Endothelin-1 infusion reduces splanchnic glucose production in humans

1994 ◽  
Vol 77 (1) ◽  
pp. 121-126 ◽  
Author(s):  
G. Ahlborg ◽  
E. Weitzberg ◽  
J. M. Lundberg
Keyword(s):  
Glucose Production ◽  
Underlying Mechanism ◽  
Suppressive Effect ◽  
Related Factors ◽  
Arterial Lactate ◽  
Endothelin 1 ◽  
Blood Flows ◽  
Level 3 ◽  
Glucagon And Insulin ◽  
Arterial Insulin

Two groups of six healthy subjects received an intravenous endothelin-1 (ET-1) infusion (4 pmol.kg-1.min-1 for 20 min) in the basal state. Blood was drawn from catheters in an artery (n = 12), a hepatic vein (n = 12), and a renal vein (n = 6) for determinations of blood flows and substrate exchanges. During the ET-1 infusion, splanchnic and renal blood flows were reduced by approximately 50 (P < 0.01) and 25% (P < 0.001), respectively. Arterial glucose concentration and splanchnic glucose production fell by approximately 4 (P < 0.01) and 55% (P < 0.001), respectively. The latter was still 30% below basal level 3 h after the infusion (P < 0.001). Arterial glycerol increased by 64% (P < 0.01), whereas arterial lactate was unchanged. Splanchnic uptakes of lactate and glycerol were unchanged. Arterial insulin and glucagon showed transient falls with a maximal drop of approximately 35% (P < 0.001) during the infusion. In conclusion, ET-1 infusion causes reduced splanchnic glucose production due to reduced glycogen-derived glucose release. The latter could partly be connected with the transient fall in arterial glucagon, but the prolonged suppressive effect on splanchnic glycogenolysis seems to be linked with other ET-1-related factors. We propose that the underlying mechanism to the transient falls in both arterial glucagon and insulin might be coupled to the ET-1-arginine-NO system.

Circulating endothelin-1 reduces splanchnic and renal blood flow and splanchnic glucose production in humans

1995 ◽  
Vol 79 (1) ◽  
pp. 141-145 ◽  
Author(s):  
G. Ahlborg ◽  
E. Weitzberg ◽  
J. M. Lundberg
Keyword(s):  
Blood Pressure ◽  
Blood Flow ◽  
Plasma Concentration ◽  
Healthy Subjects ◽  
Glucose Production ◽  
Physiological Saline ◽  
Sepsis Syndrome ◽  
Endothelin 1 ◽  
Blood Flows ◽  
Arterial Blood

The effect of minimal changes in circulating plasma endothelin-1 (ET-1) was studied in 12 healthy subjects receiving either 60 min of ET-1 (0.2 pmol.kg-1.min-1) or physiological saline intravenously. Blood was drawn from arterial, renal, and central hepatic vein catheters. Arterial ET-1-like immunoreactivity (ET-1-LI) increased from 4.7 +/- 0.4 (SE) to 8.6 +/- 1.0 pmol/l during ET-1 infusion. After 10 min, plasma ET-1-LI had increased to 6.12 +/- 0.29 pmol/l. For comparison the plasma ET-1-LI level was 12.9 +/- 4.2 pmol/in five patients with sepsis syndrome. Mean arterial blood pressure rose from 92 +/- 3 to 99 +/- 4 mmHg. Estimated splanchnic and renal blood flows fell by 18 +/- 5 and 10 +/- 3%, respectively, and splanchnic glucose production fell by 42 +/- 6% within 10 min of the ET-1 infusion and differed compared with corresponding control values. Only estimated splanchnic blood flow had increased 60 min after the ET-1 infusion. No change in splanchnic uptake of lactate or glycerol was seen. In conclusion, we suggest that circulating ET-1 with small or no demonstrable change in plasma concentration interferes with vasoactivity and splanchnic glycogenolyses in health and possibly pathophysiological conditions.

