Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01275 (glucagon)
 26,492 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In idiopathic or generalized epilepsy, serum glucose and cholesterol concentrations tend to be low, especially just before the seizure. Glucose tolerance curves are abnormal and variable. The electrolyte balance is disturbed, and epileptics tend to go readily into alkalosis. Serum [Na+] is usually unaffected, but [K+] is normal to low between attacks and increases during and after the seizure. Serum [Cl-] is usually high just before the seizure. Epileptics are generally mildly hypocalcemic, especially in the period before the seizure. Serum urea and nonprotein nitrogen values are low between paroxysms but increase after the seizure. Serum protein concentration is usually normal. Stress, which releases epinephrine and corticotropin, results in high serum citrate concentration, which probably contributes to decreased serum [Ca2+] just before a seizure. In the healthy individual, any increase in serum citrate is accompanied by increasing [Ca2+]. In the rabbit, convulsions can be induced with corticotropin, a result of increased serum citrate concentration coupled with a decrease in [Ca2+]. The net result is severe hypo-ionic-calcemia. A similar phenomenon has been reported in a few humans. Administration of insulin causes serum citrate concentrations to decrease. Apparently, the dynamic system that controls glucose and lipid metabolism, and thus electrolyte balance, through the hormones epinephrine, corticotropin, insulin, glucagon, calcitonin, and parathormone, is abnormal in the epileptic.
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PMID:Clinical biochemistry of epilepsy. I. Nature of the disease and a review of the chemical findings in epilepsy. 22 Nov 36

The effects of acute pH changes on whole body leucine kinetics (1-13C-leucine infusion technique) were determined in normal subjects. Plasma insulin, glucagon, and growth hormone concentrations were kept constant by somatostatin and replacement infusions of the three hormones. When acidosis was produced by ingestion of NH4Cl (4 mmol kg-1 p.os; n = 8) arterialized pH decreased within 3 h from 7.39 +/- 0.01 to 7.31 +/- 0.01 (P less than 0.001) and leucine plasma appearance increased by 0.13 +/- 0.04 mumol kg-1 min-1 (P less than 0.02); in contrast, when alkalosis was produced by intravenous infusion of 4 mmol kg-1 NaHCO3 (n = 7, pH 7.47 +/- 0.01), leucine plasma appearance decreased by -0.09 +/- 0.04 mumol kg-1 min-1 (P less than 0.01 vs. acidosis). Whole body leucine flux also increased during acidosis compared to alkalosis (P less than 0.05), suggesting an increase in whole body protein breakdown during acidosis. Apparent leucine oxidation increased during acidosis compared to alkalosis (P = 0.05). Net forearm leucine exchange remained unaffected by acute pH changes. Plasma FFA concentrations decreased during acidosis by -107 +/- 67 mumol l-1 (P less than 0.05) and plasma glucose increased by 1.90 +/- 0.25 mmol l-1 (P less than 0.02); in contrast, alkalosis resulted in an increase in plasma FFA by 83 +/- 40 mumol l-1 (P less than 0.02; P less than 0.01 vs. acidosis), suggesting an increase in lipolysis; plasma glucose decreased compared to acidosis (P less than 0.01). The data demonstrate that acute metabolic acidosis and alkalosis, as they occur in clinical conditions, influence protein breakdown, and in the opposite direction, lipolysis.
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PMID:Effect of acute acidosis and alkalosis on leucine kinetics in man. 154 Oct 83

