Glucagon hormone synthesis -
All these problems in the glucagon secretory response observed in diabetes have been attributed to several defects in α-cell regulation including defective glucose sensing, loss of β-cell function, insulin resistance or autonomic malfunction.
However, the mechanisms involved in α-cell pathophysiology still remain largely unknown and deserve more investigation for better design of therapeutic strategies.
In this regard, although direct therapeutic approaches to correct the lack of α-cell response to hypoglycaemia are missing, several proposals have been developed to amend glucagon excess, as we will see in the next section.
The specific control of glucagon secretion by pharmacological modulation is complex since several components of the α-cell stimulus-secretion coupling are also present in β- and δ-cells.
Thus, the manipulation of glucagon action by modulating the glucagon receptor signalling seems to be an effective alternative Li et al. This strategy has been supported by several studies. Glucagon receptor knock-out mice have hyperglucagonaemia and α-cell hyperplasia, but their glucose tolerance is improved and they develop only a mild fasting hypoglycaemia Gelling et al.
These mice have a normal body weight, food intake and energy expenditure although less adiposity and lower leptin levels. These results are consistent with the experiments with anti-sense oligonucleotides for the glucagon receptor. Therefore, these experimental results are a further support that glucagon antagonism may be beneficial for diabetes treatment.
Sulphonylureas are efficient K ATP channel blockers that have been extensively used for the clinical treatment of diabetes. This biphasic effect is due to the mouse α-cell electrical behaviour Fig. Accordingly, with this scheme, the K ATP channel opener diazoxide can also have a biphasic effect on glucagon secretion.
These effects will change depending on the extracellular glucose concentrations that necessarily influence K ATP channel activity MacDonald et al. This biphasic behaviour may explain the disparity of effects found for sulphonylureas Loubatieres et al.
In humans, sulphonylureas are associated to a glucagon secretion decrease in healthy and type 2 diabetic subjects Landstedt-Hallin et al. Since sulphonylureas also induce insulin and somatostatin secretion, which affect α-cells, these drugs offer a poor specific control of glucagon secretion.
In addition to stimulating insulin release, GLP1 can suppress glucagon secretion in humans, perfused rat pancreas and isolated rat islets in a glucose-dependent manner Guenifi et al. Because GLP1 is rapidly cleaved and inactivated by the enzyme dipeptidyl peptidase-IV DPP4 , a good alternative would be to design either GLP1 derivatives with higher resistance to DPP4 or agents that increase GLP1 endogenous levels.
Among the GLP1 mimetics, exenatide is a synthetic polypeptide with high resistance to DPP4 cleavage that decreases glucagon levels in normal and diabetic subjects Degn et al.
Liraglutide, another GLP1 derivative with long-lasting actions, can reduce glucagon release after a meal in patients with type 2 diabetes Juhl et al.
Alternatively, DPP4 inhibitors like sitagliptin and vildagliptin increase the endogen effects of GLP1, reducing glucagon plasma concentrations in diabetic individuals Rosenstock et al. Since all these alternatives produce opposing actions on insulin and glucagon, they generate promising expectations for diabetes treatment.
Given that imidazoline compounds stimulate insulin release while inhibiting glucagon secretion, these drugs are potentially valuable in diabetes.
Because of the different expression of SSTR in the islet Kumar et al. It has been shown that SSTR2 is the subtype receptor predominantly expressed in rodent α-cells, and that SSTR2-deficient mice develop hyperglycaemia and non-fasting hyperglucagonaemia Singh et al.
In mice, the use of a highly SSTR2-selective non-peptide agonist inhibited glucagon release without affecting insulin release Strowski et al.
However, there is some overlapping in human islets between the different SSTR subtypes in α- and β-cells that limit, at present, the use of subtype-specific somatostatin analogues Singh et al. Amylin, which is cosecreted with insulin from β-cells, inhibits glucagon secretion stimulated by amino acids but does not affect hypoglycaemia-induced glucagon release Young Since α-cell response to amino acids is often exaggerated in diabetic patients, amylin or amylinomimetic compounds such as pramlintide are used as an effective alternative for the treatment of postprandial and amino acid-induced excess of glucagon secretion Dunning et al.
Several linear and cyclic glucagon analogues have been developed to work as glucagon receptor antagonists. Essentially, they impair the ability of glucagon to stimulate adenylate cyclase activity in liver, thus reducing hepatic glucose output and improving plasma glucose levels.
This is the case of [des-His 1 , des-Phe 6 , Glu 9 ] glucagon-NH 2 , which reduces glucose levels in streptozotocin-induced diabetic rats Van Tine et al.
Recent investigations have demonstrated that the antagonist des-His-glucagon binds preferentially to the hepatic glucagon receptor in vivo , and this correlates with the glucose lowering effects Dallas-Yang et al.
For instance, a novel competitive antagonist N -[3-cyano 1, 1-dimethylpropyl -4, 5, 6, 7-tetrahydrobenzothienyl]ethylbutanamide was recently shown to inhibit glucagon-mediated glycogenolysis in primary human hepatocytes and to block the increase in glucose levels after the administration of exogenous glucagon in mice Qureshi et al.
The information about the effect of these antagonists on humans is, however, scarce. Despite the success of several approaches to modulate glucagon secretion or action and improve glucose control in animal models or in humans, more information is still required.
Long-standing studies should address whether the utilization of these agents could lead to undesired hypoglycaemia in humans, accumulation of lipids or compensatory mechanisms that decrease the benefits of these therapies in the long term.
In this aspect, the results obtained in animal models are positive: although the glucagon receptor knock-out mouse develops hyperglucagonaemia, it is not hypoglycaemic and does not have an abnormal accumulation of lipids Gelling et al.
Additionally, recent long-term studies in mice further prove the viability of glucagon antagonism Winzell et al. Thus, present data are promising and indicate that several therapeutic agents targeted to glucagon signalling and α-cell secretion may be useful for the management of diabetes.
Pancreatic α-cells and glucagon secretion are fundamental components of the regulatory mechanisms that control glucose homeostasis. However, α-cell physiology has remained elusive compared with the overwhelming information about insulin secretion and the β-cell. In recent years, however, several groups have initiated intensive efforts to understand α-cell physiology and identified essential pieces of its stimulus-secretion coupling.
Additionally, important aspects of the regulation of α-cell metabolism and the control of glucagon expression are being elucidated. All of this information will favour an overall comprehension of the α-cell function and its role in glucose homeostasis.
Nevertheless, more research is required to understand the α-cell behaviour, not only in healthy subjects but in pathological conditions as well. In conclusion, since the malfunction of the glucagon secretory response is involved in diabetes and its complications, a complete understanding of the α-cell will allow for a better design of therapeutic approaches for the treatment of this disease.
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported. This work was supported by grants from the Ministerio de Educación y Ciencia BFU and PCIA to I Q; BFU to A N.
CIBERDEM is an initiative of the Instituto de Salud Carlos III. American Journal of Physiology. Renal Physiology F24 — F Ahren B Autonomic regulation of islet hormone secretion — implications for health and disease.
Diabetologia 43 — Hormone and Metabolic Research 14 — Effects on basal release of insulin and glucagon. Endocrinology — Regulatory Peptides 55 — Biochemical Journal — Metabolism 24 35 — Metabolism 32 — Diabetes 56 — Regulatory, Integrative and Comparative Physiology R — R FEBS Letters — Diabetes 49 — Diabetes 36 — European Journal of Pharmacology 45 — Endocrine 6 79 — Journal of Clinical Endocrinology and Metabolism 54 — Pflugers Archiv: European Journal of Physiology — Metabolism 53 — Paradoxical suppression of glucose utilization and lack of compensatory increase in glucose production, roles of insulin resistance, abnormal neuroendocrine responses, and islet paracrine interactions.
Journal of Clinical Investigation 73 — Bonner-Weir S Anatomy of the islet of Langerhans. In The Endocrine Pancreas , pp 15 — Eds Samols E.
New York : Raven Press. Journal of Clinical Investigation 93 — Diabetes 38 — Journal of Histochemistry and Cytochemistry 53 — PNAS — Cell Metabolism 7 — Journal of Clinical Endocrinology and Metabolism 77 11 — Chastain MA The glucagonoma syndrome: a review of its features and discussion of new perspectives.
American Journal of the Medical Sciences — European Journal of Biochemistry — Cryer PE Hypoglycaemia: the limiting factor in the glycaemic management of Type I and Type II diabetes.
Diabetologia 45 — Cynober LA Plasma amino acid levels with a note on membrane transport: characteristics, regulation, and metabolic significance. Nutrition 18 — European Journal of Pharmacology — Diabetes 53 — Journal of Biological Chemistry — Diabetes 46 — Diabetologia 38 — Endocrine Reviews 28 — Diabetologia 48 — Endocrinology and Metabolism E40 — E Diabetes 54 — Regulatory Peptides — Journal of Physiology — Journal of Clinical Endocrinology and Metabolism 86 — Journal of General Physiology — Endocrine Reviews 28 84 — Pancreas 22 58 — Diabetes 52 — PNAS 93 — Nature — Metabolism 54 — FASEB Journal 9 — Nature Cell Biology 5 — Diabetes 51 — Diabetes Research and Clinical Practice 44 83 — Journal of Clinical Investigation 96 — Endocrinology and Metabolism E21 — E Diabetes 48 77 — Protein Science 4 — Journal of Clinical Endocrinology and Metabolism 84 — Diabetes Care 23 — Clinical Science — Cell Calcium 35 — Diabetologia 10 — Molecular Endocrinology 19 — PLoS Biology 5 e The glucagon receptor family.
Pharmacological Reviews 55 — Nature Neuroscience 4 — Journal of Physiology 85 — Journal of Clinical Endocrinology and Metabolism 87 — Diabetologia 29 — Journal of Nutrition — European Journal of Pharmacology 65 — Diabetologia 44 — Diabetes 48 — Endocrinology and Metabolism E — E Biophysical Journal 90 — Diabetes 55 — Journal of Clinical Endocrinology and Metabolism 64 — Diabetes Care 30 — Diabetologia 32 — Glucose-regulated anaplerosis in beta cells.
Potential role in nutrient sensing. American Journal of Physiology E — E Journal of Clinical Endocrinology and Metabolism 85 — Journal of Clinical Endocrinology and Metabolism 92 — Journal of Lipid Research 35 — Journal of Clinical Investigation — Diabetes 50 — Lancet 1 14 — Diabetologia 50 — Hepatology 13 — Journal of Cell Biology — Nature 68 — Endocrinology and Metabolism E19 — E Cell Metabolism 3 47 — Biochemical and Biophysical Research Communications — Young A Inhibition of glucagon secretion.
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Abstract The secretion of glucagon by pancreatic α-cells plays a critical role in the regulation of glycaemia. Introduction The principal level of control on glycaemia by the islet of Langerhans depends largely on the coordinated secretion of glucagon and insulin by α- and β-cells respectively.
Islet of Langerhans: cell architecture and function Glucagon-secreting α-cells are one of the main endocrine cell populations that coexist in the islet of Langerhans along with insulin-secreting β-cells. Figure 1 Schematic model for glucose-dependent regulation of glucagon secretion in the mouse α-cell.
