Category: Home

Glucagon secretion

Glucagon secretion

Therefore, disruptions in secrwtion routing of glucagon through the eecretion pathway may contribute secrrtion the hyperglucagonemia Glucagon secretion diabetes Figure Glucagon secretion. Glucagon Glucagon secretion to the Boost metabolism for satiety receptora G protein-coupled receptorlocated in the plasma membrane of the cell. One mechanism underlying the intrinsic response to glucose is the direct effect on alpha cell electrical activity. gh Data represent the average of three independent experiments, each performed in duplicates.

Video

Endocrinology - Pancreas: Glucagon Function

Glucagon secretion -

We acknowledge that other mechanisms for intrinsic regulation of glucagon secretion have been proposed reviewed by Gylfe; see ref. Clearly, Gck in α-cells is a necessary component of the glucose-sensing apparatus. It is interesting that α-cells remain capable of electrical activity even after genetic ablation of Gck.

How this occurs remains unclear, but it is notable that α-cells express hexokinase 1 Hk1 , a high-affinity hexokinase. It will be interesting to explore the phenotype in mice lacking Hk1. Circulating glucagon levels were identical in Ctrl and αGckKO mice in fasted conditions and similarly reduced after a short period of refeeding.

This indicates that suppression of glucagon secretion in vivo relies on multiple mechanisms in addition to the Gck -dependent inhibitory effect. A paracrine action of insulin and somatostatin may play a role in this refed condition.

Regardless of the mechanism s involved, it is clear that hyperglucagonemia in the fed state of αGckKO mice has a significant impact on hepatic glucose metabolism, as revealed by the increases in p-CREB levels, in Pepck and G6pase expression and in pyruvate-stimulated gluconeogenesis.

In young mice, these defects are not associated with fed hyperglycemia or glucose intolerance because of the measured increase in glucose uptake by muscles. This increased uptake cannot be linked to higher insulin sensitivity as measured in insulin tolerance tests; it could perhaps be explained by the recently identified muscle-specific glucose sensing mechanism that increases muscle glucose uptake Interestingly, glucose-induced insulin secretion was markedly higher in islets isolated from αGckKO mice than from Ctrl mice, despite similar insulin contents.

This indicates that glucagon oversecretion is compensated by an adaptation of the β-cell insulin secretion capacity, which develops over time since insulin secretion by islets from young Ctrl and αGckKO mice was identical.

This β-cell adaptation may result from direct α-cell to β-cell communication, other than through glucagon or GLP-1 signaling, or may be indirect, following changes in hepatic glucose metabolism that could increase β-cell glucose competence as described, for instance, in mice with liver-specific Glut2 inactivation Both type 1 and type 2 diabetes are associated with increased glucagon secretion and exacerbates the hyperglycemia resulting from the lack of insulin 22 , Hyperglucagonemia in type 1 diabetes may be caused by the total loss of insulin secretion, and of its inhibitory effect on α-cells.

In type 2 diabetes, oral glucose fails to normally suppress glucagon secretion 24 , and insulin resistance of the α-cells may explain part of this defect As mentioned above 14 , plasma glucagon levels are suppressed at a higher glycemic levels in MODY2 patients as compared to control individuals.

Our data suggest that this deregulation can be explained, at least in part, by reduced Gck activity in α-cells. Collectively, our data demonstrate the role of Gck in the glucose-dependent suppression of glucagon secretion, and identify a glucose-signaling step in α-cells whose defect can contribute to disturbances of glucose homeostasis, principally through deregulation of hepatic glucose metabolism.

These deregulations are accompanied with an adaptation of β-cell secretion capacity, which may, however, not be sufficient to prevent development of a prediabetes phenotype. Better characterization of α-cell Gck activity, its regulation in diabetic conditions, and its response to specific endogenous or pharmacological modulators could provide new ways to control hyperglucagonemia in diabetes.

Studies were conducted in animals of 18—36 weeks of age, and included age-matched and sex-matched littermate control mice. For all experiments, the mice were randomly assigned to experimental groups to ensure an unbiased distribution of animals.

No blinding was used. All animal procedures were performed at the University of Lausanne and were reviewed and approved by the Veterinary Office of Canton de Vaud.

