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.

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.

Absorption and disposition of a glucose load in the conscious dog

1982 ◽  
Vol 242 (6) ◽  
pp. E398-E406 ◽  
Author(s):  
N. N. Abumrad ◽  
A. D. Cherrington ◽  
P. E. Williams ◽  
W. W. Lacy ◽  
D. Rabin
Keyword(s):  
Hepatic Glucose Production ◽  
Control Period ◽  
Glucose Production ◽  
Glucose Disposal ◽  
Glucose Load ◽  
Insulin Levels ◽  
Glucose Ingestion ◽  
Hepatic Glucose ◽  
Glucose Output ◽  
Arterial Glucose

The quantitative disposition of an intragastrically administered glucose load was studied in eight conscious 18-h fasted dogs using isotopic and arteriovenous (A-V) techniques. During the control period, the gut utilized 25% of the basal net hepatic glucose output (2.8 +/- 0.2 mg.kg-1.min-1). After glucose ingestion, 80% of the load was absorbed as glucose, 11% was converted across the gut to lactate and alanine, and 4% was oxidized to CO2. Two percent of the load remained in the gut 4 h after glucose administration and 3% was unaccounted for. During the absorptive period, net hepatic glucose balance (NHGB) varied considerably (mean range = output of 1.8 to uptake of 9.1 mg.kg-1.min-1), while endogenous hepatic glucose production (Ra hp) showed a consistent 80% suppression. The total net hepatic glucose uptake during the absorptive period (150 +/- 10 min) accounted for the disposal of 24 +/- 10% of the ingested load, and the amount of glucose escaping the splanchnic bed was 40 +/- 3%. Overall NHGB correlated positively with basal arterial glucose and insulin levels and negatively with basal arterial glycerol and FFA and with peak absorptive arterial glucose and insulin levels. These data suggest that the hepatic response to an ingested glucose load depends in part on the degree of metabolic fast of the animal at the time of glucose ingestion; the latter may be a major determinant of the roles played by the tissues in glucose disposal.

scholarly journals The impact of obesity, sex, and diet on hepatic glucose production in cats

2009 ◽  
Vol 296 (4) ◽  
pp. R936-R943 ◽  
Author(s):  
Saskia Kley ◽  
Margarethe Hoenig ◽  
John Glushka ◽  
Eunsook S. Jin ◽  
Shawn C. Burgess ◽  
...  
Keyword(s):  
Phosphoenolpyruvate Carboxykinase ◽  
Citrate Synthase ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Endogenous Glucose Production ◽  
Hepatic Glucose Metabolism ◽  
Peripheral Insulin Resistance ◽  
Pyruvate Cycling ◽  
Hepatic Glucose ◽  
The Impact

Obesity is a risk factor for type 2 diabetes in cats. The risk of developing diabetes is severalfold greater for male cats than for females, even after having been neutered early in life. The purpose of this study was to investigate the role of different metabolic pathways in the regulation of endogenous glucose production (EGP) during the fasted state considering these risk factors. A triple tracer protocol using 2H2O, [U-13C3]propionate, and [3,4-13C2]glucose was applied in overnight-fasted cats (12 lean and 12 obese; equal sex distribution) fed three different diets. Compared with lean cats, obese cats had higher insulin ( P < 0.001) but similar blood glucose concentrations. EGP was lower in obese cats ( P < 0.001) due to lower glycogenolysis and gluconeogenesis (GNG; P < 0.03). Insulin, body mass index, and girth correlated negatively with EGP ( P < 0.003). Female obese cats had ∼1.5 times higher fluxes through phosphoenolpyruvate carboxykinase ( P < 0.02) and citrate synthase ( P < 0.05) than male obese cats. However, GNG was not higher because pyruvate cycling was increased 1.5-fold ( P < 0.03). These results support the notion that fasted obese cats have lower hepatic EGP compared with lean cats and are still capable of maintaining fasting euglycemia, despite the well-documented existence of peripheral insulin resistance in obese cats. Our data further suggest that sex-related differences exist in the regulation of hepatic glucose metabolism in obese cats, suggesting that pyruvate cycling acts as a controlling mechanism to modulate EGP. Increased pyruvate cycling could therefore be an important factor in modulating the diabetes risk in female cats.

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.

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.

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.

scholarly journals Effect of 11β-hydroxysteroid dehydrogenase-1 inhibition on hepatic glucose metabolism in the conscious dog

2010 ◽  
Vol 298 (5) ◽  
pp. E1019-E1026 ◽  
Author(s):  
Dale S. Edgerton ◽  
Rita Basu ◽  
Christopher J. Ramnanan ◽  
Tiffany D. Farmer ◽  
Doss Neal ◽  
...  
Keyword(s):  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Hydroxysteroid Dehydrogenase ◽  
Insulin Deficiency ◽  
Potential Therapeutic Target ◽  
Hepatic Glucose Metabolism ◽  
Hepatic Glucose ◽  
Healthy Dogs ◽  
Excess Glucose

Inactive cortisone is converted to active cortisol within the liver by 11β-hydroxysteroid dehydrogenase-1 (11β-HSD1), and impaired regulation of this process may be related to increased hepatic glucose production (HGP) in individuals with type 2 diabetes. The primary aim of this study was to investigate the effect of acute 11β-HSD1 inhibition on HGP and fat metabolism during insulin deficiency. Sixteen conscious, 42-h-fasted, lean, healthy dogs were studied. Somatostatin was infused to create insulin deficiency, and the animals were treated with a specific 11β-HSD1 inhibitor (compound 531) or placebo for 5 h. 11β-HSD1 inhibition completely suppressed hepatic cortisol production, and this attenuated the increase in HGP that occurred during insulin deficiency. PEPCK and glucose-6-phosphatase expression were decreased when 11β-HSD1 was inhibited, but gluconeogenic flux was unchanged, implying an effect on glycogenolysis. Since inhibition of hepatic cortisol production reduces HGP during insulin deficiency, 11β-HSD1 is a potential therapeutic target for the treatment of excess glucose production that occurs in diabetes.

Regulation of blood glucose concentration: response of liver to glucose administration

1961 ◽  
Vol 201 (1) ◽  
pp. 41-46 ◽  
Author(s):  
Bernard R. Landau ◽  
Jack R. Leonards ◽  
Frank M. Barry
Keyword(s):  
Blood Glucose ◽  
Glucose Concentration ◽  
Blood Glucose Concentration ◽  
Dominant Role ◽  
Hepatic Glucose Production ◽  
High Protein Diet ◽  
Glucose Production ◽  
Hepatic Veins ◽  
Hepatic Glucose ◽  
Glucose Output

Hepatic glucose output has been determined during the infusion of glucose in gradually increasing quantities into unanesthetized dogs with cannulas inserted in their aortas, hepatic veins and portal veins. Profound changes in hepatic response to the infusions were consequent to differences in the composition of the diets ingested by the dogs in the days prior to these experiments. Infusion of glucose into dogs maintained on a high protein diet resulted in a rise in blood glucose concentration, with a cessation of net hepatic glucose production only at hyperglycemic levels. In contrast, in carbohydrate-fed dogs the blood glucose concentration increased very little on glucose infusion, and there was a net uptake of glucose by the liver. Under these conditions the liver appears to play a dominant role in the regulation of the constancy of the blood glucose concentration, and the regulating mechanism appears to be particularly sensitive to small changes in glucose concentration.

Sign in / Sign up

Export Citation Format

Share Document