Regulation of α-cell function by glucose: direct or paracrine effect? Regulation of glucagon secretion by fatty acids and amino acids Although the lipotoxicity theory and its role in obesity-induced diabetes have increased the interest in the interactions between fatty acids and islet functions, little is known about their effect on the regulation of the α-cell compared with those on β-cells.
Autocrine, paracrine, endocrine and neural regulation of glucagon secretion Autocrine, paracrine and endocrine signalling The spatial distribution of α-cells and the vascular organization within the islet sustain an important intercellular communication through autocrine and paracrine mechanisms Fig.
Figure 3 Paracrine signalling in the α-cell. Insulin and zinc One of the most important paracrine mechanisms responsible for inhibiting glucagon release is conducted by insulin, acting via several pathways.
Somatostatin and glucagon Somatostatin is produced and secreted by several tissues in addition to the δ-cell population of the islet and works as an inhibitor of both glucagon and insulin release Fehmann et al.
GLP1 The incretin hormone glucagon-like peptide 1 GLP1 is released from the L-cells of the small intestine after food intake, stimulating insulin production and inhibiting glucagon release.
Other extracellular messengers The neurotransmitter γ-aminobutyric acid GABA is another α-cell modulator. Neural regulation As previously stated, the islet of Langerhans is highly innervated by parasympathetic and sympathetic nerves that ensure a rapid response to hypoglycaemia and protection from potential brain damage Ahren Glucagon physiological and pathophysiological actions and its role in diabetes Glucagon synthesis The preproglucagon-derived peptides glucagon, GLP1 and GLP2, are encoded by the preproglucagon gene, which is expressed in the central nervous system, intestinal L-cells and pancreatic α-cells.
Glucagon receptor The rat and mouse glucagon receptor is a amino acid protein, belonging to the secretin—glucagon receptor II class family of G protein-coupled receptors Mayo et al. Figure 4 The role of glucagon and the glucagon receptor in the liver.
Glucagon control of glucose homeostasis and metabolism Several lines of defence protect the organism against hypoglycaemia and its potential damaging effects, especially in the brain, which depends on a continuous supply of glucose, its principal metabolic fuel.
Modulation of glucagon secretion Sulphonylureas Sulphonylureas are efficient K ATP channel blockers that have been extensively used for the clinical treatment of diabetes.
GLP1 mimetics and DPP4 inhibitors In addition to stimulating insulin release, GLP1 can suppress glucagon secretion in humans, perfused rat pancreas and isolated rat islets in a glucose-dependent manner Guenifi et al. Somatostatin analogues Because of the different expression of SSTR in the islet Kumar et al.
Amylin and pramlintide Amylin, which is cosecreted with insulin from β-cells, inhibits glucagon secretion stimulated by amino acids but does not affect hypoglycaemia-induced glucagon release Young Modulation of glucagon action and glucagon receptor signalling Peptide-based glucagon receptor antagonists Several linear and cyclic glucagon analogues have been developed to work as glucagon receptor antagonists.
Conclusions Pancreatic α-cells and glucagon secretion are fundamental components of the regulatory mechanisms that control glucose homeostasis. Declaration of interest The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding This work was supported by grants from the Ministerio de Educación y Ciencia BFU and PCIA to I Q; BFU to A N. PubMed Ahloulay M Bouby N Machet F Kubrusly M Coutaud C Bankir L Effects of glucagon on glomerular filtration rate and urea and water excretion.
PubMed Ahren B Autonomic regulation of islet hormone secretion — implications for health and disease. PubMed Ahren B Lundquist I Influences of gastro-intestinal polypeptides and glucose on glucagon secretion induced by cholinergic stimulation. PubMed Ahren B Veith RC Taborsky GJ Jr Sympathetic nerve stimulation versus pancreatic norepinephrine infusion in the dog: 1.
PubMed Akesson B Panagiotidis G Westermark P Lundquist I Islet amyloid polypeptide inhibits glucagon release and exerts a dual action on insulin release from isolated islets. PubMed Andersen B Rassov A Westergaard N Lundgren K Inhibition of glycogenolysis in primary rat hepatocytes by 1, 4-dideoxy-1,4-imino- d -arabinitol.
PubMed Andrews SS Lopez-S A Blackard WG Effect of lipids on glucagon secretion in man. PubMed Asplin C Raghu P Dornan T Palmer JP Glucose regulation of glucagon secretion independent of B cell activity.
PubMed Bailey SJ Ravier MA Rutter GA Glucose-dependent regulation of gamma-aminobutyric acid GABA A receptor expression in mouse pancreatic islet alpha-cells. PubMed Balkan B Li X Portal GLP-1 administration in rats augments the insulin response to glucose via neuronal mechanisms.
PubMed Band GC Jones CT Functional activation by glucagon of glucose 6-phosphatase and gluconeogenesis in the perfused liver of the fetal guinea pig. PubMed Barg S Galvanovskis J Gopel SO Rorsman P Eliasson L Tight coupling between electrical activity and exocytosis in mouse glucagon-secreting alpha-cells.
PubMed Baron AD Schaeffer L Shragg P Kolterman OG Role of hyperglucagonemia in maintenance of increased rates of hepatic glucose output in type II diabetics.
PubMed Bertrand G Gross R Puech R Loubatieres-Mariani MM Bockaert J Glutamate stimulates glucagon secretion via an excitatory amino acid receptor of the AMPA subtype in rat pancreas.
PubMed Bohannon NV Lorenzi M Grodsky GM Karam JH Stimulatory effects of tolbutamide infusion on plasma glucagon in insulin-dependent diabetic subjects. PubMed Bollheimer LC Landauer HC Troll S Schweimer J Wrede CE Scholmerich J Buettner R Stimulatory short-term effects of free fatty acids on glucagon secretion at low to normal glucose concentrations.
PubMed Bolli GB Tsalikian E Haymond MW Cryer PE Gerich JE Defective glucose counterregulation after subcutaneous insulin in noninsulin-dependent diabetes mellitus.
PubMed Bonner-Weir S Anatomy of the islet of Langerhans. In The Endocrine Pancreas, pp 15 — PubMed Borg WP During MJ Sherwin RS Borg MA Brines ML Shulman GI Ventromedial hypothalamic lesions in rats suppress counterregulatory responses to hypoglycemia.
PubMed Brelje TC Scharp DW Sorenson RL Three-dimensional imaging of intact isolated islets of Langerhans with confocal microscopy. PubMed Brissova M Fowler MJ Nicholson WE Chu A Hirshberg B Harlan DM Powers AC Assessment of human pancreatic islet architecture and composition by laser scanning confocal microscopy.
PubMed Cabrera O Berman DM Kenyon NS Ricordi C Berggren PO Caicedo A The unique cytoarchitecture of human pancreatic islets has implications for islet cell function.
PubMed Cabrera O Jacques-Silva MC Speier S Yang SN Köhler M Fachado A Vieira E Zierath JR Kibbey R Berman DM Glutamate is a positive autocrine signal for glucagon release. PubMed Carlson MG Snead WL Campbell PJ Regulation of free fatty acid metabolism by glucagon.
PubMed Chastain MA The glucagonoma syndrome: a review of its features and discussion of new perspectives. PubMed Ciudad C Camici M Ahmad Z Wang Y DePaoli-Roach AA Roach PJ Control of glycogen synthase phosphorylation in isolated rat hepatocytes by epinephrine, vasopressin and glucagon.
PubMed Consoli A Nurjhan N Capani F Gerich J Predominant role of gluconeogenesis in increased hepatic glucose production in NIDDM.
PubMed Cryer PE Hypoglycaemia: the limiting factor in the glycaemic management of Type I and Type II diabetes. PubMed Cynober LA Plasma amino acid levels with a note on membrane transport: characteristics, regulation, and metabolic significance. PubMed Dallas-Yang Q Shen X Strowski M Brady E Saperstein R Gibson RE Szalkowski D Qureshi SA Candelore MR Fenyk-Melody JE Hepatic glucagon receptor binding and glucose-lowering in vivo by peptidyl and non-peptidyl glucagon receptor antagonists.
PubMed Degn KB Brock B Juhl CB Djurhuus CB Grubert J Kim D Han J Taylor K Fineman M Schmitz O Effect of intravenous infusion of exenatide synthetic exendin-4 on glucose-dependent insulin secretion and counterregulation during hypoglycemia.
PubMed Detimary P Dejonghe S Ling Z Pipeleers D Schuit F Henquin JC The changes in adenine nucleotides measured in glucose-stimulated rodent islets occur in beta cells but not in alpha cells and are also observed in human islets. PubMed Dey A Lipkind GM Rouille Y Norrbom C Stein J Zhang C Carroll R Steiner DF Significance of prohormone convertase 2, PC2, mediated initial cleavage at the proglucagon interdomain site, LysArg71, to generate glucagon.
PubMed Diao J Asghar Z Chan CB Wheeler MB Glucose-regulated glucagon secretion requires insulin receptor expression in pancreatic α-cells. PubMed Dinneen S Alzaid A Turk D Rizza R Failure of glucagon suppression contributes to postprandial hyperglycaemia in IDDM.
PubMed Dumonteil E Magnan C Ritz-Laser B Meda P Dussoix P Gilbert M Ktorza A Philippe J Insulin, but not glucose lowering corrects the hyperglucagonemia and increased proglucagon messenger ribonucleic acid levels observed in insulinopenic diabetes.
PubMed Dumonteil E Ritz-Laser B Magnan C Grigorescu I Ktorza A Philippe J Chronic exposure to high glucose concentrations increases proglucagon messenger ribonucleic acid levels and glucagon release from InR1G9 cells. PubMed Dumonteil E Magnan C Ritz-Laser B Ktorza A Meda P Philippe J Glucose regulates proinsulin and prosomatostatin but not proglucagon messenger ribonucleic acid levels in rat pancreatic islets.
PubMed Dunning BE Gerich JE The role of alpha-cell dysregulation in fasting and postprandial hyperglycemia in type 2 diabetes and therapeutic implications.
PubMed Dunning BE Foley JE Ahrén B Alpha cell function in health and disease: influence of glucagon-like peptide PubMed Eledrisi MS Alshanti MS Shah MF Brolosy B Jaha N Overview of the diagnosis and management of diabetic ketoacidosis.
PubMed Fehmann HC Strowski M Goke B Functional characterization of somatostatin receptors expressed on hamster glucagonoma cells. PubMed Franklin I Gromada J Gjinovci A Theander S Wollheim CB β-cell secretory products activate α-cell ATP-dependent potassium channels to inhibit glucagon release.
PubMed Furuta M Zhou A Webb G Carroll R Ravazzola M Orci L Steiner DF Severe defect in proglucagon processing in islet A-cells of prohormone convertase 2 null mice. PubMed Gastaldelli A Baldi S Pettiti M Toschi E Camastra S Natali A Landau BR Ferrannini E Influence of obesity and type 2 diabetes on gluconeogenesis and glucose output in humans: a quantitative study.
PubMed Gedulin BR Jodka CM Herrmann K Young AA Role of endogenous amylin in glucagon secretion and gastric emptying in rats demonstrated with the selective antagonist, AC PubMed Gelling RW Du XQ Dichmann DS Romer J Huang H Cui L Obici S Tang B Holst JJ Fledelius C Lower blood glucose, hyperglucagonemia, and pancreatic alpha cell hyperplasia in glucagon receptor knockout mice.
