scholarly journals The kinetics of glucagon action on the liver during insulin-induced hypoglycemia

2020 ◽  
Vol 318 (5) ◽  
pp. E779-E790
Author(s):  
Christina Pedersen ◽  
Guillaume Kraft ◽  
Dale S. Edgerton ◽  
Melanie Scott ◽  
Ben Farmer ◽  
...  
Keyword(s):  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Counterregulatory Hormones ◽  
Glucose Levels ◽  
Sustained Effect ◽  
Hepatic Glucose ◽  
Biphasic Effect ◽  
Sympathetic Nervous ◽  
Kinetics Of ◽  
Arterial Glucose

Glucagon’s effect on hepatic glucose production (HGP), under hyperglycemic conditions, is time dependent such that after an initial burst of HGP, it slowly wanes. It is not known whether this is also the case under hypoglycemic conditions, where an increase in HGP is essential. This question was addressed using adrenalectomized dogs to avoid the confounding effects of other counterregulatory hormones. During the study, infusions of epinephrine and cortisol were given to maintain basal levels. Somatostatin and insulin (800 µU·kg−1·min−1) were infused to induce hypoglycemia. After 30 min, glucagon was infused at a basal rate (1 ng·kg−1·min−1, baGGN group, n = 5 dogs) or a rate eightfold basal (8 ng·kg−1·min−1, hiGGN group, n = 5 dogs) for 4 h. Glucose was infused to match the arterial glucose levels between groups (≈50 mg/dL). Our data showed that glucagon has a biphasic effect on the liver despite hypoglycemia. Hyperglucagonemia stimulated a rapid, transient peak in HGP (4-fold basal production) over ~60 min, which was followed by a slow reduction in HGP to a rate 1.5-fold basal. During the last 2 h of the experiment, hiGGN stimulated glucose production at a rate fivefold greater than baGGN (2.5 vs. 0.5 mg·kg−1·min−1, respectively), indicating a sustained effect of the hormone. Of note, the hypoglycemia-induced rises in norepinephrine and glycerol were smaller in hiGGN compared with the baGGN group despite identical hypoglycemia. This finding suggests that there is reciprocity between glucagon and the sympathetic nervous system such that when glucagon is increased, the sympathetic nervous response to hypoglycemia is downregulated.

Hypoglycemia counterregulation in elderly humans: relationship to glucose levels

1994 ◽  
Vol 267 (4) ◽  
pp. E497-E506 ◽  
Author(s):  
F. J. Ortiz-Alonso ◽  
A. Galecki ◽  
W. H. Herman ◽  
M. J. Smith ◽  
J. A. Jacquez ◽  
...  
Keyword(s):  
Glucose Utilization ◽  
Hepatic Glucose Production ◽  
Severe Hypoglycemia ◽  
Glucose Production ◽  
Counterregulatory Hormones ◽  
Glucose Levels ◽  
Hepatic Glucose ◽  
Consistent Increase ◽  
Step Study ◽  
Elderly Humans

This study was designed to define the effect of human aging on hypoglycemia counterregulatory mechanisms. A hyperinsulinemic (2 mU.kg-1.min-1) glucose clamp procedure was used to control glucose and insulin levels during stepwise lowering of plasma glucose. Counterregulatory hormones, hepatic glucose production (HGP), glucose utilization, and symptoms of hypoglycemia were studied in 13 healthy young [age 24 +/- 1 (SE) yr] and 11 healthy old (age 65 +/- 1 yr) nondiabetic volunteers on two occasions: 1) at matched euglycemia and 70 and 60 mg/dl (study 1) and 2) at matched euglycemia and 60 and 50 mg/dl (study 2). The old had consistently lower epinephrine (P < 0.005), glucagon (P < 0.02), cortisol (P < 0.05), and pancreatic polypeptide (P < 0.02) responses at the 60-mg/dl glucose step in study 1. However, these differences were no longer detectable at the more severe hypoglycemic stimulus of 50 mg/dl in study 2. A consistent increase in HGP occurred in both groups only at the 50-mg/dl glucose step (study 2) and was not different between young and old. There were also no differences in symptom responses between young and old. In summary, we found that elderly individuals have a subtle impairment of the glucose counterregulatory response during moderate hypoglycemia, but this impairment is no longer detectable during more severe hypoglycemia.

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 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.

scholarly journals Glucagon Deficiency Reduces Hepatic Glucose Production and Improves Glucose Tolerance In Adult Mice

2010 ◽  
Vol 31 (4) ◽  
pp. 606-606
Author(s):  
Aidan S. Hancock ◽  
Aiping Du ◽  
Jingxuan Liu ◽  
Mayumi Miller ◽  
Catherine L. May
Keyword(s):  
Glucose Homeostasis ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Postprandial Glucose ◽  
Glucagon Receptor ◽  
Glucose Levels ◽  
Adult Mice ◽  
Hepatic Glucose ◽  
Knockout Animals

Abstract The major role of glucagon is to promote hepatic gluconeogenesis and glycogenolysis to raise blood glucose levels during hypoglycemic conditions. Several animal models have been established to examine the in vivo function of glucagon in the liver through attenuation of glucagon via glucagon receptor knockout animals and pharmacological interventions. To investigate the consequences of glucagon loss to hepatic glucose production and glucose homeostasis, we derived mice with a pancreas specific ablation of the α-cell transcription factor, Arx, resulting in a complete loss of the glucagon-producing pancreatic α-cell. Using this model, we found that glucagon is not required for the general health of mice but is essential for total hepatic glucose production. Our data clarifies the importance of glucagon during the regulation of fasting and postprandial glucose homeostasis.

