Muscle fructose-2,6-bisphosphate and glucose-1,6-bisphosphate during insulin-induced hypoglycemia

1994 ◽  
Vol 76 (2) ◽  
pp. 853-858 ◽  
Author(s):  
W. W. Winder ◽  
J. M. Carling ◽  
C. Duan ◽  
J. P. Jones ◽  
S. L. Palmer ◽  
...  
Keyword(s):  
Insulin Infusion ◽  
Lactate Production ◽  
Glucose Production ◽  
Elevated Plasma ◽  
Hepatic Gluconeogenesis ◽  
Muscle Lactate ◽  
Fasted State ◽  
Lactate Levels ◽  
Fasted Rats ◽  
Gluconeogenic Substrate

Glucose production during insulin-induced hypoglycemia in the fasted state is heavily dependent on the process of hepatic gluconeogenesis. Skeletal muscle glycogen is one possible source of lactate for hepatic gluconeogenesis. Fructose 2,6-bisphosphate (F-2,6-P2) and glucose 1,6-bisphosphate (G-1,6-P2) are two allosteric activators of muscle glycolysis. To investigate their putative role in the control of muscle lactate production during hypoglycemia, fasted rats were infused via jugular catheters with insulin in 0.9% NaCl or with 0.9% NaCl alone for 60 or 120 min. Muscles were removed and clamp frozen in liquid nitrogen. The insulin infusion produced plasma insulin values of 97 +/- 13 microU/ml after 1 h and 100 +/- 9 microU/ml after 2 h. Blood glucose in the saline-infused rats was 4.6 +/- 0.2 mM after 1 h and 5.1 +/- 0.1 mM after 2 h compared with 1.5 +/- 0.01 and 1.0 +/- 0.1 mM after 1 and 2 h, respectively, in the insulin-infused rats. The hypoglycemic rats had significantly elevated plasma epinephrine and blood lactate levels compared with the saline-infused rats. F-2,6-P2 and G-1,6-P2 were increased two- to five-fold in white quadriceps of hypoglycemic rats compared with that of saline-infused rats. The results are consistent with F-2,6-P2 and G-1,6-P2 playing a role in stimulating muscle lactate production as a source of gluconeogenic substrate during insulin-induced hypoglycemia.

Role of epinephrine during insulin-induced hypoglycemia in fasted rats

1994 ◽  
Vol 77 (1) ◽  
pp. 270-276 ◽  
Author(s):  
W. W. Winder ◽  
P. S. MacLean ◽  
S. L. Chandler ◽  
W. Huang ◽  
R. H. Mills
Keyword(s):  
Skeletal Muscle ◽  
Blood Glucose ◽  
Plasma Insulin ◽  
Insulin Infusion ◽  
Lactate Production ◽  
Plasma Epinephrine ◽  
Fasted Rats ◽  
Gluconeogenic Substrate ◽  
Stimulation Of

Responses to insulin-induced hypoglycemia in fasted sham-operated (SHAM), adrenodemedullated (ADM), and epinephrine-infused ADM (ADM + E) rats were studied to ascertain the specific role of epinephrine in increasing resting skeletal muscle content of adenosine 3′,5′-cyclic monophosphate (cAMP) and fructose 2,6-bisphosphate (F-2,6-P2), which are involved in stimulation of muscle glycogenolysis and lactate production. Rats from each group were fasted for 24 h and then infused intravenously with insulin (30, 60, or 90 min) to produce plasma insulin values of approximately 92 microU/ml. One-half of the insulin-infused ADM rats were also infused with epinephrine (ADM + E). Muscle and blood lactate, muscle cAMP, and muscle F-2,6-P2 increased and muscle glycogen decreased in SHAM rats. Each of these changes was prevented or attenuated in ADM rats and restored in ADM + E rats. Liver cAMP, glycogen, and F-2,6-P2 responses to hypoglycemia were similar in SHAM, ADM, and ADM + E rats. Blood glucose decreased to 0.74 +/- 0.05 mM in ADM rats compared with 1.54 +/- 0.11 mM in SHAM and 1.34 +/- 0.15 mM in ADM + E rats after 90 min of insulin infusion. The increase in plasma epinephrine is therefore essential in the counterregulatory response to insulin-induced hypoglycemia in fasted rats. Resting skeletal muscle glycogenolysis and lactate production for hepatic gluconeogenic substrate appear to be important components of the counterregulatory response in fasted rats.