The numbers of animals studied per genotype are indicated within each experiment. To validate proper gene targeting, genomic DNA has been extracted from liver, hindbrain, ileum, and pancreatic islets using a Quick gDNA mini-prep kit Zymo Research, USA. RT-PCR analysis was performed using a Biometra T Thermocycler.

Recombination efficiency was assessed in αGckKO-Rosa26tdtomato mice. Sections that were 5-μm-thick were stained with guinea pig anti-glucagon Linco, diluted Recombination efficiency was calculated as the percentage of glucagon-positive cells that also expressed tdtomato. α-cell mass and β-cell mass were then calculated based on individual pancreas weight.

Insulin and glucagon content of the supernatant was then assessed by radioimmunoassay Merck Millipore , using insulin and glucagon standards, and expressed relative to initial pancreatic weight.

Before removal of the pancreas, a solution of Liberase TL 0. Measurements of insulin and glucagon secretion were performed using the static incubations of islets isolated from week-old mice. Immediately after incubation, the aliquots of the medium were removed for an in-house assay of insulin and glucagon Measurements of insulin secretion were also performed on islets isolated from week-old mice.

At the end of each static incubation, the islets were collected and lysed in acid ethanol to assess insulin and glucagon content. The islets were perfused with extracellular solution containing in mM : NaCl, 3. Glucose, methyl-succinate, and FCCP have been added as indicated in Fig.

Images were acquired at a frequency of 0. Electrical activity, transmembrane currents, and cell capacitance were recorded from randomly chosen cells on the peripheral of the islets.

α-cells were identified by the expression of fluorescent protein tdtomato see Mouse Validation. α-cells were identified by their electrical activity in response to glucose and lack of tdtomato fluorescence. Electrical activity and K ATP conductance were recorded using perforated patch-clamping technique.

Perforating reagent gramicidin 0. Extracellular solution contains in mM : NaCl, 3. After the experiments, the membrane potential recordings were exported as ASCII files and converted to ABF files axon binary file using ABF utility software version 2.

The resultant ABF files were then imported into Clampfit software version 9. Depolarization-triggered cell exocytosis was monitored as increase in membrane capacitance. The intracellular solution used for capacitance measurement contains in mM : Cs-glutamate, 10 CsCl, 10 NaCl, 1 MgCl 2 , 5 HEPES, 0.

The extracellular solution contains in mM : NaCl, 5. Plasma glucagon levels were quantitated by radioimmunoassay Merck Millipore and by ELISA Mercodia.

Plasma insulin levels were assessed by ultra-sensitive ELISA Mercodia. A portion of mouse liver were homogenized in ice-cold homogeneisation buffer in mM: sucrose, 10 HEPES pH 7. Proteins from nuclear fractions were extracted, and the protein content was determined by bicinchoninic acid assay Pierce, Thermo Scientific.

Transfer to nitrocellulose membranes was performed using the Mini Trans-Blot apparatus from Bio-Rad. Bands corresponding to the specific proteins were visualized using enhanced chemiluminescence reagent Advansta.

Digital images were acquired with Fusion FX7 system Vilber Lourmat and Bio-1D software Vilber Lourmat for quantification and normalization. The same membranes were reprobed with anti-β-actin antibodies to confirm the equal loading of proteins for each sample.

Real-time PCR was performed using Power SYBR Green Master Mix Applied Biosystems. All reactions were normalized to β-actin levels. Specific mouse primers for each gene are listed in Supplementary Table 1.

The animals were processed in the morning in the random-fed state. The mice received a bolus of 14 Cdeoxy-D-glucose Perkin-Elmer; dil. The mice were then placed in cages without water or food.

After the last blood sampling, the mice were killed by cervical dislocation under isoflurane anesthesia. Tissues were immediately dissected and frozen for further assessment of 14 Cdeoxy-D-glucosephosphate 2-DGP content. The Plasma radioactivity was determined at each time point by liquid scintillation counting, in order to calculate the area under the curve of the plasma tracer decay.

For the determination of tissue 2-DGP content, the tissue samples were homogenized, and the supernatants were passed through ion-exchange columns to separate 2-DGP from 2-DG. Tissue 2DG uptake was calculated by normalizing the tissue 2DG-6P content as disintegrations per minute to the tissue weight and to the AUC of the plasma tracer decay.

