
Doss W. Neal ◽  
...  
Keyword(s):  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Test Period ◽  
Receptor Subtypes ◽  
Adrenergic Blockade ◽  
Direct Effects ◽  
Period 2 ◽  
Hepatic Glucose ◽  
Group 2 ◽  
Glucose Output

The role of α- and β-adrenergic receptor subtypes in mediating the actions of catecholamines on hepatic glucose production (HGP) was determined in sixteen 18-h-fasted conscious dogs maintained on a pancreatic clamp with basal insulin and glucagon. The experiment consisted of a 100-min equilibration, a 40-min basal, and two 90-min test periods in groups 1 and 2, plus a 60-min third test period in groups 3 and 4. In group 1 [α-blockade with norepinephrine (α-blo+NE)], phentolamine (2 μg · kg−1 · min−1) was infused portally during both test periods, and NE (50 ng · kg−1 · min−1) was infused portally at the start of test period 2. In group 2, β-blockade with epinephrine (β-blo+EPI), propranolol (1 μg · kg−1 · min−1) was infused portally during both test periods, and EPI (8 ng · kg−1 · min−1) was infused portally during test period 2. In group 3 (α1-blo+NE), prazosin (4 μg · kg−1 · min−1) was infused portally during all test periods, and NE (50 and 100 ng · kg−1 · min−1) was infused portally during test periods 2 and 3, respectively. In group 4(β2-blo+EPI), butoxamine (40 μg · kg−1 · min−1) was infused portally during all test periods, and EPI (8 and 40 ng · kg−1 · min−1) was infused portally during test periods 2 and 3, respectively. In the presence of α- or α1-adrenergic blockade, a selective rise in hepatic sinusoidal NE failed to increase net hepatic glucose output (NHGO). In a previous study, the same rate of portal NE infusion had increased NHGO by 1.6 ± 0.3 mg · kg−1 · min−1. In the presence of β- or β2-adrenergic blockade, the selective rise in hepatic sinusoidal EPI caused by EPI infusion at 8 ng · kg−1 · min−1 also failed to increase NHGO. In a previous study, the same rate of EPI infusion had increased NHGO by 1.6 ± 0.4 mg · kg−1 · min−1. In conclusion, in the conscious dog, the direct effects of NE and EPI on HGP are predominantly mediated through α1- and β2-adrenergic receptors, respectively.

scholarly journals Autoregulation of hepatic glucose production

1998 ◽  
pp. 240-248 ◽  
Author(s):  
MC Moore ◽  
CC Connolly ◽  
AD Cherrington
Keyword(s):  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Hepatic Glycogen ◽  
Neural Pathways ◽  
Hepatic Glucose Output ◽  
Counterregulatory Hormones ◽  
Hepatic Glucose ◽  
Glucose Output

In vitro evidence indicates that the liver responds directly to changes in circulating glucose concentrations with reciprocal changes in glucose production and that this autoregulation plays a role in maintenance of normoglycemia. Under in vivo conditions it is difficult to separate the effects of glucose on neural regulation mediated by the central nervous system from its direct effect on the liver. Nevertheless, it is clear that nonhormonal mechanisms can cause significant changes in net hepatic glucose balance. In response to hyperglycemia, net hepatic glucose output can be decreased by as much as 60-90% by nonhormonal mechanisms. Under conditions in which hepatic glycogen stores are high (i.e. the overnight-fasted state), a decrease in the glycogenolytic rate and an increase in the rate of glucose cycling within the liver appear to be the explanation for the decrease in hepatic glucose output seen in response to hyperglycemia. During more prolonged fasting, when glycogen levels are reduced, a decrease in gluconeogenesis may occur as a part of the nonhormonal response to hyperglycemia. A substantial role for hepatic autoregulation in the response to insulin-induced hypoglycemia is most clearly evident in severe hypoglycemia (< or = 2.8 mmol/l). The nonhormonal response to hypoglycemia apparently involves enhancement of both gluconeogenesis and glycogenolysis and is capable of supplying enough glucose to meet at least half of the requirement of the brain. The nonhormonal response can include neural signaling, as well as autoregulation. However, even in the absence of the ability to secrete counterregulatory hormones (glucocorticoids, catecholamines, and glucagon), dogs with denervated livers (to interrupt neural pathways between the liver and brain) were able to respond to hypoglycemia with increases in net hepatic glucose output. Thus, even though the endocrine system provides the primary response to changes in glycemia, autoregulation plays an important adjunctive role.

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