Response to intravenous injections of amylin and glucagon in fasted, fed, and hypoglycemic rats

1993 ◽  
Vol 264 (6) ◽  
pp. E943-E950 ◽  
Author(s):  
A. A. Young ◽  
G. J. Cooper ◽  
P. Carlo ◽  
T. J. Rink ◽  
M. W. Wang
Keyword(s):  
Plasma Glucose ◽  
Insulin Infusion ◽  
Sodium Lactate ◽  
Plasma Lactate ◽  
Glucose Response ◽  
Intravenous Injections ◽  
Glucose Levels ◽  
Fasted State ◽  
Islet Hormone ◽  
Lactate Levels

The actions of intravenous glucagon and amylin, a newly discovered hyperglycemic pancreatic islet hormone, have been compared in 20-h fasted and fed, lightly anesthetized rats, and in rats made hypoglycemic with an insulin infusion. In fasted animals, amylin (75 nmol/kg) was more effective than glucagon (90 nmol/kg) in increasing plasma glucose (glucose increment 4.55 vs. 1.71 mM, P < 0.001). Amylin elicited a marked increase in plasma lactate, as previously reported, whereas glucagon did not alter plasma lactate. In fed animals, glucagon elicited twice as much increase in plasma glucose as did amylin; amylin again elicited a marked lactate increase that was greater (increment 1.45 vs. 0.97 mM, P < 0.05) and more prolonged than in the fasted state, whereas glucagon was without effect on lactate levels. These findings are consistent with glucagon's known action to promote hyperglycemia from hepatic glycogenolysis and amylin's demonstrated action to promote muscle glycogenolysis and increase lactate supply to the liver. Infusions of sodium lactate that produced plasma lactate increments similar to those evoked by 75 nmol/kg amylin evoked patterns of glucose response in fasted and fed rats similar to those evoked by amylin. Thus increased lactate supply to the liver may account for amylin's hyperglycemic effects. Amylin and glucagon could each restore plasma glucose to control levels in fasted animals made hypoglycemic by insulin infusion (plasma glucose reduced to 3.3 mM). A bolus of 75 nmol/kg amylin was more effective than 180 nmol/kg glucagon, restoring basal glucose levels for > 3 h, whereas glucagon restored it for < 1 h.(ABSTRACT TRUNCATED AT 250 WORDS)

Glucose turnover in 48-hour-fasted running rats

1987 ◽  
Vol 252 (3) ◽  
pp. R587-R593 ◽  
Author(s):  
B. Sonne ◽  
K. J. Mikines ◽  
H. Galbo
Keyword(s):  
Plasma Glucose ◽  
Muscle Glycogen ◽  
Lactate Production ◽  
Glucose Production ◽  
Liver Glycogen ◽  
Glucose Turnover ◽  
Feedback Mechanisms ◽  
Glycogen Stores ◽  
Resting Muscle ◽  
Fasted Rats

In fed rats, hyperglycemia develops during exercise. This contrasts with the view based on studies of fasted human and dog that euglycemia is maintained in exercise and glucose production (Ra) controlled by feedback mechanisms. Forty-eight-hour-fasted rats (F) were compared to fed rats (C) and overnight food-restricted (FR) rats. [3-3H]- and [U-14C] glucose were infused and blood and tissue sampled. During running (21 m/min, 0% grade) Ra increased most in C and least in F and only in F did Ra not significantly exceed glucose disappearance. Plasma glucose increased more in C (3.3 mmol/l) than in FR (1.6 mmol/l) and only modestly (0.6 mmol/l) and transiently in F. Resting liver glycogen and exercise glycogenolysis were highest in C and similar in FR and F. Resting muscle glycogen and exercise glycogenolysis were highest in C and lowest in F. During running, lactate production and gluconeogenesis were higher in FR than in F. At least in rats, responses of production and plasma concentration of glucose to exercise depend on size of liver and muscle glycogen stores; glucose production matches increase in clearance better in fasted than in fed states. Probably glucose production is stimulated by “feedforward” mechanisms and “feedback” mechanisms are added if plasma glucose decreases.