5-Aminoimidazole-4-carboxamide-1-β-d-ribofuranoside renders glucose output by the liver of the dog insensitive to a pharmacological increment in insulin

2005 ◽  
Vol 289 (6) ◽  
pp. E1039-E1043 ◽  
Author(s):  
Raul C. Camacho ◽  
D. Brooks Lacy ◽  
Freyja D. James ◽  
E. Patrick Donahue ◽  
David H. Wasserman
Keyword(s):  
Portal Vein ◽  
Vena Cava ◽  
Glucose Production ◽  
Suppressive Effect ◽  
Endogenous Glucose Production ◽  
Hepatic Glucose Output ◽  
Study Protocols ◽  
Hepatic Glucose ◽  
Glucose Output ◽  
Arterial Insulin

This study aimed to test whether stimulation of net hepatic glucose output (NHGO) by increased concentrations of the AMP analog, 5-aminoimidazole-4-carboxamide-1-β-d-ribosyl-5-monophosphate, can be suppressed by pharmacological insulin levels. Dogs had sampling (artery, portal vein, hepatic vein) and infusion (vena cava, portal vein) catheters and flow probes (hepatic artery, portal vein) implanted >16 days before study. Protocols consisted of equilibration (−130 to −30 min), basal (−30 to 0 min), and hyperinsulinemic-euglycemic (0–150 min) periods. At time ( t) = 0 min, somatostatin was infused, and basal glucagon was replaced via the portal vein. Insulin was infused in the portal vein at either 2 (INS2) or 5 (INS5) mU·kg−1·min−1. At t = 60 min, 1 mg·kg−1·min−1portal venous 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR) infusion was initiated. Arterial insulin rose ∼9- and ∼27-fold in INS2 and INS5, respectively. Glucagon, catecholamines, and cortisol did not change throughout the study. NHGO was completely suppressed before t = 60 min. Intraportal AICAR stimulated NHGO by 1.9 ± 0.5 and 2.0 ± 0.5 mg·kg−1·min−1in INS2 and INS5, respectively. AICAR stimulated tracer-determined endogenous glucose production similarly in both groups. Intraportal AICAR infusion significantly increased hepatic acetyl-CoA carboxylase (ACC, Ser79) phosphorylation in INS2. Hepatic ACC (Ser79) phosphorylation, however, was not increased in INS5. Thus intraportal AICAR infusion renders hepatic glucose output insensitive to pharmacological insulin. The effectiveness of AICAR in countering the suppressive effect of pharmacological insulin on NHGO occurs even though AICAR-stimulated ACC phosphorylation is completely blocked.

Hepatic glucose autoregulation: responses to small, non-insulin-induced changes in arterial glucose

2004 ◽  
Vol 287 (2) ◽  
pp. E269-E274 ◽  
Author(s):  
Raul C. Camacho ◽  
D. Brooks Lacy ◽  
Freyja D. James ◽  
Robert H. Coker ◽  
David H. Wasserman
Keyword(s):  
Glucose Production ◽  
Pancreatic Hormones ◽  
Small Increment ◽  
Study Protocols ◽  
Hepatic Glucose ◽  
Glucagon And Insulin ◽  
Induced Changes ◽  
Arterial Insulin ◽  
Arterial Glucose

The purpose of this study was to determine whether the sedentary dog is able to autoregulate glucose production (Ra) in response to non-insulin-induced changes (<20 mg/dl) in arterial glucose. Dogs had catheters implanted >16 days before study. Protocols consisted of basal (−30 to 0 min) and bilateral renal arterial phloridzin infusion (0–180 min) periods. Somatostatin was infused, and glucagon and insulin were replaced to basal levels. In one protocol (Phl ± Glc), glucose was allowed to fall from t = 0–90 min. This was followed by a period when glucose was infused to restore euglycemia (90–150 min) and a period when glucose was allowed to fall again (150–180 min). In a second protocol (EC), glucose was infused to compensate for the renal glucose loss due to phloridzin and maintain euglycemia from t = 0–180 min. Arterial insulin, glucagon, cortisol, and catecholamines remained at basal in both protocols. In Phl ± Glc, glucose fell by ∼20 mg/dl by t = 90 min with phloridzin infusion. Radid not change from basal in Phl ± Glc despite the fall in glucose for the first 90 min. Rawas significantly suppressed with restoration of euglycemia from t = 90–150 min ( P < 0.05) and returned to basal when glucose was allowed to fall from t = 150–180 min. Radid not change from basal in EC. In conclusion, the liver autoregulates Rain response to small changes in glucose independently of changes in pancreatic hormones at rest. However, the liver of the resting dog is more sensitive to a small increment, rather than decrement, in arterial glucose.