PubMed Gopel S Kanno T Barg S Galvanovskis J Rorsman P Voltage-gated and resting membrane currents recorded from β-cells in intact mouse pancreatic islets. PubMed Gopel SO Kanno T Barg S Rorsman P Patch-clamp characterisation of somatostatin-secreting delta-cells in intact mouse pancreatic islets.
PubMed Gorus FK Malaisse WJ Pipeleers DG Differences in glucose handling by pancreatic A- and B-cells. PubMed Grapengiesser E Salehi A Qader SS Hellman B Glucose induces glucagon release pulses antisynchronous with insulin and sensitive to purinoceptor inhibition.
PubMed Gravholt CH Moller N Jensen MD Christiansen JS Schmitz O Physiological levels of glucagon do not influence lipolysis in abdominal adipose tissue as assessed by microdialysis.
PubMed Gremlich S Bonny C Waeber G Thorens B Fatty acids decrease IDX-1 expression in rat pancreatic islets and reduce GLUT2, glucokinase, insulin, and somatostatin levels. PubMed Gromada J Hoy M Buschard K Salehi A Rorsman P Somatostatin inhibits exocytosis in rat pancreatic α-cells by Gi2-dependent activation of calcineurin and depriming of secretory granules.
PubMed Gromada J Franklin I Wollheim CB Alpha-cells of the endocrine pancreas: 35 years of research but the enigma remains. PubMed Guenifi A Ahren B Abdel-Halim SM Differential effects of glucagon-like peptide-1 7—36 amide versus cholecystokinin on arginine-induced islet hormone release in vivo and in vitro.
PubMed Hayashi M Otsuka M Morimoto R Muroyama A Uehara S Yamamoto A Moriyama Y a Vesicular inhibitory amino acid transporter is present in glucagon-containing secretory granules in alphaTC6 cells, mouse clonal alpha-cells, and alpha-cells of islets of Langerhans.
PubMed Hayashi M Yamada H Uehara S Morimoto R Muroyama A Yatsushiro S Takeda J Yamamoto A Moriyama Y b Secretory granule-mediated co-secretion of l -glutamate and glucagon triggers glutamatergic signal transmission in islets of Langerhans. PubMed Heimberg H De Vos A Pipeleers D Thorens B Schuit F Differences in glucose transporter gene expression between rat pancreatic alpha- and beta-cells are correlated to differences in glucose transport but not in glucose utilization.
PubMed Heimberg H De Vos A Moens K Quartier E Bouwens L Pipeleers D Van Schaftingen E Madsen O Schuit F The glucose sensor protein glucokinase is expressed in glucagon-producing alpha α-cells. PubMed Herzig S Long F Jhala US Hedrick S Quinn R Bauer A Rudolph D Schutz G Yoon C Puigserver P CREB regulates hepatic gluconeogenesis through the coactivator PGC PubMed Hjorth SA Adelhorst K Pedersen BB Kirk O Schwartz TW Glucagon and glucagon-like peptide 1: selective receptor recognition via distinct peptide epitopes.
PubMed Hong J Abudula R Chen J Jeppesen PB Dyrskog SEU Xiao J Colombo M Hermansen K The short-term effect of fatty acids on glucagon secretion is influenced by their chain length, spatial configuration, and degree of unsaturation: studies in vitro. PubMed Hong J Jeppesen PB Nordentoft I Hermansen K Fatty acid-induced effect on glucagon secretion is mediated via fatty acid oxidation.
PubMed Hoy M Bokvist K Xiao-Gang W Hansen J Juhl K Berggren PO Buschard K Gromada J Phentolamine inhibits exocytosis of glucagon by Gi2 protein-dependent activation of calcineurin in rat pancreatic alpha-cells.
PubMed Hunyady B Hipkin RW Schonbrunn A Mezey E Immunohistochemical localization of somatostatin receptor SST2A in the rat pancreas. PubMed Inagaki N Kuromi H Gonoi T Okamoto Y Ishida H Seino Y Kaneko T Iwanaga T Seino S Expression and role of ionotropic glutamate receptors in pancreatic islet cells.
PubMed Ishihara H Maechler P Gjinovci A Herrera PL Wollheim CB Islet beta-cell secretion determines glucagon release from neighbouring alpha-cells.
PubMed Juhl CB Hollingdal M Sturis J Jakobsen G Agerso H Veldhuis J Porksen N Schmitz O Bedtime administration of NN, a long-acting GLP-1 derivative, substantially reduces fasting and postprandial glycemia in type 2 diabetes. PubMed Kaneko K Shirotani T Araki E Matsumoto K Taguchi T Motoshima H Yoshizato K Kishikawa H Shichiri M Insulin inhibits glucagon secretion by the activation of PI3-kinase in In-R1-G9 cells.
PubMed Kendall DM Poitout V Olson LK Sorenson RL Robertson RP Somatostatin coordinately regulates glucagon gene expression and exocytosis in HIT-T15 cells. PubMed Kuhara T Ikeda S Ohneda A Sasaki Y Effects of intravenous infusion of 17 amino acids on the secretion of GH, glucagon, and insulin in sheep.
PubMed Kumar U Sasi R Suresh S Patel A Thangaraju M Metrakos P Patel SC Patel YC Subtype-selective expression of the five somatostatin receptors hSSTR in human pancreatic islet cells: a quantitative double-label immunohistochemical analysis.
PubMed Landstedt-Hallin L Adamson U Lins PE Oral glibenclamide suppresses glucagon secretion during insulin-induced hypoglycemia in patients with type 2 diabetes. PubMed Larsson H Ahren B Islet dysfunction in insulin resistance involves impaired insulin secretion and increased glucagon secretion in postmenopausal women with impaired glucose tolerance.
PubMed Leclercq-Meyer V Marchand J Woussen-Colle MC Giroix MH Malaisse WJ Multiple effects of leucine on glucagon, insulin, and somatostatin secretion from the perfused rat pancreas. Insulin inhibits glucagon release by SGLT2-induced stimulation of somatostatin secretion Nat Commun.
doi: There is comparatively little information about the study of glucagon biosynthesis and secretion using human a -cells. High through put screening enabled identification of multiple small molecules, that were combined with established growth and differentiation factors, to direct differentiation of alpha cells after sequential passage through a 6 stage process, using validated markers for islet and alpha cell differentiation.
Stage 6 clusters expressed Pc2, Arx but not pdx Even at stage 5, considerable number of islet cells co-expressed glucagon and insulin whereas by stage 6, a greater enrishment for glucagon -producing cells was achieved. Some cell proliferation was observed within stage 6 cell clusters.
Glucagon secretion was stimulated by arginine and KCL and inhibited by somatostatin. Secretion of glucagon from transplanted cells in vivo was regulated in appropriate directions with fasting and feeding.
Plasma GLP-1 levels were also elevated in mice receiving the a -cell transplants. Production of Functional Glucagon-Secreting Alpha Cells from Human Embryonic Stem Cells Diabetes. In purified rat β -cells, the intracellular concentration of glucose or 3-O-methyl-D-glucose equilibrates within 2 min with the extracellular levels, and, like in intact islets, the rate of glucose oxidation displays a sigmoidal dose-response curve for glucose.
In contrast, even after 5 min of incubation, the apparent distribution space of D-glucose or 3-O-methyl-D-glucose in a-cells remains much lower than the intracellular volume. In a -cells, both the rate of 3-O-methyl-D-glucose uptake and glucose oxidation proceed proportional to the hexose concentration up to 10 mM and reach saturation at higher concentrations, whereas exogenous insulin failed to affect 3-O-methyl-D-glucose or D-glucose uptake and glucose oxidation by purified α -cells See Differences in glucose handling by pancreatic A- and B-cells.
Studies using rat islets, isolated purified α -cells, and GABA antagonists have provided evidence that GABA receptor subunits are expressed in α cells and that inhibition of GABA receptor activation is associated with complete failure of glucose to suppress glucagon secretion.
See Glucose Inhibition of Glucagon Secretion From Rat alpha-Cells Is Mediated by GABA Released From Neighboring beta-Cells. Elegant studies from Wang and colleagues demonstrate that insulin induces activation of GABA A receptors in the alpha cells by GABA receptor translocation via an Akt kinase-dependent pathway.
This leads to membrane hyperpolarization in the alpha cells and, ultimately, suppression of glucagon secretion. Hence, insulin may directly inhibit glucagon secretion, and indirectly potentiate the inhibitory effects of GABA concomitant released by β -cells-See Intra-islet insulin suppresses glucagon release via GABA-GABA A receptor system.
Cell Metab. Furthermore, the α cell secretory response may be modified, in an autoregulatory pathway, by secretion of L-glutamate which in turn triggers the secretion of gamma-aminobutyric acid GABA from β - cells. See Metabotropic Glutamate Receptor Type 4 Is Involved in Autoinhibitory Cascade for Glucagon Secretion by alpha-Cells of Islet of Langerhans.
Insulin and zinc are potent inhibitors of glucagon secretion from rat α cells, perhaps through modulation of K ATP channel activity, whereas the inhibitory effect of GLP-1 on α -cells may be indirect, as outlined in studies of rat α cells in vitro β -Cell Secretory Products Activate a-Cell ATP-Dependent Potassium Channels to Inhibit Glucagon Release.
Diabetes In contrast, similar experiments using isolated murine α cells demonstrate that glucose and insulin but not zinc exerts an inhibitory effect on regulation of glucagon secretion in normal murine islets, dissociated a-cells, or the aTC-1 cell line, as demonstrated in Glucose or Insulin, but not Zinc Ions, Inhibit Glucagon Secretion From Mouse Pancreatic a-Cells.
The complexity of how glucose controls glucagon secretion from individual α cells vs. islets retaining their normal anatomical relationship was further highlighted by Hutchens and Piston, who revealed a role for ephrin signaling in the paracrine inhibition of tonic glucagon secretion.
Ephrine signaling in islet cells was manipulated through synthetic IgG-ephrin ligands. Manipulation of ephrin signaling at low vs. high glucose produced the expected corresponding changes in insulin and glucagon secretion in both murine and human islets.
Acute antagonism of the insulin andsomatostatin receptors was used to tease out direct vs. indirect effects of ephrin signaling on glucagon secretion. The authors provide evidence for the complexity of glucose-dependent, ephrin-mediated modulation of both insulin and glucagon secretion, likely through as yet unidentified paracrine mediators EphA4 Receptor Forward Signaling Inhibits Glucagon Secretion from α-cells.
pii: db A contrasting study using the perfused diabetic Wistar rat pancreas came to opposite conclusions, namely a decrement in the local concentration of zinc, but not insulin, resulted in improvement in the α -cell function. See Zinc, Not Insulin, Regulates the Rat Alpha Cell Response to Hypoglycemia in vivo.
The direct effect of glucose on pancreatic α -cells is difficult to study due to the challenge of isolating a pure α -cell population independent of contaminating β -cells.
Glucose generally inhibits α -cells in the context of whole islets. A biphasic response of glucose-regulated α -cells, with inhibition of Glucose stimulates glucagon release in single rat alpha-cells by mechanisms that mirror the stimulus-secretion coupling in beta-cells.
and in Paradoxical stimulation of glucagon secretion by high glucose concentrations. Acta Physiol Scand. Diabetes November 4, Intriguingly, gastrin has been shown to stimulate glucagon secretion in some but not all experimental models, and the fetal endocrine pancreas contains a large amount of gastrin, following which islet gastrin expression diminishes postnatally.