Effect of endurance training on activators of glycolysis in muscle during exercise

1994 ◽  
Vol 76 (2) ◽  
pp. 846-852 ◽  
Author(s):  
C. Duan ◽  
W. W. Winder
Keyword(s):  
Endurance Training ◽  
Blood Lactate ◽  
Lactate Concentration ◽  
Lactate Production ◽  
Blood Lactate Concentration ◽  
Quadriceps Muscle ◽  
Muscle Lactate ◽  
Cyclic Monophosphate ◽  
Lactate Levels ◽  
Exercise Induced

Endurance training attenuates exercise-induced increases in blood lactate at the same submaximal work rate. Three intramuscular compounds that influence muscle lactate production were measured in fasted non-trained (NT) and endurance-trained (T) rats. The T rats were subjected to a progressive endurance-training program. At the end of the program (11 wk), they were running 2 h/day at 31 m/min up a 15% grade 5 days/wk. NT and T rats were fasted for 24 h and then anesthetized (pentobarbital, iv) at rest or after running for 30 min at 21 m/min (15% grade). Blood lactate levels were significantly lower in the T rats than in the NT rats after 30 min of running (2.3 +/- 0.2 vs. 3.9 +/- 0.2 mM). The lower blood lactate concentration was accompanied by lower plasma epinephrine (2.8 +/- 0.4 vs. 6.0 +/- 0.8 nM), adenosine 3′, 3′,5′-cyclic monophosphate (0.36 +/- 0.02 vs. 0.50 +/- 0.03 pmol/mg), mg), glucose 1,6-diphosphate (26 +/- 2 vs. 40 +/- 5 pmol/mg), and fructose 2,6-diphosphate (3.2 +/- 0.2 vs. 4.3 +/- 0.3 pmol/mg) in white quadriceps muscle in T than in NT rats. Red quadriceps muscle glucose 1,6-diphosphate and adenosine 3′,5′-cyclic monophosphate were also lower in T than in NT rats. These adaptations may be responsible in part for the lower exercise-induced blood lactate in fasted rats as a consequence of endurance training.

scholarly journals [13C]bicarbonate labelled from hyperpolarized [1-13C]pyruvate is an in vivo marker of hepatic gluconeogenesis in fasted state

2022 ◽  
Vol 5 (1) ◽  
Author(s):  
Emine Can ◽  
Jessica A. M. Bastiaansen ◽  
Dominique-Laurent Couturier ◽  
Rolf Gruetter ◽  
Hikari A. I. Yoshihara ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Pyruvate Dehydrogenase ◽  
Pyruvate Carboxylase ◽  
Phosphoenolpyruvate Carboxykinase ◽  
Hepatic Gluconeogenesis ◽  
Fasted State ◽  
Basal Plasma ◽  
Fasted Rats ◽  
In Vivo Assessment

AbstractHyperpolarized [1-13C]pyruvate enables direct in vivo assessment of real-time liver enzymatic activities by 13C magnetic resonance. However, the technique usually requires the injection of a highly supraphysiological dose of pyruvate. We herein demonstrate that liver metabolism can be measured in vivo with hyperpolarized [1-13C]pyruvate administered at two- to three-fold the basal plasma concentration. The flux through pyruvate dehydrogenase, assessed by 13C-labeling of bicarbonate in the fed condition, was found to be saturated or partially inhibited by supraphysiological doses of hyperpolarized [1-13C]pyruvate. The [13C]bicarbonate signal detected in the liver of fasted rats nearly vanished after treatment with a phosphoenolpyruvate carboxykinase (PEPCK) inhibitor, indicating that the signal originates from the flux through PEPCK. In addition, the normalized [13C]bicarbonate signal in fasted untreated animals is dose independent across a 10-fold range, highlighting that PEPCK and pyruvate carboxylase are not saturated and that hepatic gluconeogenesis can be directly probed in vivo with hyperpolarized [1-13C]pyruvate.

scholarly journals Inhibition of hepatic gluconeogenesis by the Rp-diastereomer of adenosine cyclic 3′,5′-phosphorothioate

1986 ◽  
Vol 237 (2) ◽  
pp. 463-468 ◽  
Author(s):  
C J Dragland-Meserve ◽  
M C Olivieri ◽  
L H P Botelho
Keyword(s):  
Protein Kinase ◽  
Cyclic Amp ◽  
Glycogen Synthase ◽  
Glucose Production ◽  
Liver Glycogen ◽  
Hepatic Gluconeogenesis ◽  
Dependent Protein Kinase ◽  
Dependent Protein ◽  
Fasted Rats