Studies were performed on previously nephrectomized dogs to examine roles of hormonal factors in plasma potassium alterations in acute alkalosis. Respiratory and metabolic alkalosis were induced by hyperventilation and intravenous NaHCO3 or tris(hydroxymethyl)aminomethane (Tris) infusion, respectively. Respiratory and NaHCO3-induced alkalosis provoked decreases in plasma potassium from the control value of 5.12 +/- 0.68 (SE) to 4.21 +/- 0.55 meq/l (P less than 0.01) and from 4.65 +/- 0.26 to 3.91 +/- 0.16 meq/l (P less than 0.01) within 180 min, respectively. In contrast, Tris-induced alkalosis elicited an increase in plasma potassium from the control value of 4.56 +/- 0.30 to 5.31 +/- 0.30 meq/l (P less than 0.01). Hypokalemia in respiratory alkalosis was associated with a decrease in the plasma norepinephrine concentration from the control level of 377 +/- 104 to 155 +/- 41 pg/ml (P less than 0.05) but not with changes in plasma levels of epinephrine, insulin, glucagon, cortisol, and aldosterone. However, this hypokalemia was not affected by phentolamine. Also, somatostatin did not modify the hypokalemic response. NaHCO3-induced hypokalemia was associated with a decline in the plasma aldosterone and norepinephrine concentrations. The decline in plasma norepinephrine in NaHCO3-induced alkalosis followed the decrease in plasma potassium. In Tris-induced alkalosis, plasma insulin increased but norepinephrine decreased. The findings do not suggest fundamental roles of the hormonal factors in the plasma potassium alterations in bilaterally nephrectomized dogs with acute alkalosis.
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PMID:Role of hormonal factors in plasma K alterations in acute respiratory and metabolic alkalosis in dogs. 215 37

Previously, we reported that change from the normal pH of 7.4 surrounding the islet cells to 7.8 results in a decreased B-cell response to 16.6 mM glucose, 10 mM arginine or 400 micrograms/ml tolbutamide. In the present report we studied the effect of modifications in the extracellular pH on glucose- and arginine-induced glucagon and insulin secretion by the perfused rat pancreas. It was found that at pH 7.8, arginine-induced glucagon secretion was significantly greater than at pH 7.4. On the other hand, the switch from pH 7.4 to 7.8 in a pancreas already stimulated by either low glucose or arginine, produced fast and transient glucagon release. Sequential extracellular pH changes from 7.4 to 7.8 and back to 7.4 in the presence of 8.3 mM glucose and a 5 mM arginine stimulus demonstrated that A- and B-cells rapidly modify their secretion in response to extracellular alkalosis in opposite directions. While glucagon output was enhanced (mean secretory rates at pH 7.4, 0.692 +/- 0.042 ng/min and 0.948 +/- 0.57 at pH 7.8), insulin secretion was clearly reduced (72.6 +/- 6.2 ng/min and 35.7 +/- 2.8 ng/min at pH 7.4 and 7.8, respectively). The above observations, together with our previously reported data, indicate that extracellular pH plays an important role in the regulation of glucagon and insulin release. Particularly, extracellular alkalosis enhances A-cell response to 2.3 mM glucose and 5 mM arginine while partially inhibiting B-cell secretion in the perfused rat pancreas.
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PMID:Glucagon and insulin secretion during acid-base alterations. 635 36

The precise mechanism(s) of action of PTH, insulin or glucagon in the regulation of renal glutamine and ammonia metabolism is unknown. Our aim was to delineate the effects and the site(s) of action of these hormones on renal glutamine metabolism. Experiments were carried out using OK cells as a model system. Cell cultures were incubated for three hours in a bicarbonate buffer of pH 7.4 supplemented with either 1 mM [2-15N] or [5-15N] glutamine and 10(-7) M PTH, insulin or glucagon. Comparative studies were performed at pH 6.8, 7.4 or 7.6 without hormone. PTH and acute acidosis significantly stimulated glutamine metabolism via both the phosphate-dependent glutaminase (PDG) and glutamate dehydrogenase (GLDH) pathways. The opposite was observed at pH 7.6. Insulin augmented flux via PDG with little effect on the GLDH pathway. Glucagon had insignificant effects on either PDG or GLDH pathways. Intracellular [15N] glutamate formed from [2-15N] glutamine was removed partially by transamination to alanine, aspartate and serine and partially by translocation to an extracellular compartment. Acidosis, PTH and insulin enhanced the formation of [15N] alanine with little effect on [15N] aspartate. PTH, insulin and glucagon significantly stimulated the production of [15N]serine, whereas acidosis had little effect. The translocation of intracellular glutamate was significantly increased by acidosis, PTH and insulin and decreased by acute alkalosis. The data indicate that: (a) PTH mimicks the effect of acute acidosis on renal glutamine metabolism, that is, augmented glutamine metabolism through both PDG and GLDH pathways and stimulated the output of intracellular glutamate. This effect might be mediated via decreased activity of the Na(+)-H+ exchanger associated with cellular acidification and/or through a second messenger; (b) insulin, but not glucagon, increased glutamine uptake and metabolism, and simultaneously enhanced output of intracellular glutamate sufficiently to stimulate the PDG pathway; and (c) overall, glucagon had little effect on glutamine metabolism by OK cells compared with either PTH or insulin.
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PMID:Hormonal regulation of glutamine metabolism by OK cells. 773 Nov 75