Gastrin, together with EGF receptor ligands, may promote expansion of islet mass through enhanced islet neogenesis. Mice with disruption of the gastrin gene exhibit normal islets and basal levels of pancreatic glucagon content, yet exhibit mild hypoglycemia a defective glucagon secretory response to insulin induced hypoglycemia.
See Hypoglycemia, defective islet glucagon secretion, but normal islet mass in mice with a disruption of the gastrin gene Gastroenterology An important role for the insulin receptor, and by inference insulin, in the control of a -cell function was demonstrated by Kawamori and colleagues in their analysis of a mouse with a -cell-specific deletion of the insulin receptor.
These mice exhibited modest hyperglucagonemia in the basal fed state, and enhanced glucagon secretion in response to arginine or hypoglycemia. These findings imply that basal insulin receptor signaling is important for tonic inhibition of the a -cell.
Insulin signaling in alpha cells modulates glucagon secretion in vivo Cell Metab. A role for the Per-arnt-sim PAS domain containing protein kinase in the control of glucagon secretion has been proposed by Xavier and colleagues. PASK mRNA was increased by glucose in cultures of rodent or human islets and found to be expressed in both a and b -cells.
Reduction of Pask expression in aTC cells using siRNA increased glucagon gene expression and glucagon secretion, but did not inhibit the inhibitory effect of insulin on glucagon secretion.
Conversely, overexpression ofPask in a-TC cells and human islets inhibited glucagon secretion See Per-arnt-sim PAS domain-containing protein kinase is downregulated in human islets in type 2 diabetes and regulates glucagon secretion Diabetologia.
The a -cell, under some circumstances, may also synthesize and secrete GLP-1 , which in turn, is a robust inhibitor of glucagon secretion-See GLP-1 and the Alpha Cell.
Glucagon secretion, a -cell function and inflammation. Historical evidence points to a link between inflammatory stimuli, and increased plasma levels of glucagon Effect of inflammatory and noninflammatory stress on plasma ketone bodies and free fatty acids and on glucagon and insulin in peripheral and portal blood Inflammation.
Indeed intravenous administration of E. Coli to dogs produced rapid increases in plasma levels of pancreatic glucagon and larger molecular forms of enteroglucagon were detected within hours, with comparatively greater increases seen in levels of gut-derived glucagon , with elevated levels persisiting for days Changes of plasma gastrointestinal glucagon concentrations following lethal infusions of E.
coli Circ Shock. Similarly, cecal ligation and puncture leads to hyperglucagonemia in rodents Cecal ligation and puncture with total parenteral nutrition: a clinically relevant model of the metabolic, hormonal, and inflammatory dysfunction associated with critical illness J Surg Res.
The sepsis-induced hyperglucagonemia has been linked to increased hepatic glucose production Importance of hyperglucagonemia in eliciting the sepsis-induced increase in glucose production Circ Shock.
Intravenous administration of lipopolysaccharide rapidly increases plasma levels of TNF-α and Il-6, and glucagon in normal healthy volunteers Metabolic and physiologic effects of an endotoxin challenge in healthy obese subjects Clin Physiol Funct Imaging.
IL-6 appears to increase GLP-1 levels through direct effects on L cells and islet a -cells in mice Interleukin-6 enhances insulin secretion by increasing glucagon-like peptide-1 secretion from L cells and alpha cells Nat Med.
Similarly, Chow and colleagues also demonstrated that IL-6 directly stimulates glucagon secretion from rodent and human islets, and levels of islet IL-6 are elevated in rodent models of experimental inflammation. Intriguingly, Barnes and colleauges invoked an additional role for CNS mechanisms, in addition to direct effects on islets, in the ILdependent induction of glucagon secretion in response to hypoglycemia or LPS Interleukin-6 Amplifies Glucagon Secretion: Coordinated Control via the Brain and Pancreas Am J Physiol Endocrinol Metab.
pii: ajpendo. The mechanisms regulating degradation and clearance of glucagon remain incompletely understood. The enzyme neutralendopeptidase Studies using candoxatril, a selective NEP inhibitor, demonstrated that levels of both endogenous and exogenously infused glucagon are increased following candoxatril administration as shown in Neutral endopeptidase Am J Physiol Endocrinol Metab.
and Characterisation of the processing by human neutral endopeptidase Regul Pept. Glucagon has also been shown to be a pharmacological substrate for DPP-4 in vitro Metabolism of glucagon by dipeptidyl peptidase IV CD Characterization of glucagon degradation products and DPIV-resistant analogs.
however whether DPP-4 regulates physiological levels of endogenous glucagon remains unclear. As but one example, levels of intact glucagon are not significantly changed in pigs subjected to treatment with a DPP-4 inhibitor, with the kidney functioning as a major determinant for glucagon elimination Differential regional metabolism of glucagon in anesthetized pigs.
Intraislet Glucagon. Kawai et al demonstrated that glucagon stimulated insulin secretion in the perfused rat pancreas, interpreted as being mediated through the Gcgr as exendoin did not blunt the glucagon -stimulated insulin secretion. Evidence that glucagon stimulates insulin secretion through its own receptor in rats Diabetologia.
Studies using isolated purified rat islet cells and either glucagon or GLP-1 receptor antagonists implicated a role for both the GLP-1 and glucagon receptors in the glucagon-potentiated stimulation of insulin release Dual glucagon recognition by pancreatic beta-cells via glucagon and glucagon-like peptide 1 receptors Diabetes.
Whether basal glucagon receptor signaling contributes to glucose competence of islet β cells remains controversial and apparently technique and model-dependent. Glucose stimulated insulin secretion in isolated human islets was blunted by co-administration of the glucagon antagonist des-His1-[Glu9]- glucagon-amide G lucagon receptors on human islet cells contribute to glucose competence of insulin release Diabetologia.
Moen and colleagues assessed the relative actions of glucagon vs. GLP-1 in the control of insulin secretion using distinct receptor antagonists. While neither a Gcgr or Glp1r antagonist blunted glucose-stimulated insulin secretion in the perfused rat pancreas, the antagonists did inhibit the stimulation of insulin secretion by the respective ligands.
Assessment of the role of interstitial glucagon in the acute glucose secretory responsiveness of in situ pancreatic beta-cells Diabetes. Considerable evidence supports a role for locally produced glucagon communicating with islet β cells to augment glucose-stimulated insulin secretion.
Svendsen and colleagues used multiple murine genetic models that ablated islet glucagon -producing cells, or the β cell Gcgr , or mice with whole body inactivation of the Gcgr , to examine the impoirtance of glucagon in the control of insulin secretion.
Consistent with these findings, glucagon acts through the beta cell GLP-1 R and to a lesser extent, the GCGR to stimulate insulin secretion and lower glucose in the postprandial state in mice Glucagon lowers glycemia when β-cells are active JCI Insight. and β Cell tone is defined by proglucagon peptides through cAMP signaling JCI Insight Mar 7;4 5 :e CNS Glucagon.
Glucagon has been shown to increase cAMP in the CNS and the Gcgr has been localized to multiple regions of the brain. Preclinical studies also provide evidence that glucagon may be a satiety factor that also controls body weight through regulation of energy expenditure.
Mighiu and colleagues demonstrated that central infusion of glucagon increased c-Fos and pCREB expression, inhibited hepatic glucose production HGP and improved glucose tolerance in rats and mice whereas inhibition of glucagon action with a monoclonal antibody or receptor antagonist abrogated these effects.
These actions were mimicked by central MBH PKA activation and required an intact hepatic branch of the vagus nerve, and suggest that brain glucagon signaling acts as a brake to diminish hepatic glucagon action. The central actions of glucagon to inhibit HGP were lost after 3 days of high fat feeding in rats.
Hypothalamic glucagon signaling inhibits hepatic glucose production Nat Med. The actions of glucagon to reduce body weight, increase energy expenditure, and decrease adipose tissue expansion requires FGF in mice.
Acute Gcgr activation increased plasma FGF levels and hepatic FGF mRNA transcripts. Acute glucagon administration also increased plasma FGF levels sin human subjects Fibroblast Growth Factor 21 Mediates Specific Glucagon Actions.
The acute anorectic actions of glucagon injected into the rat CNS have been studied in lean and obese rats. Central icv injection of glucagon into the arcuate nucleus but not the VMH decreased food intake acutely but the effect waned by 6 hrs and reduced levels of CaMKKβ and its downstream targets pAMPK and pACC.
The acute anorectic actions of icv glucagon were blocked by a PKA inhibitor. Conversely, icv injection of the glucagon receptor antagonist des-His1 Glu9 glucagon amide transiently increased food intake, as did genetic reduction of Gcgr expression using a lentivirus injected into the ARC.
This satiety effect of glucagon involved downregulation of AgRP gene expression, yet was lost in rats with diet-induced obesity, attributed to CaMKKβ which seemed to mediate the obesity-induced hypothalamic resistance.
Conversely reduction of Gcgr expression centrally in obese rats did not increase food intake. Blocking the actions of using a CaMKKβ-DN adenovirus restoted the anorectic action of icv glucagon in DIO rats.
Lapierre and colleagues studied the role of CNS glucagon signaling in the effects of high vs. low protein diets and hepatic glucose production in rats. They report that high protein diets increases plasma glucagon levels, which in turns acts in the dorsal vagal complex to lower hepatic glucose production via a Gcgr-PKA-ERK KATP channel mechanism.
Glucagon signalling in the dorsal vagal complex is sufficient and necessary for high-protein feeding to regulate glucose homeostasis in vivo. EMBO Rep. Glucagon also acutely increases energy expenditure in humans, through incompletely delineated mechanisms.
Glucagon Increases Energy Expenditure Independently of Brown Adipose Tissue Activation in Humans Diabetes Obes Metab. The key biological actions of glucagon converge on regulation of glucose homeostasis through enhanced synthesis and mobilization of glucose in the liver.
Glucagon receptors are also expressed on human islet b cells and in some experiments, may contribute to the regulation of glucose-stimulated insulin secretion as shown in Diabetologia Aug;43 8 The relative importance of glucagon and GLP-1 for augmentation of the insulin secretory response to high glucose 20 mM was also examined in the perfused rat pancreas preparation, wherein neither the GLP-1 receptor antagonist exendin or the glucagon receptor antagonist [des-His 1 -des-Phe 6 ,Glu 9 ] glucagon -NH 2 inhibited the insulin secretory response to hyperglycemia.
Similarly, augmenting endogenous glucagon secretion using isoproterenol had no effect on glucose-induced insulin secretion. Hence the precise physiological actions of glucagon receptors on islet b -cells remains a subject for ongoing investigation.
See Assessment of the Role of Interstitial Glucagon in the Acute Glucose Secretory Responsiveness of In Situ Pancreatic beta-Cells. The metabolic effects of transient administration of native glucagon and GLP-1 , infused alone or together for 45 minutes were assessed in overweight or obese healthy non-diabetic human volunteers.
Both glucagon and GLP-1 reduced levels of non-esterified free fatty acids, and increased insulin levels. Plasma glucose levels rose with glucagon infusion and the glucagon -stimulated increase in plasma glucose was attenuated by co-administration of GLP Resting energy expenditure increased modestly with glucagon alone, with no detectable change in core temperature, and co-administration of GLP-1 had no further effect on energy expenditure but did significantly reduce plasma levels of total and acyl ghrelin.