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)

Increased hepatic glucose production response to glucagon in trained subjects

1998 ◽  
Vol 274 (1) ◽  
pp. E23-E28 ◽  
Author(s):  
Réjean Drouin ◽  
Carole Lavoie ◽  
Josée Bourque ◽  
Francine Ducros ◽  
Danielle Poisson ◽  
...  
Keyword(s):  
Endurance Training ◽  
Hepatic Glucose Production ◽  
Area Under The Curve ◽  
Glucose Production ◽  
Trained Subjects ◽  
Endogenous Insulin ◽  
Hepatic Glucose ◽  
Glucagon And Insulin ◽  
The Impact ◽  
Male Subjects

This study was designed to characterize the impact of endurance training on the hepatic response to glucagon. We measured the effect of glucagon on hepatic glucose production (HGP) in resting trained ( n = 8) and untrained ( n = 8) healthy male subjects (maximal rate of O2 consumption: 65.9 ± 1.6 vs. 46.8 ± 0.6 ml O2 ⋅ kg−1 ⋅ min−1, respectively, P < 0.001). Endogenous insulin and glucagon were suppressed by somatostatin (somatotropin release-inhibiting hormone) infusion (450 μg/h) over 4 h. Insulin (0.15 mU ⋅ kg−1 ⋅ min−1) was infused throughout the study, and glucagon (1.5 ng ⋅ kg−1 ⋅ min−1) was infused over the last 2 h. During the latter period, plasma glucagon and insulin remained constant at 138.2 ± 3.1 vs. 145.3 ± 2.1 ng/l and at 95.5 ± 4.5 vs. 96.2 ± 1.9 pmol/l in trained and untrained subjects, respectively. Plasma glucose increased and peaked at 11.4 ± 1.1 mmol/l in trained subjects and at 8.9 ± 0.8 mmol/l in untrained subjects ( P < 0.001). During glucagon stimulation, the mean increase in HGP area under the curve was 15.8 ± 2.8 mol ⋅ kg−1 ⋅ min−1in trained subjects compared with 7.4 ± 1.6 mol ⋅ kg−1 ⋅ min−1in untrained subjects ( P < 0.01) over the first hour and declined to 6.8 ± 2.8 and 4.9 ± 1.4 mol ⋅ kg−1 ⋅ min−1during the second hour. In conclusion, these observations indicate that endurance training is associated with an increase in HGP in response to physiological levels of glucagon, thus suggesting an increase in hepatic glucagon sensitivity.

scholarly journals Leptin Activates a Novel CNS Mechanism for Insulin-Independent Normalization of Severe Diabetic Hyperglycemia

Endocrinology ◽  
2010 ◽  
Vol 152 (2) ◽  
pp. 394-404 ◽  
Author(s):  
Jonathan P. German ◽  
Joshua P. Thaler ◽  
Brent E. Wisse ◽  
Shinsuke Oh-I ◽  
David A. Sarruf ◽  
...  
Keyword(s):  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Underlying Mechanism ◽  
Glucose Levels ◽  
Blood Glucose Levels ◽  
Uncontrolled Diabetes ◽  
Urinary Glucose ◽  
Hepatic Glucose ◽  
Glucose Excretion ◽  
The Brain