The specific intracellular cyclic AMP-dependent protein kinase antagonist, the Rp-diastereomer of adenosine cyclic 3′,5′-phosphorothioate (Rp-cAMPS), inhibited both basal and cyclic AMP-agonist-induced rates of gluconeogenesis in hepatocytes isolated from fasted rats. Incubation of the cells in the presence of pyruvate and lactate and either the Sp-diastereomer of adenosine cyclic 3′,5′-phosphorothioate (Sp-cAMPS) or glucagon produced a concentration-dependent increase in the rate of gluconeogenic glucose production which was shifted to higher concentrations of Sp-cAMPS or glucagon in the presence of Rp-cAMPS. Incubation of the cells with Rp-cAMPS in the absence of agonist produced no increase in the rate of glucose production and, in most cases, 100 microM-Rp-cAMPS resulted in 14-20% decrease in the substrate-stimulated rate of glucose production. Sp-cAMPS-induced gluconeogenesis was inhibited half-maximally at 1 microM-Rp-cAMPS and glucagon-induced gluconeogenesis was inhibited half-maximally at 12 microM-Rp-cAMPS. Approx. 10-15% of the inhibition of gluconeogenesis observed in the presence of Rp-cAMPS was due to conversion of glucose 6-phosphate to liver glycogen, consistent with Rp-cAMPS-induced reactivation of glycogen synthase. The remaining 85-90% inhibition of gluconeogenic glucose production resulted from the action of Rp-cAMPS on the cyclic AMP-sensitive enzymes controlling the rate of gluconeogenesis.

FFA cause hepatic insulin resistance by inhibiting insulin suppression of glycogenolysis

2002 ◽  
Vol 283 (1) ◽  
pp. E12-E19 ◽  
Author(s):  
Guenther Boden ◽  
Peter Cheung ◽  
T. Peter Stein ◽  
Karen Kresge ◽  
Maria Mozzoli
Keyword(s):  
Insulin Resistance ◽  
Fatty Acids ◽  
Insulin Infusion ◽  
Glucose Production ◽  
Endogenous Glucose Production ◽  
Hepatic Insulin Resistance ◽  
Elevated Plasma ◽  
Heparin Infusion ◽  
Plasma Ffa ◽  
Endogenous Glucose

Free fatty acids (FFA) have been shown to inhibit insulin suppression of endogenous glucose production (EGP). To determine whether this is the result of stimulation by FFA of gluconeogenesis (GNG) or glycogenolysis (GL) or a combination of both, we have determined rates of GNG and GL (with2H2O) and EGP in 16 healthy nondiabetic volunteers (11 males, 5 females) during euglycemic-hyperinsulinemic (∼450 pM) clamping performed either with or without simultaneous intravenous infusion of lipid plus heparin. During insulin infusion, FFA decreased from 571 to 30 μmol/l ( P < 0.001), EGP from 15.7 to 2.0 μmol · kg−1 · min−1( P < 0.01), GNG from 8.2 to 3.7 μmol · kg−1 · min−1( P < 0.05), and GL from 7.4 to −1.7 μmol · kg−1 · min−1( P < 0.02). During insulin plus lipid/heparin infusion, FFA increased from 499 to 1,247 μmol/l ( P< 0.001). EGP decreased 64% less than during insulin alone (−5.1 ± 0.7 vs. −13.7 ± 3.4 μmol · kg−1 · min−1). The decrease in GNG was not significantly different from the decrease of GNG during insulin alone (−2.6 vs. −4.5 μmol · kg−1 · min−1, not significant). In contrast, GL decreased 66% less than during insulin alone (−3.1 vs. −9.2 μmol · kg−1 · min−1, P < 0.05). We conclude that insulin suppressed EGP by inhibiting GL more than GNG and that elevated plasma FFA levels attenuated the suppression of EGP by interfering with insulin suppression of GL.

Divergence of muscle and liver fructose 2,6-diphosphate in fasted exercising rats

1991 ◽  
Vol 260 (5) ◽  
pp. E756-E761 ◽  
Author(s):  
W. W. Winder ◽  
S. R. Fisher ◽  
S. P. Gygi ◽  
J. A. Mitchell ◽  
E. Ojuka ◽  
...  
Keyword(s):  
Lactate Production ◽  
Treadmill Running ◽  
Hepatic Gluconeogenesis ◽  
Signal Molecule ◽  
Threefold Increase ◽  
Fasted Rats