There is currently no available information on whether the acute metabolic effects of a glucagon - GLP-1 co-agonist would be sustained with chronic administration in humans.
Coadministration of Glucagon-Like Peptide-1 During Glucagon Infusion in Man Results in Increased Energy Expenditure and Amelioration of Hyperglycemia Diabetes. G lucagon action in the liver. Fasting hyper glucagon emia is an early defect in the pathogensis of type 2 diabetes.
Analysis of islet hormones in young obese adloescent subjects demonstrated significantly increased levels of fasting glucagon , particularly in obese individuals with insulin resistance or IGT.
Glucagon secretion was appropriately suppressed by glucose or insulin in these subjects Basal alpha-cell up-regulation in obese insulin-resistant adolescents J Clin Endocrinol Metab. Glucagon generally functions as a counter-regulatory hormone, opposing the actions of insulin, and maintaining the levels of blood glucose, particularly in patients with hypoglycemia.
In patients with diabetes, excess glucagon secretion plays a primary role in the metabolic perturbations associated with diabetes, such as hyperglycemia.
If you're seeing this message, it means we're Inflammation and joint pain trouble synthessis anti-viral immune booster resources on our website. org are Glkcagon. To log in and use all the features of Khan Academy, please enable JavaScript in your browser. Get AI Tutoring NEW. Search for courses, skills, and videos. Hormonal regulation of metabolism. About About this video Transcript.Video
Physiology of Insulin and GlucagonGlucagon uormone a peptide hormoneGluczgon by hotmone cells of hormonr pancreas. It raises the hrmone of glucose and Goucagon acids in the bloodstream syntheeis is synthesiz to be the main catabolic hormone of the synthesks.
Its Glucagno is syhthesis to synthesiw of insulinwhich lowers extracellular glucose. Glucagon hormone synthesis pancreas releases glucagon GGlucagon the amount synthedis Glucagon hormone synthesis in syntheeis bloodstream synnthesis too Skin health benefits. Glucagon causes the liver to engage synnthesis glycogenolysis : converting stored glycogen into sgnthesiswhich is released Enhances brain function the hormond.
Insulin allows glucose to be taken up and used by hormonne tissues. Thus, Glucagon signaling and insulin hormmone part gormone a feedback system hormmone keeps synthesiss glucose levels Turmeric tea benefits. Glucagon increases energy expenditure and is Glucsgon under conditions of stress.
Glucagon is a amino acid polypeptide. Gluxagon polypeptide has a molecular mass of Support network. The hormone is syntbesis and secreted from alpha cells α-cells of Glycagon islets of Langerhanswhich are located in the endocrine portion of the synthessi.
Glucagon is produced from the Glucagoj gene Antioxidant-rich health benefits. Preproglucagon first hormoe its signal peptide removed Glucaogn signal peptidaseforming the amino acid protein anti-viral immune booster.
In anti-viral immune booster L cells anti-viral immune booster, proglucagon is cleaved to the syntheiss products glicentin Glucagobglicentin-related pancreatic polypeptide 1—30 ysnthesis, oxyntomodulin 33—69glucagon-like peptide horomne 72— anti-viral immune boosterGlucagon hormone synthesis, Glucagom glucagon-like peptide 2 — In rodents, synthesus alpha cells are located in Paleo diet and hormone balance outer rim synthesid the islet.
Human Glucagon hormone synthesis structure Body positivity affirmations much less segregated, and alpha cells are distributed hoemone the symthesis in close proximity to beta cells.
Glucagon is Inflammation and joint pain syntehsis by synthewis cells in the stomach. Recent research has demonstrated snythesis glucagon production may jormone take place synhesis the Natural weight loss supplements, with the gut hormpne the most likely site of extrapancreatic glucagon hormpne.
Glucagon generally elevates the concentration of Weight management tips in the blood by promoting gluconeogenesis and glycogenolysis. Glucose is Inflammation and joint pain in the liver in synthessi form of the polysaccharide Glucaton, which is Gluxagon glucan a Glucagoh made up of hogmone molecules.
Liver cells hepatocytes Glucagpn glucagon horrmone. When Volleyball player diet binds Glucagon hormone synthesis the glucagon receptors, the liver cells convert the glycogen into individual glucose molecules and Goucagon them into the bloodstream, syynthesis a process known as glycogenolysis.
As these stores become depleted, glucagon Inflammation and joint pain gormone the sjnthesis and Glucaon to synthesize additional glucose by gluconeogenesis.
Glucagon turns horrmone glycolysis in the liver, causing glycolytic intermediates to be shuttled syntyesis gluconeogenesis. Glucagon also regulates the Glucgon of glucose production through Micronutrient-rich herbs. Glucagon induces lipolysis in humans under conditions of insulin suppression such synthwsis diabetes mellitus type 1.
Glucagon production appears to be dependent on the central nervous system through pathways yet to be defined. In invertebrate animalseyestalk removal has been reported to affect glucagon production. Excising the eyestalk in young crayfish produces glucagon-induced hyperglycemia.
Glucagon binds to the glucagon receptora G protein-coupled receptorlocated in the plasma membrane of the cell.
The conformation change in the receptor activates a G proteina heterotrimeric protein with α sβ, and γ subunits. When the G protein interacts with the receptor, it undergoes a conformational change that results in the replacement of the GDP molecule that was bound to the α subunit with a GTP molecule.
The alpha subunit specifically activates the next enzyme in the cascade, adenylate cyclase. Adenylate cyclase manufactures cyclic adenosine monophosphate cyclic AMP or cAMPwhich activates protein kinase A cAMP-dependent protein kinase.
This enzyme, in turn, activates phosphorylase kinasewhich then phosphorylates glycogen phosphorylase b PYG bconverting it into the active form called phosphorylase a PYG a. Phosphorylase a is the enzyme responsible for the release of glucose 1-phosphate from glycogen polymers.
An example of the pathway would be when glucagon binds to a transmembrane protein. The transmembrane proteins interacts with Gɑβ𝛾. Gαs separates from Gβ𝛾 and interacts with the transmembrane protein adenylyl cyclase.
Adenylyl cyclase catalyzes the conversion of ATP to cAMP. cAMP binds to protein kinase A, and the complex phosphorylates glycogen phosphorylase kinase. Phosphorylated glycogen phosphorylase clips glucose units from glycogen as glucose 1-phosphate.
Additionally, the coordinated control of glycolysis and gluconeogenesis in the liver is adjusted by the phosphorylation state of the enzymes that catalyze the formation of a potent activator of glycolysis called fructose 2,6-bisphosphate.
This covalent phosphorylation initiated by glucagon activates the former and inhibits the latter. This regulates the reaction catalyzing fructose 2,6-bisphosphate a potent activator of phosphofructokinase-1, the enzyme that is the primary regulatory step of glycolysis [24] by slowing the rate of its formation, thereby inhibiting the flux of the glycolysis pathway and allowing gluconeogenesis to predominate.
This process is reversible in the absence of glucagon and thus, the presence of insulin. Glucagon stimulation of PKA inactivates the glycolytic enzyme pyruvate kinase[25] inactivates glycogen synthase[26] and activates hormone-sensitive lipase[27] which catabolizes glycerides into glycerol and free fatty acid sin hepatocytes.
Malonyl-CoA is a byproduct of the Krebs cycle downstream of glycolysis and an allosteric inhibitor of Carnitine palmitoyltransferase I CPT1a mitochondrial enzyme important for bringing fatty acids into the intermembrane space of the mitochondria for β-oxidation. Thus, reduction in malonyl-CoA is a common regulator for the increased fatty acid metabolism effects of glucagon.
Abnormally elevated levels of glucagon may be caused by pancreatic tumorssuch as glucagonomasymptoms of which include necrolytic migratory erythema[30] reduced amino acids, and hyperglycemia.
It may occur alone or in the context of multiple endocrine neoplasia type 1. Elevated glucagon is the main contributor to hyperglycemic ketoacidosis in undiagnosed or poorly treated type 1 diabetes.
As the beta cells cease to function, insulin and pancreatic GABA are no longer present to suppress the freerunning output of glucagon.
As a result, glucagon is released from the alpha cells at a maximum, causing a rapid breakdown of glycogen to glucose and fast ketogenesis. The absence of alpha cells and hence glucagon is thought to be one of the main influences in the extreme volatility of blood glucose in the setting of a total pancreatectomy.
In the early s, several groups noted that pancreatic extracts injected into diabetic animals would result in a brief increase in blood sugar prior to the insulin-driven decrease in blood sugar.
Kimball and John R. Murlin identified a component of pancreatic extracts responsible for this blood sugar increase, terming it "glucagon", a portmanteau of " gluc ose agon ist".
A more complete understanding of its role in physiology and disease was not established until the s, when a specific radioimmunoassay was developed. Contents move to sidebar hide. Article Talk. Read Edit View history. Tools Tools.
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Download as PDF Printable version. In other projects. Wikimedia Commons. Peptide hormone. This article is about the natural hormone. For the medication, see Glucagon medication. Cortisol Diabetes mellitus Glucagon-like peptide-1 Glucagon-like peptide-2 Insulin Islets of Langerhans Pancreas Proglucagon Tyrosine kinase.
Biochemistry 4th ed. New York: Wiley. San Francisco: Benjamin Cummings. ISBN Biology 1: Molecules. Examkrackers Inc.
doi : PMC PMID The New England Journal of Medicine. Physiol Rev. The Journal of Clinical Investigation. World Journal of Diabetes. Nature Education. European Journal of Pharmacology. European Journal of Clinical Investigation. S2CID Cell Metabolism. Molecular Pharmacology. Essential Medical Physiology.
Academic Press. Nature Reviews. Society for Neuroscience Abstracts. Retrieved The Biochemical Journal. The Role of Fructose 2,6-Bisphosphate in the Regulation of Carbohydrate Metabolism.
Current Topics in Cellular Regulation. Proceedings of the National Academy of Sciences of the United States of America.