Abstract The brain has emerged as a target for the insulin-sensitizing effects of several hormonal and nutrient-related signals. The current studies were undertaken to investigate mechanisms whereby leptin lowers circulating blood glucose levels independently of insulin. After extending previous evidence that leptin infusion directly into the lateral cerebral ventricle ameliorates hyperglycemia in rats with streptozotocin-induced uncontrolled diabetes mellitus, we showed that the underlying mechanism is independent of changes of food intake, urinary glucose excretion, or recovery of pancreatic β-cells. Instead, leptin action in the brain potently suppresses hepatic glucose production while increasing tissue glucose uptake despite persistent, severe insulin deficiency. This leptin action is distinct from its previously reported effect to increase insulin sensitivity in the liver and offers compelling evidence that the brain has the capacity to normalize diabetic hyperglycemia in the presence of sufficient amounts of central nervous system leptin.

Effects of selective insulin or glucagon deficiency on glucose turnover.

1979 ◽  
Vol 236 (3) ◽  
pp. E255
Author(s):  
H L Lickley ◽  
G G Ross ◽  
M Vranic
Keyword(s):  
Glucose Production ◽  
Plasma Free Fatty Acid ◽  
Metabolic Effects ◽  
Glucose Turnover ◽  
Immunoreactive Insulin ◽  
Hormonal Changes ◽  
Futile Cycling ◽  
Plasma Immunoreactive Insulin ◽  
Glucagon Suppression ◽  
Glucagon And Insulin

To study the importance of glucagon and insulin in diabetes, somatostatin (ST) was infused, alone or with insulin or glucagon, in 11 conscious dogs. Plasma immunoreactive insulin (IRI) and glucagon (IRG) levels fell 65 +/- 4% and 33 +/- 3%, respectively, with somatostatin infusion. Glucose production (Ra) assessed by [3-3H]glucose, [2-3H]glucose, or [1-14C]glucose decreased transiently. This is in contrast to the rise in Ra seen after insulin withdrawal in depancreatized dogs, which have normal levels of IRG. Thus, suppression of IRG with somatostatin prevented an increase in Ra in spite of suppression of IRI. When near basal IRG levels were provided during ST infusion in normal dogs, Ra increased, indicating that glucagon contributes to the acute development of diabetes. When basal IRI levels were provided with ST, suppression of Ra was maintained, suggesting that the transience of the metabolic effects of ST-induced glucagon suppression requires concomitant insulin suppression. A comparison of glucose turnover measured using different tracers showed that ST-related hormonal changes did not alter the rate of futile cycling in the liver. ST induced a rise in plasma free fatty acid (FFA) levels, attributed solely to insulin deficiency, as glucagon suppression did not significantly alter FFA concentrations when normal insulin levels were maintained.

Glucagon enhances the direct suppressive effect of insulin on hepatic glucose production in humans

1997 ◽  
Vol 272 (3) ◽  
pp. E371-E378 ◽  
Author(s):  
G. F. Lewis ◽  
M. Vranic ◽  
A. Giacca
Keyword(s):  
Type I Diabetes ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Insulin Delivery ◽  
Suppressive Effect ◽  
Type I ◽  
Constant Rate ◽  
Hepatic Glucose ◽  
Infusion Method

The present study examines the role of glucagon in modulating the hepatic and extrahepatic effects of insulin on hepatic glucose production (HGP). We infused glucagon at a constant rate (0.65 ng x kg(-1) x min(-1)) during equimolar portal and peripheral insulin delivery in seven healthy males by our previously published tolbutamide infusion method. In contrast to our previous study, in which glucagon fell by approximately 30% during hyperinsulinemia and suppression of HGP was significantly greater with equimolar peripheral than with portal insulin delivery, HGP was actually suppressed to a lesser extent with peripheral insulin delivery (69 +/- 10%) than when insulin was delivered portally (76 +/- 5%, P < 0.05). To further examine whether glucagon was enhancing the effect of portal insulin, in four additional individuals HGP was suppressed to a greater extent during a tolbutamide infusion when glucagon was administered continuously throughout the basal and hyperinsulinemic periods than when glucagon was infused during the basal period only; HGP suppressed by 63 +/- 3 vs. 52 +/- 3%, respectively, P = 0.02). Tolbutamide had no effect on HGP when infused into three C-peptide-negative individuals with type I diabetes during a low-dose insulin and glucagon infusion. These data suggest that glucagon levels are an important determinant of the balance between insulin's direct and indirect effects on HGP, with glucagon likely potentiating the direct hepatic effect of insulin.