Experiments on white rats found that both chronic acidosis and chronic alkalosis cause fasting hyperglycemia and decreases glucose tolerance. In hypophysectomized animals, alkalosis causes similar effects and acidosis leads to hypoglycemia. Acute acidosis stimulates insulin and corticotropin secretions acute alkalosis reduces blood insulin and corticotropin levels and increases glucagon concentration. Chronic acidosis and alkalosis decrease insulin secretion and stimulates corticotropin secretion. Glucagon levels remain increased in chronic alkalosis. It has been concluded that primary cause of diabetogenic action of chronic acidosis is glucocorticoid hyperfunction and exhausting stimulation of B cells with glucose. Alkalosis causes a direct inhibitory action on B cells and activates A cells of Langerhans' islets.
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PMID:[The mechanisms of disorders of carbohydrate metabolism in changes to the acid-base balance]. 811 90

We have utilized both [5-15N]glutamine and [3-13C] pyruvate as metabolic tracers in order to: (i) examine the effect of pH, glucagon (GLU), or insulin on the precursor-product relationship between 15NH3, [15N]citrulline, and, thereby, [15N]urea synthesis and (ii) elucidate the mechanism(s) by which pyruvate stimulates [15N] urea synthesis. Hepatocytes isolated from rat were incubated at pH 6.8, 7.4, or 7.6 with 1 mM [5-15N]glutamine and 0.1 mM 14NH4Cl in the presence or the absence of [3-13C] pyruvate (2 mM). A separate series of experiments was performed at pH 7.4 in the presence of insulin or GLU. 15NH3 enrichment exceeded or was equal to that of [15N]citrulline under all conditions except for pH 7.6, when the 15N enrichment in citrulline exceeded that in ammonia. The formation of [15N]citrulline (atom % excess) was increased with higher pH. Flux through phosphate-dependent glutaminase (PDG) and [15N]urea synthesis were stimulated (p < 0.05) at pH 7.6 or with GLU and decreased (p < 0.05) at pH 6.8. Insulin had no significant effect on flux through PDG or on [15N]urea synthesis. Decreased [15N]urea production at pH 6.8 was associated with depleted aspartate and glutamate levels. Pyruvate attenuated this decrease in the aspartate and glutamate pools and stimulated [15N]urea synthesis. Production of Asp from pyruvate was increased with increasing medium pH. Approximately 80% of Asp was derived from [3-13C]pyruvate regardless of incubation pH or addition of hormone. Furthermore, approximately 20, 40, and 50% of the mitochondrial N-acetylglutamate (NAG) pool was derived from [3-13C]pyruvate at pH 6.8, 7.4, and 7.6, respectively. Both the concentration and formation of [13C]NAG from [3-13C]pyruvate were increased (p < 0.05) with glucagon and decreased (p < 0.05) with insulin or at pH 6.8. The data suggest a correlation between changes in [15N]urea synthesis and alterations in the level and synthesis of [13C]NAG from pyruvate. The current observations suggest that the stimulation of [15N]urea synthesis in acute alkalosis is mediated via increased flux through PDG and subsequent increased utilization of [5-15N] of glutamine for [15N]citrulline synthesis and/or increased synthesis of NAG from glutamate and pyruvate. The opposite may have occurred in acute acidosis. Glucagon, but not insulin, stimulated [15N]urea synthesis via increased flux through PDG and synthesis of NAG. Pyruvate stimulated urea synthesis via increased availability of aspartate and/or increased synthesis of NAG. The formation of NAG and aspartate from pyruvate are both pH-sensitive processes.
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PMID:Regulation of [15N]urea synthesis from [5-15N]glutamine. Role of pH, hormones, and pyruvate. 894 Jan 26