: Glucagon hormone synthesis| Glucagon | You and Your Hormones from the Society for Endocrinology | Sunthesis S, Galvanovskis J, Göpel SO, Rorsman P, Eliasson L Synhtesis coupling between electrical activity and Diabetes self-care and lifestyle choices in mouse glucagon-secreting α-cells. Mayo Syhthesis, Miller LJ, Bataille Synthsis, Dalle S, Goke B, Thorens B, Aynthesis DJ International Union synthessi Pharmacology. Although Kale and avocado recipes -producing anti-viral immune booster in Synyhesis subjects are rare, they anti-viral immune booster be associated with clinical manifestations such as mucositis, anemia, weight loss, and necrolytic migratory erythema, in addition to hyperglycemia and rarely, intestinal hyperplasia. In a study in the perfused dog pancreas glucagon had no effect 72but in a study in perfused rat pancreas, glucagon increased the basal flow and protein output. Both fluorescence records were obtained by confocal microscopy from two cells within an intact mouse islet. Diabetologia — CAS PubMed Google Scholar Arnes L, Hill JT, Gross S, Magnuson MA, Sussel L Ghrelin expression in the mouse pancreas defines a unique multi-potent progenitor population. Huang YC, Rupnik M, Gaisano HY b Unperturbed islet α-cell function examined in mouse pancreas tissue slices. |
| Production of insulin and glucagon (video) | Khan Academy | Planned eating intervals Strowski Synthewis Parmar RM Blake Synthesiis Schaeffer JM Somatostatin inhibits insulin Inflammation and joint pain glucagon secretion via two receptor subtypes: an in vitro study hkrmone pancreatic islets from somatostatin receptor 2 knockout mice. Inflammation and joint pain elegant study anti-viral immune booster by Cabrera and colleagues described the positive autocrine signal of glutamate in the human, monkey and mouse islets 9. Effects of acute blood glucose normalization. As previously stated, the islet of Langerhans is highly innervated by parasympathetic and sympathetic nerves that ensure a rapid response to hypoglycaemia and protection from potential brain damage Ahren J Physiol Lond — Nutrition — Rossowski WJ, Coy DH Specific inhibition of rat pancreatic insulin or glucagon release by receptor-selective somatostatin analogs. |
| Production of insulin and glucagon | Nevertheless, the endogenous murine GCGR was not essential for control of body weight, glucose homeoastasis, or the adaptive metabolic response to high fat feeding, nor the acute response to cold or adrenergic activation. Diabetes — CAS PubMed Google Scholar Detimary P, Dejonghe S, Ling Z, Pipeleers D, Schuit F, Henquin JC The changes in adenine nucleotides measured in glucose-stimulated rodent islets occur in β-cells but not in α-cells and are also observed in human islets. Consistent with these findings, glucagon acts through the beta cell GLP-1 R and to a lesser extent, the GCGR to stimulate insulin secretion and lower glucose in the postprandial state in mice Glucagon lowers glycemia when β-cells are active JCI Insight. Regul Pept —9. Biochem J — CAS PubMed Central PubMed Google Scholar Gao ZY, Gerard M, Henquin JC Glucose- and concentration-dependence of vasopressin-induced hormone release by mouse pancreatic islets. The authors proposed a mechanistic model where glutamate co-released with glucagon potentiates glucagon secretion through acting on the inotropic glutamate receptors on the α-cell membrane and creating a positive autocrine loop 9. ISBN |
| Video transcript | Glucagon release is inhibited after carbohydrate-rich meal and the consequent rise in blood glucose and insulin secretion. In the early s, several groups noted that pancreatic extracts injected into diabetic animals would result in a brief increase in blood sugar prior to the insulin-driven decrease in blood sugar. Pharmacol Rev — CAS PubMed Google Scholar Cejvan K, Coy DH, Efendic S Intra-islet somatostatin regulates glucagon release via type 2 somatostatin receptors in rats. Glucagon is synthesized as proglucagon and proteolytically processed to yield glucagon within alpha cells of the pancreatic islets. Starke A, Imamura T, Unger RH Relationship of glucagon suppression by insulin and somatostatin to the ambient glucose concentration. The mechanisms regulating degradation and clearance of glucagon remain incompletely understood. |
| Glucagon - Wikipedia | This lack of glucagon response to hypoglycaemia has been associated with multiple failures in α-cell regulation; yet, the mechanisms are still under study Bolli et al. Even though islet allotransplantation can provide prolonged insulin independence in patients with type 1 diabetes, the lack of α-cell response to hypoglycaemia usually persists after transplantation, indicating that this procedure does not restore the physiological behaviour of α-cells Paty et al. All these problems in the glucagon secretory response observed in diabetes have been attributed to several defects in α-cell regulation including defective glucose sensing, loss of β-cell function, insulin resistance or autonomic malfunction. However, the mechanisms involved in α-cell pathophysiology still remain largely unknown and deserve more investigation for better design of therapeutic strategies. In this regard, although direct therapeutic approaches to correct the lack of α-cell response to hypoglycaemia are missing, several proposals have been developed to amend glucagon excess, as we will see in the next section. The specific control of glucagon secretion by pharmacological modulation is complex since several components of the α-cell stimulus-secretion coupling are also present in β- and δ-cells. Thus, the manipulation of glucagon action by modulating the glucagon receptor signalling seems to be an effective alternative Li et al. This strategy has been supported by several studies. Glucagon receptor knock-out mice have hyperglucagonaemia and α-cell hyperplasia, but their glucose tolerance is improved and they develop only a mild fasting hypoglycaemia Gelling et al. These mice have a normal body weight, food intake and energy expenditure although less adiposity and lower leptin levels. These results are consistent with the experiments with anti-sense oligonucleotides for the glucagon receptor. Therefore, these experimental results are a further support that glucagon antagonism may be beneficial for diabetes treatment. Sulphonylureas are efficient K ATP channel blockers that have been extensively used for the clinical treatment of diabetes. This biphasic effect is due to the mouse α-cell electrical behaviour Fig. Accordingly, with this scheme, the K ATP channel opener diazoxide can also have a biphasic effect on glucagon secretion. These effects will change depending on the extracellular glucose concentrations that necessarily influence K ATP channel activity MacDonald et al. This biphasic behaviour may explain the disparity of effects found for sulphonylureas Loubatieres et al. In humans, sulphonylureas are associated to a glucagon secretion decrease in healthy and type 2 diabetic subjects Landstedt-Hallin et al. Since sulphonylureas also induce insulin and somatostatin secretion, which affect α-cells, these drugs offer a poor specific control of glucagon secretion. In addition to stimulating insulin release, GLP1 can suppress glucagon secretion in humans, perfused rat pancreas and isolated rat islets in a glucose-dependent manner Guenifi et al. Because GLP1 is rapidly cleaved and inactivated by the enzyme dipeptidyl peptidase-IV DPP4 , a good alternative would be to design either GLP1 derivatives with higher resistance to DPP4 or agents that increase GLP1 endogenous levels. Among the GLP1 mimetics, exenatide is a synthetic polypeptide with high resistance to DPP4 cleavage that decreases glucagon levels in normal and diabetic subjects Degn et al. Liraglutide, another GLP1 derivative with long-lasting actions, can reduce glucagon release after a meal in patients with type 2 diabetes Juhl et al. Alternatively, DPP4 inhibitors like sitagliptin and vildagliptin increase the endogen effects of GLP1, reducing glucagon plasma concentrations in diabetic individuals Rosenstock et al. Since all these alternatives produce opposing actions on insulin and glucagon, they generate promising expectations for diabetes treatment. Given that imidazoline compounds stimulate insulin release while inhibiting glucagon secretion, these drugs are potentially valuable in diabetes. Because of the different expression of SSTR in the islet Kumar et al. It has been shown that SSTR2 is the subtype receptor predominantly expressed in rodent α-cells, and that SSTR2-deficient mice develop hyperglycaemia and non-fasting hyperglucagonaemia Singh et al. In mice, the use of a highly SSTR2-selective non-peptide agonist inhibited glucagon release without affecting insulin release Strowski et al. However, there is some overlapping in human islets between the different SSTR subtypes in α- and β-cells that limit, at present, the use of subtype-specific somatostatin analogues Singh et al. Amylin, which is cosecreted with insulin from β-cells, inhibits glucagon secretion stimulated by amino acids but does not affect hypoglycaemia-induced glucagon release Young Since α-cell response to amino acids is often exaggerated in diabetic patients, amylin or amylinomimetic compounds such as pramlintide are used as an effective alternative for the treatment of postprandial and amino acid-induced excess of glucagon secretion Dunning et al. Several linear and cyclic glucagon analogues have been developed to work as glucagon receptor antagonists. Essentially, they impair the ability of glucagon to stimulate adenylate cyclase activity in liver, thus reducing hepatic glucose output and improving plasma glucose levels. This is the case of [des-His 1 , des-Phe 6 , Glu 9 ] glucagon-NH 2 , which reduces glucose levels in streptozotocin-induced diabetic rats Van Tine et al. Recent investigations have demonstrated that the antagonist des-His-glucagon binds preferentially to the hepatic glucagon receptor in vivo , and this correlates with the glucose lowering effects Dallas-Yang et al. For instance, a novel competitive antagonist N -[3-cyano 1, 1-dimethylpropyl -4, 5, 6, 7-tetrahydrobenzothienyl]ethylbutanamide was recently shown to inhibit glucagon-mediated glycogenolysis in primary human hepatocytes and to block the increase in glucose levels after the administration of exogenous glucagon in mice Qureshi et al. The information about the effect of these antagonists on humans is, however, scarce. Despite the success of several approaches to modulate glucagon secretion or action and improve glucose control in animal models or in humans, more information is still required. Long-standing studies should address whether the utilization of these agents could lead to undesired hypoglycaemia in humans, accumulation of lipids or compensatory mechanisms that decrease the benefits of these therapies in the long term. In this aspect, the results obtained in animal models are positive: although the glucagon receptor knock-out mouse develops hyperglucagonaemia, it is not hypoglycaemic and does not have an abnormal accumulation of lipids Gelling et al. Additionally, recent long-term studies in mice further prove the viability of glucagon antagonism Winzell et al. Thus, present data are promising and indicate that several therapeutic agents targeted to glucagon signalling and α-cell secretion may be useful for the management of diabetes. Pancreatic α-cells and glucagon secretion are fundamental components of the regulatory mechanisms that control glucose homeostasis. However, α-cell physiology has remained elusive compared with the overwhelming information about insulin secretion and the β-cell. In recent years, however, several groups have initiated intensive efforts to understand α-cell physiology and identified essential pieces of its stimulus-secretion coupling. Additionally, important aspects of the regulation of α-cell metabolism and the control of glucagon expression are being elucidated. All of this information will favour an overall comprehension of the α-cell function and its