Counterregulation of Hypoglycemia: Skeletal Muscle Glycogen Metabolism During Three Hours of Physiological Hyperinsulinemia in Humans
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Abstract:
We examined the role of skeletal muscle in counterregulation of hypoglycemia (3.4 +/- 0.1 mmol/l) in 12 nondiabetic individuals (age 26 +/- 1 years, body mass index 24.2 +/- 0.7 kg/m2) during physiological hyperinsulinemia (280 +/- 25 pmol/l) compared with euglycemia (4.8 +/- 0.1 mmol/l). During hypoglycemia, hepatic glucose output (3-[3H]-glucose) was greater (7.72 +/- 2.72 mumol.kg-1.min-1, P < 0.01), glucose uptake was approximately 49% lower (21.20 +/- 3.55 mumol.kg-1.min-1, P < 0.005), and glucose clearance was reduced (P < 0.002) compared with euglycemia. Rates of flux of plasma-derived glucosyl units through glycolysis were similar in the two experiments, while glycogen synthetic rates were significantly reduced during hypoglycemia (P < 0.01) and accounted entirely for the reduction in glucose disposal. The insulin-induced activation of skeletal muscle glycogen synthase (reflected by Km decline by approximately 50% from 0.408 +/- 0.056 mmol/l and fractional velocity increase by approximately twofold from 21.8 +/- 2.7%) was completely abolished in hypoglycemia. In concert, glycogen phosphorylase activity increased during hypoglycemia by approximately 40% (P = 0.0001). Hypoglycemia resulted in seven- to eightfold increments in plasma epinephrine (P < 0.0001) and growth hormone (P < 0.001) and 40-60% increments in plasma glucagon (P < 0.005) and cortisol (P < 0.05). We conclude that, in this model of mild hypoglycemia of moderate duration, the majority of the glucose made available during the counterregulatory process (approximately 60-70%) is due to the limitation of glucose disposal, mostly via decreased glycogen synthetic activity in skeletal muscle.Keywords:
Hyperinsulinemia
Glycogenolysis
The aim of the present study was to assess the role of calcium fluxes in the action of glucagon on glycogenolysis and gluconeogenesis in isolated rat hepatocytes. Calcium influx was blocked by two ways: by use of the compound tetramethrin and by reduction of extracellular calcium to 1 microM. The minimal concentration of tetramethrin that inhibited glucagon-mediated calcium entry was 7.5 x 10(-7) M. In the presence of 7.5 x 10(-7) M tetramethrin, glucagon-induced glycogenolysis was markedly attenuated when glucagon concentration was 10(-9) M or higher. In contrast, tetramethrin had no effect on glucogenolysis evoked by lower concentrations of glucagon. Similarly, tetramethrin greatly reduced gluconeogenesis induced by high concentrations of glucagon without affecting the effect of low concentrations of glucagon. The same results were obtained in the presence of 1 microM extracellular calcium. To abolish glucagon-induced elevation of cytoplasmic free calcium concentration, we heavily loaded quin2 into hepatocytes. In these cells, glycogenolysis evoked by low concentrations of glucagon was completely abolished. Glycogenolysis caused by high concentrations of glucagon was markedly inhibited. These results indicate that glucagon action on hepatic glucose metabolism is mediated by two different mechanisms, which depend on concentrations of glucagon.
Glycogenolysis
Gluconeogenesis
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To determine the possibility of a threshold concentration of plasma epinephrine that stimulates liver glycogenolysis during exercise, adrenodemedullated (ADM) and sham-operated (SHAM) rats were infused with saline or epinephrine at rates that produced plasma concentrations ranging between 0.01 ng/ml (0.06 nM) and 4.3 ng/ml (23.7 nM). During the infusion rats were run on a rodent treadmill for 0, 30, or 60 min at 21 m/min up a 15% grade. Liver glycogen decreased at similar rates in all exercising rats regardless of plasma epinephrine concentration. Epinephrine infusion stimulated significant muscle glycogen depletion in the soleus and red and white vastus lateralis muscles. ADM saline-infused animals exhibited the least muscle glycogen depletion. Blood glucose and lactate in exercising ADM rats increased as the epinephrine infusion concentration increased. During exercise, there was no epinephrine concentration that stimulated liver glycogenolysis more effectively than physiological saline.
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Intravenous administration of crystalline glucagon 02 mg.⁄kg. was used to study hepatic glycogenolysis and associated events in the unanesthetized dog. An increase in hepatic blood flow and hepatic glucose output regularly occurred following glucagon administration. Approximately 9.6 gm, of glucose were released from the liver during the first hour after a single intravenous injection of glucagon; this represents a net increase over control values of about 6 gm. Depletion of glycogen stores induced by fasting was associated with a decreased or absent response of hepatic blood flow and hepatic glucose output to glucagon. Hepatic uptake of alpha amino nitrogen increased after glucagoninduced glycogenolysis; this increase began promptly and reached a maximum about 45 minutes after glucagon administration. These changes were interperted as reflecting increased gluconeogenesis following depletion of liver glycogen stores. GLYCOGENOLYSIS may be induced in the liver in a controlled fashion by means of glucagon administration.