Previous studies demonstrate that nonexercising muscle may serve as a source of lactate for hepatic gluconeogenesis during long-term exercise. The concentration of fructose 2,6-diphosphate (F-2,6-P2), a signal molecule that accelerates glycolysis, was examined in liver and muscles of fed and fasted resting rats and in fasted rats run for 5, 15, or 30 min at 21 m/min (15% grade). Liver F-2,6-P2 decreased in response to fasting and exercise. White quadriceps (composed predominantly of type IIb fibers) F-2,6-P2 increased from 2.2 +/- 0.1 to 4.5 +/- 0.4 pmol/mg in the fasted rats in response to 30 min of treadmill running. No increase was observed in the red region of the quadriceps (composed of type IIa fibers). The fasted rats also exhibited a threefold increase in glucose 1,6-diphosphate (G-1,6-P2) in the white quadriceps after 30 min of exercise, whereas no significant changes were observed in the red quadriceps or in liver. The increases in F-2,6-P2 and G-1,6-P2 may be important in accelerating glycolysis and enhancing lactate production in muscles that are not glycogen depleted during long-term exercise.

Epinephrine, glucose, and lactate infusion in exercising adrenodemedullated rats

1987 ◽  
Vol 62 (4) ◽  
pp. 1442-1447 ◽  
Author(s):  
W. W. Winder ◽  
H. T. Yang ◽  
A. W. Jaussi ◽  
C. R. Hopkins
Keyword(s):  
Blood Lactate ◽  
Plasma Insulin ◽  
Treadmill Exercise ◽  
Metabolic Function ◽  
Elevated Plasma ◽  
Plasma Epinephrine ◽  
Epinephrine Infusion ◽  
Lactate Infusion ◽  
Fasted Rats ◽  
Gluconeogenic Substrate

The purpose of this study was to determine the metabolic function of the marked increase in plasma epinephrine which occurs in fasted rats during treadmill exercise. Fasted adrenodemedullated (ADM) and sham-operated (SHAM) rats were run on a rodent treadmill (21 m/min, 15% grade) for 30 min or until exhaustion. ADM rats were infused with saline, epinephrine, glucose, or lactate during the exercise bouts. ADM saline-infused rats showed markedly reduced endurance, hypoglycemia, elevated plasma insulin, reduced blood lactate, and reduced muscle glycogenolysis compared with exercising SHAM's. Epinephrine infusion corrected all deficiencies. Glucose infusion restored endurance run times and blood glucose to normal without correcting the deficiencies in blood lactate and muscle glycogenolysis. Infusion of lactate partially corrected the hypoglycemia at 30 min of exercise, but endurance was not restored to normal and rats were hypoglycemic at exhaustion. We conclude that in the fasted exercising rat, actions of epinephrine in addition to provision of gluconeogenic substrate are essential for preventing hypoglycemia and allowing the rat to run for long periods of time.

Central KATP channels modulate glucose effectiveness in humans and rodents

2020 ◽  
Author(s):  
Ada Admin ◽  
Michelle Carey ◽  
Eric Lontchi-Yimagou ◽  
William Mitchell ◽  
Sarah Reda ◽  
...  
Keyword(s):  
Katp Channel ◽  
Glucose Production ◽  
Katp Channels ◽  
Endogenous Glucose Production ◽  
Elevated Plasma ◽  
Sprague Dawley ◽  
Glucose Effectiveness ◽  
Sprague Dawley Rats ◽  
The Central Nervous System

Hyperglycemia is a potent regulator of endogenous glucose production (EGP). Loss of this ‘glucose effectiveness’ is a major contributor to elevated plasma glucose concentrations in type 2 diabetes (T2D). ATP-sensitive potassium channels (K<sub>ATP</sub> channels) in the central nervous system (CNS) have been shown to regulate EGP in humans and rodents. We examined the contribution of central K<sub>ATP</sub> channels to glucose effectiveness. Under fixed hormonal conditions (‘pancreatic clamp’ studies), hyperglycemia suppressed EGP by ~50% in both non-diabetic humans and normal Sprague Dawley rats. By contrast, antagonism of K<sub>ATP</sub> channels with glyburide significantly reduced the EGP-lowering effect of hyperglycemia in both humans and rats. Furthermore, the effects of glyburide on EGP and gluconeogenic enzymes in rats were abolished by intracerebroventricular (ICV) administration of the KATP channel agonist diazoxide. These findings indicate that about half of EGP suppression by hyperglycemia is mediated by central K<sub>ATP</sub> channels. These central mechanisms may offer a novel therapeutic target for improving glycemic control in T2D.

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