Sympathomimetic drugs are commonly used in many circumstances to increase cardiac output, blood pressure, and myocardial contractility. However, factors such as acidosis or alkalosis are known to influence the action of these drugs. This study looked at the response to the administration of epinephrine, norepinephrine, dopamine, dobutamine, isoproterenol, and glucagon at normal pH and under acidotic (pH 7.2 +/- 0.01) and alkalotic (pH 7.59 +/- 0.01) conditions in 17 dogs. Acidosis was produced with an infusion of hydrochloric acid and alkalosis by infusion of sodium bicarbonate. The infusions were given over one hour followed by a 15- to 30-minute stabilization period. With the administration of each sympathomimetic drug at each pH level, hemodynamic parameters and measurements of myocardia; contractility were recorded. Epinephrine increased cardiac output at normal pH, but decreased cardiac output under conditions of both acidosis and alkalosis; the net change from values at pH 7.40 was nearly 3 L/min. The only other drug to demonstrate this reversal of cardiac output, though to a lesser degree, was dopamine, 10 microg/kg/min, and only in the alkalotic state. Dobutamine was the only drug that decreased contractility under acidotic conditions, while all other drugs caused an increase. In sum, epinephrine was the only drug markedly affected by metabolic acidosis and alkalosis. Isoproterenol's hemodynamic effects were altered the least by changes in acid-base balance. Alkalosis had an equally adverse effect on the cardiovascular system as compared with acidosis.
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PMID:The effects of metabolic acidosis and alkalosis on the response to sympathomimetic drugs in dogs. 1717 33

The cardiac sodium channel is comprised of proteins that span the cardiac cell membrane and form the channel pore. Depolarisation causes the proteins to move and open the sodium channel. Once the channel is open (active conformation), sodium ions move into the cell. The channel then changes from the active conformation to an inactive conformation - the channel remains open, but influx of sodium ions ceases. Recovery occurs as the channel moves from the inactive conformation back to the closed conformation and is then ready to open following the next depolarisation. Sodium channel blocking drugs (NCBDs) occupy receptors in the channel during the active and inactive conformations. The drug dissociates from most of the channel receptors during recovery, but the time it takes the drug to dissociate slows recovery. The slowed recovery prolongs conduction time, the main toxicity of NCBD overdose. Conduction time is further prolonged if heart rate increases as there are more available active and inactive conformations/unit time, which increases channel receptor binding sites for the NCBD. In addition to prolonging conduction time, NCBDs also decrease inotropy. Treatment of NCBD cardiotoxicity has been based on in vitro and animal experiments, and case reports. Assumptions based on this evidence must now be reassessed. For example, canines consistently develop ventricular tachycardia (VT) when tricyclic antidepressants (TCAs) are administered. Much of the literature discussing NCBD cardiotoxicity assumes that TCA poisoning induces VT in humans with the same regularity that occurs in canines. Seemingly, in support of this assumption was the finding that patients with remote myocardial infarction developed VT when therapeutically ingesting a NCBD. However, conduction is prolonged in myocardium that is or has been ischaemic. NCBD prolong conduction more in previously ischaemic myocardium than in normal myocardium, which causes nonuniform conduction and allows the development of re-entrant arrhythmias such as VT. Although some nonuniform conduction may occur in the healthy heart following a NCBD overdose, there is no evidence that nonuniform conduction occurs to the extent that it will cause re-entrant arrhythmias in this setting. Using various animal models and a variety of NCBDs, sodium ions, bicarbonate ions and alkalosis have been compared for the treatment of ventricular arrhythmias, hypotension and mortality. The results of these experiments have been extrapolated to NCBD overdose in humans. Animal models and single treatment approaches may have narrowed our scope. More recent evidence indicates that properties of each individual NCBD may require unique treatment. There is limited evidence that glucagon, which increases initial sodium ion influx into the cardiac cell, should be considered early in the treatment of cardiotoxicity. Another consideration may be treatment of NCBD with faster kinetics. Conduction time is decreased if a NCBD occupying the receptor is replaced by a NCBD that moves off and on the receptor more quickly. There is less evidence for this treatment, as risk may be greater. With greater understanding of the sodium channel and NCBDs, we must reassess our approach to the treatment of patients with healthy hearts who overdose on NCBD.
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PMID:A critical reconsideration of the clinical effects and treatment recommendations for sodium channel blocking drug cardiotoxicity. 1728 99