scholarly journals Contribution of systemic inflammation to permanence of KATP-induced neonatal diabetes in mice

2018 ◽  
Vol 315 (6) ◽  
pp. E1121-E1132
Author(s):  
Christopher H. Emfinger ◽  
Zihan Yan ◽  
Alecia Welscher ◽  
Peter Hung ◽  
William McAllister ◽  
...  
Keyword(s):  
Insulin Sensitivity ◽  
Systemic Inflammation ◽  
Treatment Effectiveness ◽  
Glucose Production ◽  
Neonatal Diabetes ◽  
Underlying Mechanism ◽  
Normal Serum ◽  
Severe Insulin Resistance ◽  
Severe Diabetes ◽  
Glucagon Like Peptide 1

Gain-of-function (GOF) mutations in the ATP-sensitive potassium (KATP) channels cause neonatal diabetes. Despite the well-established genetic root of the disease, pathways modulating disease severity and treatment effectiveness remain poorly understood. Patient phenotypes can vary from severe diabetes to remission, even in individuals with the same mutation and within the same family, suggesting that subtle modifiers can influence disease outcome. We have tested the underlying mechanism of transient vs. permanent neonatal diabetes in KATP-GOF mice treated for 14 days with glibenclamide. Some KATP-GOF mice show remission of diabetes and enhanced insulin sensitivity long after diabetes treatment has ended, while others maintain severe insulin-resistance. However, insulin sensitivity is not different between the two groups before or during diabetes induction, suggesting that improved sensitivity is a consequence, rather than the cause of, remission, implicating other factors modulating glucose early in diabetes progression. Leptin, glucagon, insulin, and glucagon-like peptide-1 are not different between remitters and nonremitters. However, liver glucose production is significantly reduced before transgene induction in remitter, relative to nonremitter and nontreated, mice. Surprisingly, while subsequent remitter animals exhibited normal serum cytokines, nonremitter mice showed increased cytokines, which paralleled the divergence in blood glucose. Together, these results suggest that systemic inflammation may play a role in the remitting versus non-remitting outcome. Supporting this conclusion, treatment with the anti-inflammatory meloxicam significantly increased the fraction of remitting animals. Beyond neonatal diabetes, the potential for inflammation and glucose production to exacerbate other forms of diabetes from a compensated state to a glucotoxic state should be considered.

Effect of somatostatin on plasma glucagon and insulin, and glucose turnover in exercising sheep

1979 ◽  
Vol 47 (2) ◽  
pp. 273-278 ◽  
Author(s):  
R. P. Brockman
Keyword(s):  
Insulin Secretion ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Strenuous Exercise ◽  
Glucose Turnover ◽  
Moderate Exercise ◽  
Plasma Glucagon ◽  
Hepatic Glucose ◽  
Exercise Induced ◽  
Glucagon And Insulin

To examine the roles of glucagon and insulin in exercise, four sheep were run on a treadmill with and without simultaneous infusion of somatostatin (SRIF), a peptide that suppresses glucagon and insulin secretion. SRIF infusion suppressed the exercise-induced rise in plasma glucagon during both moderate (5--5.5 km/h) and strenuous exercise (7.0 km/h). In addition, SRIF prevented the rise insulin concentrations during moderate exercise. During strenuous exercise, insulin concentrations were depressed in both groups. The infusion of SRIF was associated with a reduction in exercise-induced glucose production, as determined by infusion of [6–3H]glucose, during the first 15 min of both moderate and strenuous exercise compared to controls. Beyond 15 min glucose production was not significantly altered by SRIF infusions. These data are consistent with glucagon having an immediate, but only transient, stimulatory effect on the exercise-induced hepatic glucose production.

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