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Glycogenolysis
Carbohydrate Metabolism
Glycogenesis
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The hormonal control of glycogenolysis has been studied in 3-day-cultured fetal rat hepatocytes which contained stored glycogen. A single addition of 10 nM glucagon or 10 nM epinephrine produced an identical maximal glycogenolytic response, which developed within 4 h and ceased thereafter. The amount of glycogen degraded represented 60% of the stored glycogen or 95% of the newly synthesized glycogen after a 4-h preincubation period in the presence of [14C]glucose. The latter result demonstrates that both hormones interact on the same hepatocytes. Stimulation of glycogenolysis by glucagon or or epinephrine was preceded by an accumulation of intracellular cAMP. From the decreasing order of potency of isoproterenol, epinephrine, norepinephrine, and phenylephrine to activate glycogenolysis, it can be concluded that the epinephrine effect is mainly mediated by beta-adrenergic receptors. When glucagon and epinephrine were added simultaneously at maximal concentrations, the glycogenolytic effects were not additive. Moreover, when epinephrine was added 4 h after glucagon, it elicited a second glycogenolytic response, so that the amount of glycogen degraded represented 80% of the stored glycogen. At this stage, a second addition of glucagon was ineffective, and the extent of the glucagon-induced loss of response depended on the size of the first dose of hormone. Cell densensitizatin to glucagon for glycogenolysis was closely related to the associated response in cAMP production. This desensitization was found to be highly specific for glucagon and was accompanied by a defect in specific glucagon binding. The occurrence of a specific negative regulation of the response to glucagon explained how epinephrine was able to mobilize glycogen accumulated in the continued presence of glucagon during hepatocyte development in culture.
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Glycogenesis
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The glycogen content of the isolated perfused liver taken from fed normal rats is remarkably stable for 3–6 hours ( Am. J. Physiol. 195: 295, 1958) and thus affords an isolated system for studies of the effect of various agents on glycogen synthesis and glycogenolysis. The effects of glucagon and tolbutamide in this system are described. Glucagon given by continuous infusion (30–225 µg/hr.) caused prompt glycogenolysis, with blood glucose concentrations rising to levels as high as 970 mg%. Hyperglycemia of 600–700 mg% did not inhibit the glycogenolytic action of glucagon; however, at glucose levels of 800– 1000 mg% glycogenolysis did not proceed to completion. High concentrations of tolbutamide, maintained before and during administration of glucagon, failed to inhibit the glycogenolytic action of the latter agent.
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The effects of 10"O to lo-? M glucagon on CAMP, phosphorylase a, cell calcium, and glucose production, and glucagon interactions with epinephrine were studied in isolated hepatocytes from adult male and female rats.At physiological concentrations ( 10"10-10-9 M), glucagon activated phosphorylase by increasing cAMP and not by raising the cytosolic free calcium.At supraphysiologic concentrations (and in the male only), glucagon slightly increased the cytosolic free calcium, the fractional efflux of calcium, and, after 2 h, decreased the cell calcium content.Exposure of hepatocytes to the simultaneous administration of lo-' M glucagon and lo-? M epinephrine resulted in a prolongation of the activation of phosphorylase a and a greater release of glucose from glycogen stores than exposure to either agonist alone.In the male, the effects of low concentrations of the two hormones on phosphorylase a activity were additive.Cytosolic free calcium was increased by M epinephrine from 280 to 500 nM while physiological concentrations of glucagon did not change it.In these intact cells, there was no evidence of an a2- adrenergic inhibition of adenyl cyclase and no indication that cAMP depresses the rise in cell calcium induced by a-adrenergic stimuli.
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The rate of glycogenolysis was measured using 13C-NMR in vivo in the rat heart following a glucagon bolus. Glycogen that had just been synthesized during a 50 min infusion of D-[1-13C]glucose and insulin was degraded at a rate of 2.5 mumol/min/g wet wt following a 250 micrograms bolus of glucagon. If a second 50 min infusion of unlabelled glucose followed the D-[-13C]glucose, the rate of mobilization of the labelled glycogen following glucagon was slower (0.52 mumol/min/g wet wt), indicating that the labeled glycogen was less accessible to the activated phosphorylase. Glycogen phosphorylase a (GPa) activity was measured in hearts freeze-clamped at intervals after the glucagon bolus. Activity rose rapidly to 6-fold basal and then returned to basal over 20-30 min (t1/2 decay of phosphorylase activity = 5.1 min). This time course paralleled the exponential fall in heart glycogen which followed glucagon (t1/2 = 4.3 min). Throughout the post-glucagon period the activity of phosphorylase exceeded the rate of glycogenolysis. These findings suggest that the activity of the phosphorylated form of glycogen phosphorylase (GPa) is an important but not the sole determinant of glycogen breakdown in the heart after a glucagon bolus.
Glycogenolysis
Bolus (digestion)
Basal (medicine)
Glycogen branching enzyme
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