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 Prevention of Diabetes in db/db Mice by Dietary Soy Is Independent of Isoflavone Levels

Endocrinology ◽  
2012 ◽  
Vol 153 (11) ◽  
pp. 5200-5211 ◽  
Author(s):  
Céline Zimmermann ◽  
Christopher R. Cederroth ◽  
Lucie Bourgoin ◽  
Michelangelo Foti ◽  
Serge Nef
Keyword(s):  
Glucose Homeostasis ◽  
Cell Function ◽  
Hepatic Glucose Production ◽  
Cell Mass ◽  
Glucose Production ◽  
Metabolic Effects ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Glucose Levels ◽  
Hepatic Glucose

Abstract Recent evidence points towards the beneficial use of soy proteins and isoflavones to improve glucose control and slow the progression of type 2 diabetes. Here, we used diabetic db/db mice fed a high soy-containing diet (SD) or a casein soy-free diet to investigate the metabolic effects of soy and isoflavones consumption on glucose homeostasis, hepatic glucose production, and pancreatic islet function. Male db/db mice fed with a SD exhibited a robust reduction in hyperglycemia (50%), correlating with a reduction in hepatic glucose production and preserved pancreatic β-cell function. The rapid decrease in fasting glucose levels resulted from an inhibition of gluconeogenesis and an increase in glycolysis in the liver of db/db mice. Soy consumption also prevented the loss of pancreatic β-cell mass and thus improved glucose-stimulated insulin secretion (3-fold), which partly accounted for the overall improvements in glucose homeostasis. Comparison of SD effects on hyperglycemia with differing levels of isoflavones or with purified isoflavones indicate that the beneficial physiological effects of soy are not related to differences in their isoflavone content. Overall, these findings suggest that consumption of soy is beneficial for improving glucose homeostasis and delaying the progression of diabetes in the db/db mice but act independently of isoflavone concentration.

scholarly journals A HYPOMETABOLIC DEFENSE STRATEGY AGAINST PLASMODIUM INFECTION

2021 ◽  
Author(s):  
Susana Ramos ◽  
Temitope W. Ademolue ◽  
Elisa Jentho ◽  
Qian Wu ◽  
Joel Guerra ◽  
...  
Keyword(s):  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Organ Damage ◽  
Defense Strategy ◽  
Glucose Levels ◽  
Blood Glucose Levels ◽  
Immune Mediated ◽  
Hepatic Glucose ◽  
Reduce Blood Glucose ◽  
Hypometabolic State

SUMMARYHypoglycemia is a clinical hallmark of severe malaria, the often-lethal presentation of Plasmodium falciparum infection of humans. Here we report that mice reduce blood glucose levels in response to Plasmodium infection via a coordinated response whereby labile heme, an alarmin produced via hemolysis, induces anorexia and represses hepatic glucose production (HGP). While protective against unfettered immune-mediated inflammation, organ damage and anemia, when sustained over time heme-driven repression of HGP can progress towards hypoglycemia, compromising host energy expenditure and thermoregulation. This hypometabolic state arrests the development of asexual stages of Plasmodium spp., which undergo pyknosis and develop mitochondrial dysfunction. In response, Plasmodium activates a transcriptional program reducing its virulence and inducing sexual differentiation towards the production of transmissible gametocytes. We infer that malaria-associated hypoglycemia represents a trade-off of an evolutionarily conserved defense strategy restricting Plasmodium spp. from accessing host-derived glucose and balancing parasite virulence and transmission.

Effects of differing insulin levels on response to equivalent hypoglycemia in conscious dogs

1992 ◽  
Vol 263 (4) ◽  
pp. E688-E695 ◽  
Author(s):  
S. N. Davis ◽  
R. Dobbins ◽  
C. Tarumi ◽  
C. Colburn ◽  
D. Neal ◽  
...  
Keyword(s):  
Plasma Glucose ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Conscious Dogs ◽  
High Dose ◽  
Insulin Levels ◽  
Glucose Levels ◽  
Hepatic Glucose ◽  
High Insulin ◽  
Arterial Insulin

The aim of this study was to determine if differing concentrations of insulin can modify the counterregulatory response to equivalent hypoglycemia. Insulin was infused intraportally into normal 18-h-fasted conscious dogs at 2 (low, n = 6) or 8 mU.kg-1.min-1 (high, n = 7) on separate occasions. This resulted in steady-state arterial insulin levels of 80 +/- 8 and 610 +/- 55 microU/ml, respectively. Glucose was infused during the high dose to maintain plasma glucose similar to low (50 +/- 1 mg/dl). Despite similar plasma glucose levels, epinephrine (2,589 +/- 260, 806 +/- 180 pg/ml), norepinephrine (535 +/- 60, 303 +/- 55 pg/ml), cortisol (12.1 +/- 1.5, 5.8 +/- 1.2 micrograms/dl), and pancreatic polypeptide (1,198 +/- 150, 598 +/- 250 pg/ml) were all increased in the presence of high-dose insulin (P < 0.05). Glucagon levels were similar during both insulin infusions. Hepatic glucose production, measured with [3-3H]-glucose, rose from 2.6 +/- 0.2 to 4.7 +/- 0.3 mg.kg-1.min-1 in response to high insulin (P < 0.01) but remained unchanged, 3.0 +/- 0.5 mg.kg-1.min-1, during low-dose infusions. Six hyperinsulinemic euglycemic control experiments (2 or 8 mU.kg-1.min-1, n = 3 in each) provided baseline data. By the final hour of the high-dose euglycemic clamps, cortisol (2.4 +/- 0.4 to 4.8 +/- 0.8 micrograms/dl) and norepinephrine (125 +/- 34 to 278 +/- 60 pg/ml) had increased (P < 0.05) compared with baseline. Plasma epinephrine levels remained unchanged during both series of euglycemic studies.(ABSTRACT TRUNCATED AT 250 WORDS)

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