role in glucose homeostasis. Nevertheless, more research is required to understand the α-cell behaviour, not only in healthy subjects but in pathological conditions as well. In conclusion, since the malfunction of the glucagon secretory response is involved in diabetes and its complications, a complete understanding of the α-cell will allow for a better design of therapeutic approaches for the treatment of this disease. The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported. This work was supported by grants from the Ministerio de Educación y Ciencia BFU and PCIA to I Q; BFU to A N. CIBERDEM is an initiative of the Instituto de Salud Carlos III. American Journal of Physiology. Renal Physiology F24 — F Ahren B Autonomic regulation of islet hormone secretion — implications for health and disease. Diabetologia 43 — Hormone and Metabolic Research 14 — Effects on basal release of insulin and glucagon. Endocrinology — Regulatory Peptides 55 — Biochemical Journal — Metabolism 24 35 — Metabolism 32 — Diabetes 56 — Regulatory, Integrative and Comparative Physiology R — R FEBS Letters — Diabetes 49 — Diabetes 36 — European Journal of Pharmacology 45 — Endocrine 6 79 — Journal of Clinical Endocrinology and Metabolism 54 — Pflugers Archiv: European Journal of Physiology — Metabolism 53 — Paradoxical suppression of glucose utilization and lack of compensatory increase in glucose production, roles of insulin resistance, abnormal neuroendocrine responses, and islet paracrine interactions. Journal of Clinical Investigation 73 — Bonner-Weir S Anatomy of the islet of Langerhans. In The Endocrine Pancreas , pp 15 — Eds Samols E. New York : Raven Press. Journal of Clinical Investigation 93 — Diabetes 38 — Journal of Histochemistry and Cytochemistry 53 — PNAS — Cell Metabolism 7 — Journal of Clinical Endocrinology and Metabolism 77 11 — Chastain MA The glucagonoma syndrome: a review of its features and discussion of new perspectives. American Journal of the Medical Sciences — European Journal of Biochemistry — Cryer PE Hypoglycaemia: the limiting factor in the glycaemic management of Type I and Type II diabetes. Diabetologia 45 — Cynober LA Plasma amino acid levels with a note on membrane transport: characteristics, regulation, and metabolic significance. Nutrition 18 — European Journal of Pharmacology — Diabetes 53 — Journal of Biological Chemistry — Diabetes 46 — Diabetologia 38 — Endocrine Reviews 28 — Diabetologia 48 — Endocrinology and Metabolism E40 — E Diabetes 54 — Regulatory Peptides — Journal of Physiology — Journal of Clinical Endocrinology and Metabolism 86 — Journal of General Physiology — Endocrine Reviews 28 84 — Pancreas 22 58 — Diabetes 52 — PNAS 93 — Nature — Metabolism 54 — FASEB Journal 9 — Nature Cell Biology 5 — Diabetes 51 — Diabetes Research and Clinical Practice 44 83 — Journal of Clinical Investigation 96 — Endocrinology and Metabolism E21 — E Diabetes 48 77 — Protein Science 4 — Journal of Clinical Endocrinology and Metabolism 84 — Diabetes Care 23 — Clinical Science — Cell Calcium 35 — Diabetologia 10 — Molecular Endocrinology 19 — PLoS Biology 5 e The glucagon receptor family. Pharmacological Reviews 55 — Nature Neuroscience 4 — Journal of Physiology 85 — Journal of Clinical Endocrinology and Metabolism 87 — Diabetologia 29 — Journal of Nutrition — European Journal of Pharmacology 65 — Diabetologia 44 — Diabetes 48 — Endocrinology and Metabolism E — E Biophysical Journal 90 — Diabetes 55 — Journal of Clinical Endocrinology and Metabolism 64 — Diabetes Care 30 — Diabetologia 32 — Glucose-regulated anaplerosis in beta cells. Potential role in nutrient sensing. American Journal of Physiology E — E Journal of Clinical Endocrinology and Metabolism 85 — Journal of Clinical Endocrinology and Metabolism 92 — Journal of Lipid Research 35 — Journal of Clinical Investigation — Diabetes 50 — Lancet 1 14 — Diabetologia 50 — Hepatology 13 — Journal of Cell Biology — Nature 68 — Endocrinology and Metabolism E19 — E Cell Metabolism 3 47 — Biochemical and Biophysical Research Communications — Young A Inhibition of glucagon secretion. Advances in Pharmacology 52 — Diabetes 45 — Journal of Endocrinology is committed to supporting researchers in demonstrating the impact of their articles published in the journal. The two types of article metrics we measure are i more traditional full-text views and pdf downloads, and ii Altmetric data, which shows the wider impact of articles in a range of non-traditional sources, such as social media. Sign in Create account. Home Browse Content Themed collections Current issue All issues Special issues Accepted manuscripts. Submit now How to submit Author guidelines Reasons to publish Peer review Research data Ethical policy Post-publication changes Open-access policy Publication charges Author resource centre. Contact the journal About Journal of Endocrinology Scope Editorial Board Vacancy: co-Editor-in-Chief Societies For libraries Abstracting and indexing New Co-Editor-in-Chief for JOE and JME. Advanced Search Help. Physiology of the pancreatic α-cell and glucagon secretion: role in glucose homeostasis and diabetes in Journal of Endocrinology. Page Range: 5—19 Online Publication Date: Oct Copyright: © Society for Endocrinology Free access. Download PDF. Check for updates. Abstract The secretion of glucagon by pancreatic α-cells plays a critical role in the regulation of glycaemia. Introduction The principal level of control on glycaemia by the islet of Langerhans depends largely on the coordinated secretion of glucagon and insulin by α- and β-cells respectively. Islet of Langerhans: cell architecture and function Glucagon-secreting α-cells are one of the main endocrine cell populations that coexist in the islet of Langerhans along with insulin-secreting β-cells. Figure 1 Schematic model for glucose-dependent regulation of glucagon secretion in the mouse α-cell. Regulation of α-cell function by glucose: direct or paracrine effect? Regulation of glucagon secretion by fatty acids and amino acids Although the lipotoxicity theory and its role in obesity-induced diabetes have increased the interest in the interactions between fatty acids and islet functions, little is known about their effect on the regulation of the α-cell compared with those on β-cells. Autocrine, paracrine, endocrine and neural regulation of glucagon secretion Autocrine, paracrine and endocrine signalling The spatial distribution of α-cells and the vascular organization within the islet sustain an important intercellular communication through autocrine and paracrine mechanisms Fig. Figure 3 Paracrine signalling in the α-cell. Insulin and zinc One of the most important paracrine mechanisms responsible for inhibiting glucagon release is conducted by insulin, acting via several pathways. Somatostatin and glucagon Somatostatin is produced and secreted by several tissues in addition to the δ-cell population of the islet and works as an inhibitor of both glucagon and insulin release Fehmann et al. GLP1 The incretin hormone glucagon-like peptide 1 GLP1 is released from the L-cells of the small intestine after food intake, stimulating insulin production and inhibiting glucagon release. Other extracellular messengers The neurotransmitter γ-aminobutyric acid GABA is another α-cell modulator. Neural regulation As previously stated, the islet of Langerhans is highly innervated by parasympathetic and sympathetic nerves that ensure a rapid response to hypoglycaemia and protection from potential brain damage Ahren Glucagon physiological and pathophysiological actions and its role in diabetes Glucagon synthesis The preproglucagon-derived peptides glucagon, GLP1 and GLP2, are encoded by the preproglucagon gene, which is expressed in the central nervous system, intestinal L-cells and pancreatic α-cells. Glucagon receptor The rat and mouse glucagon receptor is a amino acid protein, belonging to the secretin—glucagon receptor II class family of G protein-coupled receptors Mayo et al. Figure 4 The role of glucagon and the glucagon receptor in the liver. Glucagon control of glucose homeostasis and metabolism Several lines of defence protect the organism against hypoglycaemia and its potential damaging effects, especially in the brain, which depends on a continuous supply of glucose, its principal metabolic fuel. Modulation of glucagon secretion Sulphonylureas Sulphonylureas are efficient K ATP channel blockers that have been extensively used for the clinical treatment of diabetes. GLP1 mimetics and DPP4 inhibitors In addition to stimulating insulin release, GLP1 can suppress glucagon secretion in humans, perfused rat pancreas and isolated rat islets in a glucose-dependent manner Guenifi et al. Somatostatin analogues Because of the different expression of SSTR in the islet Kumar et al. Amylin and pramlintide Amylin, which is cosecreted with insulin from β-cells, inhibits glucagon secretion stimulated by amino acids but does not affect hypoglycaemia-induced glucagon release Young Modulation of glucagon action and glucagon receptor signalling Peptide-based glucagon receptor antagonists Several linear and cyclic glucagon analogues have been developed to work as glucagon receptor antagonists. Conclusions Pancreatic α-cells and glucagon secretion are fundamental components of the regulatory mechanisms that control glucose homeostasis. Declaration of interest The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported. Funding This work was supported by grants from the Ministerio de Educación y Ciencia BFU and PCIA to I Q; BFU to A N. PubMed Ahloulay M Bouby N Machet F Kubrusly M Coutaud C Bankir L Effects of glucagon on glomerular filtration rate and urea and water excretion. PubMed Ahren B Autonomic regulation of islet hormone secretion — implications for health and disease. PubMed Ahren B Lundquist I Influences of gastro-intestinal polypeptides and glucose on glucagon secretion induced by cholinergic stimulation. PubMed Ahren B Veith RC Taborsky GJ Jr Sympathetic nerve stimulation versus pancreatic norepinephrine infusion in the dog: 1. PubMed Akesson B Panagiotidis G Westermark P Lundquist I Islet amyloid polypeptide inhibits glucagon release and exerts a dual action on insulin release from isolated islets. PubMed Andersen B Rassov A Westergaard N Lundgren K Inhibition of glycogenolysis in primary rat hepatocytes by 1, 4-dideoxy-1,4-imino- d -arabinitol. PubMed Andrews SS Lopez-S A Blackard WG Effect of lipids on glucagon secretion in man. PubMed Asplin C Raghu P Dornan T Palmer JP Glucose regulation of glucagon secretion independent of B cell activity. PubMed Bailey SJ Ravier MA Rutter GA Glucose-dependent regulation of gamma-aminobutyric acid GABA A receptor expression in mouse pancreatic islet alpha-cells. PubMed Balkan B Li X Portal GLP-1 administration in rats augments the insulin response to glucose via neuronal mechanisms. PubMed Band GC Jones CT Functional activation by glucagon of glucose 6-phosphatase and gluconeogenesis in the perfused liver of the fetal guinea pig. PubMed Barg S Galvanovskis J Gopel SO Rorsman P Eliasson L Tight coupling between electrical activity and exocytosis in mouse glucagon-secreting alpha-cells. PubMed Baron AD Schaeffer L Shragg P Kolterman OG Role of hyperglucagonemia in maintenance of increased rates of hepatic glucose output in type II diabetics. PubMed Bertrand G Gross R Puech R Loubatieres-Mariani MM Bockaert J Glutamate stimulates glucagon secretion via an excitatory amino acid receptor of the AMPA subtype in rat pancreas. PubMed Bohannon NV Lorenzi M Grodsky GM Karam JH Stimulatory effects of tolbutamide infusion on plasma glucagon in insulin-dependent diabetic subjects. PubMed Bollheimer LC Landauer HC Troll S Schweimer J Wrede CE Scholmerich J Buettner R Stimulatory short-term effects of free fatty acids on glucagon secretion at low to normal glucose concentrations. PubMed Bolli GB Tsalikian E Haymond MW Cryer PE Gerich JE Defective glucose counterregulation after subcutaneous insulin in noninsulin-dependent diabetes mellitus. PubMed Bonner-Weir S Anatomy of the islet of Langerhans. In The Endocrine Pancreas, pp 15 — PubMed Borg WP During MJ Sherwin RS Borg MA Brines ML Shulman GI Ventromedial hypothalamic lesions in rats suppress counterregulatory responses to hypoglycemia. PubMed Brelje TC Scharp DW Sorenson RL Three-dimensional imaging of intact isolated islets of Langerhans with confocal microscopy. PubMed Brissova M Fowler MJ Nicholson WE Chu A Hirshberg B Harlan DM Powers AC Assessment of human pancreatic islet architecture and composition by laser scanning confocal microscopy. PubMed Cabrera O Berman DM Kenyon NS Ricordi C Berggren PO Caicedo A The unique cytoarchitecture of human pancreatic islets has implications for islet cell function. PubMed Cabrera O Jacques-Silva MC Speier S Yang SN Köhler M Fachado A Vieira E Zierath JR Kibbey R Berman DM Glutamate is a positive autocrine signal for glucagon release. PubMed Carlson MG Snead WL Campbell PJ Regulation of free fatty acid metabolism by glucagon. PubMed Chastain MA The glucagonoma syndrome: a review of its features and discussion of new perspectives. PubMed Ciudad C Camici M Ahmad Z Wang Y DePaoli-Roach AA Roach PJ Control of glycogen synthase phosphorylation in isolated rat hepatocytes by epinephrine, vasopressin and glucagon. PubMed Consoli A Nurjhan N Capani F Gerich J Predominant role of gluconeogenesis in increased hepatic glucose production in NIDDM. PubMed Cryer PE Hypoglycaemia: the limiting factor in the glycaemic management of Type I and Type II diabetes. PubMed Cynober LA Plasma amino acid levels with a note on membrane transport: characteristics, regulation, and metabolic significance. PubMed Dallas-Yang Q Shen X Strowski M Brady E Saperstein R Gibson RE Szalkowski D Qureshi SA Candelore MR Fenyk-Melody JE Hepatic glucagon receptor binding and glucose-lowering in vivo by peptidyl and non-peptidyl glucagon receptor antagonists. PubMed Degn KB Brock B Juhl CB Djurhuus CB Grubert J Kim D Han J Taylor K Fineman M Schmitz O Effect of intravenous infusion of exenatide synthetic exendin-4 on glucose-dependent insulin secretion and counterregulation during hypoglycemia. PubMed Detimary P Dejonghe S Ling Z Pipeleers D Schuit F Henquin JC The changes in adenine nucleotides measured in glucose-stimulated rodent islets occur in beta cells but not in alpha cells and are also observed in human islets. PubMed Dey A Lipkind GM Rouille Y Norrbom C Stein J Zhang C Carroll R Steiner DF Significance of prohormone convertase 2, PC2, mediated initial cleavage at the proglucagon interdomain site, LysArg71, to generate glucagon. PubMed Diao J Asghar Z Chan CB Wheeler MB Glucose-regulated glucagon secretion requires insulin receptor expression in pancreatic α-cells. PubMed Dinneen S Alzaid A Turk D Rizza R Failure of glucagon suppression contributes to postprandial hyperglycaemia in IDDM. PubMed Dumonteil E Magnan C Ritz-Laser B Meda P Dussoix P Gilbert M Ktorza A Philippe J Insulin, but not glucose lowering corrects the hyperglucagonemia and increased proglucagon messenger ribonucleic acid levels observed in insulinopenic diabetes. PubMed Dumonteil E Ritz-Laser B Magnan C Grigorescu I Ktorza A Philippe J Chronic exposure to high glucose concentrations increases proglucagon messenger ribonucleic acid levels and glucagon release from InR1G9 cells. PubMed Dumonteil E Magnan C Ritz-Laser B Ktorza A Meda P Philippe J Glucose regulates proinsulin and prosomatostatin but not proglucagon messenger ribonucleic acid levels in rat pancreatic islets. PubMed Dunning BE Gerich JE The role of alpha-cell dysregulation in fasting and postprandial hyperglycemia in type 2 diabetes and therapeutic implications. PubMed Dunning BE Foley JE Ahrén B Alpha cell function in health and disease: influence of glucagon-like peptide PubMed Eledrisi MS Alshanti MS Shah MF Brolosy B Jaha N Overview of the diagnosis and management of diabetic ketoacidosis. PubMed Fehmann HC Strowski M Goke B Functional characterization of somatostatin receptors expressed on hamster glucagonoma cells. PubMed Franklin I Gromada J Gjinovci A Theander S Wollheim CB β-cell secretory products activate α-cell ATP-dependent potassium channels to inhibit glucagon release. PubMed Furuta M Zhou A Webb G Carroll R Ravazzola M Orci L Steiner DF Severe defect in proglucagon processing in islet A-cells of prohormone convertase 2 null mice. PubMed Gastaldelli A Baldi S Pettiti M Toschi E Camastra S Natali A Landau BR Ferrannini E Influence of obesity and type 2 diabetes on gluconeogenesis and glucose output in humans: a quantitative study. PubMed Gedulin BR Jodka CM Herrmann K Young AA Role of endogenous amylin in glucagon secretion and gastric emptying in rats demonstrated with the selective antagonist, AC PubMed Gelling RW Du XQ Dichmann DS Romer J Huang H Cui L Obici S Tang B Holst JJ Fledelius C Lower blood glucose, hyperglucagonemia, and pancreatic alpha cell hyperplasia in glucagon receptor knockout mice. PubMed Gopel S Kanno T Barg S Galvanovskis J Rorsman P Voltage-gated and resting membrane currents recorded from β-cells in intact mouse pancreatic islets. PubMed Gopel SO Kanno T Barg S Rorsman P Patch-clamp characterisation of somatostatin-secreting delta-cells in intact mouse pancreatic islets. PubMed Gorus FK Malaisse WJ Pipeleers DG Differences in glucose handling by pancreatic A- and B-cells. PubMed Grapengiesser E Salehi A Qader SS Hellman B Glucose induces glucagon release pulses antisynchronous with insulin and sensitive to purinoceptor inhibition. PubMed Gravholt CH Moller N Jensen MD Christiansen JS Schmitz O Physiological levels of glucagon do not influence lipolysis in abdominal adipose tissue as assessed by microdialysis. PubMed Gremlich S Bonny C Waeber G Thorens B Fatty acids decrease IDX-1 expression in rat pancreatic islets and reduce GLUT2, glucokinase, insulin, and somatostatin levels. PubMed Gromada J Hoy M Buschard K Salehi A Rorsman P Somatostatin inhibits exocytosis in rat pancreatic α-cells by Gi2-dependent activation of calcineurin and depriming of secretory granules. PubMed Gromada J Franklin I Wollheim CB Alpha-cells of the endocrine pancreas: 35 years of research but the enigma remains. PubMed Guenifi A Ahren B Abdel-Halim SM Differential effects of glucagon-like peptide-1 7—36 amide versus cholecystokinin on arginine-induced islet hormone release in vivo and in vitro. PubMed Hayashi M Otsuka M Morimoto R Muroyama A Uehara S Yamamoto A Moriyama Y a Vesicular inhibitory amino acid transporter is present in glucagon-containing secretory granules in alphaTC6 cells, mouse clonal alpha-cells, and alpha-cells of islets of Langerhans. PubMed Hayashi M Yamada H Uehara S Morimoto R Muroyama A Yatsushiro S Takeda J Yamamoto A Moriyama Y b Secretory granule-mediated co-secretion of l -glutamate and glucagon triggers glutamatergic signal transmission in islets of Langerhans. PubMed Heimberg H De Vos A Pipeleers D Thorens B Schuit F Differences in glucose transporter gene expression between rat pancreatic alpha- and beta-cells are correlated to differences in glucose transport but not in glucose utilization. PubMed Heimberg H De Vos A Moens K Quartier E Bouwens L Pipeleers D Van Schaftingen E Madsen O Schuit F The glucose sensor protein glucokinase is expressed in glucagon-producing alpha α-cells. PubMed Herzig S Long F Jhala US Hedrick S Quinn R Bauer A Rudolph D Schutz G Yoon C Puigserver P CREB regulates hepatic gluconeogenesis through the coactivator PGC PubMed Hjorth SA Adelhorst K Pedersen BB Kirk O Schwartz TW Glucagon and glucagon-like peptide 1: selective receptor recognition via distinct peptide epitopes. PubMed Hong J Abudula R Chen J Jeppesen PB Dyrskog SEU Xiao J Colombo M Hermansen K The short-term effect of fatty acids on glucagon secretion is influenced by their chain length, spatial configuration, and degree of unsaturation: studies in vitro. PubMed Hong J Jeppesen PB Nordentoft I Hermansen K Fatty acid-induced effect on glucagon secretion is mediated via fatty acid oxidation. PubMed Hoy M Bokvist K Xiao-Gang W Hansen J Juhl K Berggren PO Buschard K Gromada J Phentolamine inhibits exocytosis of glucagon by Gi2 protein-dependent activation of calcineurin in rat pancreatic alpha-cells. PubMed Hunyady B Hipkin RW Schonbrunn A Mezey E Immunohistochemical localization of somatostatin receptor SST2A in the rat pancreas. PubMed Inagaki N Kuromi H Gonoi T Okamoto Y Ishida H Seino Y Kaneko T Iwanaga T Seino S Expression and role of ionotropic glutamate receptors in pancreatic islet cells. PubMed Ishihara H Maechler P Gjinovci A Herrera PL Wollheim CB Islet beta-cell secretion determines glucagon release from neighbouring alpha-cells. PubMed Juhl CB Hollingdal M Sturis J Jakobsen G Agerso H Veldhuis J Porksen N Schmitz O Bedtime administration of NN, a long-acting GLP-1 derivative, substantially reduces fasting and postprandial glycemia in type 2 diabetes. PubMed Kaneko K Shirotani T Araki E Matsumoto K Taguchi T Motoshima H Yoshizato K Kishikawa H Shichiri M Insulin inhibits glucagon secretion by the activation of PI3-kinase in In-R1-G9 cells. PubMed Kendall DM Poitout V Olson LK Sorenson RL Robertson RP Somatostatin coordinately regulates glucagon gene expression and exocytosis in HIT-T15 cells. PubMed Kuhara T Ikeda S Ohneda A Sasaki Y Effects of intravenous infusion of 17 amino acids on the secretion of GH, glucagon, and insulin in sheep. PubMed Kumar U Sasi R Suresh S Patel A Thangaraju M Metrakos P Patel SC Patel YC Subtype-selective expression of the five somatostatin receptors hSSTR in human pancreatic islet cells: a quantitative double-label immunohistochemical analysis. PubMed Landstedt-Hallin L Adamson U Lins PE Oral glibenclamide suppresses glucagon secretion during insulin-induced hypoglycemia in patients with type 2 diabetes. Glucagon is synthesized as proglucagon and proteolytically processed to yield glucagon within alpha cells of the pancreatic islets. Proglucagon is also expressed within the intestinal tract, where it is processed not into glucagon, but to a family of glucagon-like peptides enteroglucagon. The major effect of glucagon is to stimulate an increase in blood concentration of glucose. As discussed previously, the brain in particular has an absolute dependence on glucose as a fuel, because neurons cannot utilize alternative energy sources like fatty acids to any significant extent. When blood levels of glucose begin to fall below the normal range, it is imperative to find and pump additional glucose into blood. Glucagon exerts control over two pivotal metabolic pathways within the liver, leading that organ to dispense glucose to the rest of the body:. Glucagon also appears to have a minor effect of enhancing lipolysis of triglyceride in adipose tissue, which could be viewed as an addition means of conserving blood glucose by providing fatty acid fuel to most cells. Knowing that glucagon's major effect is to increase blood glucose levels, it makes sense that glucagon is secreted in response to hypoglycemia or low blood concentrations of glucose. In terms of negative control, glucagon secretion is inhibited by high levels of blood glucose. It is not clear whether this reflects a direct effect of glucose on the alpha cell, or perhaps an effect of insulin, which is known to dampen glucagon release. Another hormone well known to inhibit glucagon secretion is somatostatin. |
Glucagon has a major role synrhesis Glucagon hormone synthesis normal concentrations of glucose Glucabon anti-viral immune booster, and is often described Gluvagon having the Synnthesis effect of insulin. That is, glucagon has the effect synthesie increasing blood glucose levels. Amino acid synthesis inhibitors is a linear peptide of 29 amino acids. Its primary sequence is almost perfectly conserved among vertebrates, and it is structurally related to the secretin family of peptide hormones. Glucagon is synthesized as proglucagon and proteolytically processed to yield glucagon within alpha cells of the pancreatic islets. Proglucagon is also expressed within the intestinal tract, where it is processed not into glucagon, but to a family of glucagon-like peptides enteroglucagon.
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