All collected data were included without data exclusion. Statistical analysis was performed using GraphPad Prism 5. The data distribution was assumed to be normal.

p -values less than 0. Other statistical methods were mentioned and indicated where they were used. No statistical methods were used to pre-determine sample sizes, but sample sizes are similar to those used in our previous studies.

The data that support the findings of this study are available from the corresponding author upon reasonable request. Unger, R. Glucagon and the A cells. Physiology and Pathophysiology.

Article CAS PubMed Google Scholar. Habegger, K. et al. The metabolic actions of glucagon revisited. Article CAS PubMed PubMed Central Google Scholar. Zhang, Q. Role of KATP channels in glucose-regulated glucagon secretion and impaired counterregulation in type 2 diabetes.

Cell Metab. Thorens, B. Brain glucose sensing and neural regulation of insulin and glucagon secretion. Diabetes Obes.

Marty, N. Brain glucose sensing, counterregulation, and energy homeostasis. Article CAS Google Scholar. Hevener, A. Novel glucosensor for hypoglycemic detection localized to the portal vein. Diabetes 46 , — Burcelin, R. Portal glucose infusion in the mouse induces hypoglycemia: evidence that the hepatoportal glucose sensor stimulates glucose utilization.

Diabetes 49 , — Google Scholar. Lamy, C. Hypoglycemia-activated glut2 neurons of the nucleus tractus solitarius stimulate vagal activity and glucagon secretion. Steinbusch, L. Sex-specific control of fat mass and counterregulation by hypothalamic glucokinase.

Diabetes 65 , — Gylfe, E. Upsala J. Article PubMed PubMed Central Google Scholar. Matschinsky, F. Pancreatic beta-cell glucokinase: closing the gap between theoretical concepts and experimental realities. Diabetes 47 , — Froguel, P.

Close linkage of glucokinase locus on chromosoms 7p to early-onset non-insulin-dependent diabetes mellitus. Nature , — Article ADS CAS PubMed Google Scholar.

Heimberg, H. The glucose sensor protein glucokinase is expressed in glucagon-producing alpha-cells. Natl Acad.

USA 93 , — Article ADS CAS PubMed PubMed Central Google Scholar. Guenat, E. Counterregulatory responses to hypoglycemia in patients with glucokinase gene mutations.

Diabetes Metab. CAS PubMed Google Scholar. Herrera, P. Adult insulin- and glucagon-producing cells differentiate from two independent cell lineages. Development , — Berg, J.

A genetically encoded fluorescent reporter of ATP:ADP ratio. Methods 6 , — Briant, L. Glucagon secretion from pancreatic alpha-cells. Walker, J. Regulation of glucagon secretion by glucose: paracrine, intrinsic or both?

Rorsman, P. ATP-regulated potassium channels and voltage-gated calcium channels in pancreatic alpha and beta cells: similar functions but reciprocal effects on secretion.

Diabetologia 57 , — Meng, Z. Glucose Sensing by Skeletal Myocytes Couples Nutrient Signaling to Systemic Homeostasis. Cell 66 , — e Seyer, P. Hepatic glucose sensing is required to preserve beta cell glucose competence. Invest , — Lee, Y. Glucagon is the key factor in the development of diabetes.

Diabetologia 59 , — Glucagonocentric restructuring of diabetes: a pathophysiologic and therapeutic makeover. Invest , 4—12 Mitrakou, A. Role of reduced suppression of glucose production and diminished early insulin release in impaired glucose tolerance.

New Engl. Kawamori, D. Insulin signaling in alpha cells modulates glucagon secretion in vivo. Agius, L. Hormonal and metabolite regulation of hepatic glucokinase. Nakamura, A.

Present status of clinical deployment of glucokinase activators. Diabetes Investig. Panagiotidis, G. Homologous islet amyloid polypeptide: effects on plasma levels of glucagon, insulin and glucose in the mouse.

Diabetes Res. Download references. This work was supported by grants to B. from the Swiss National Science Foundation A0B and the European Research Council Advanced grants INSIGHT and INTEGRATE. was supported by a Diabetes UK RD Lawrence Fellowship. PR was supported by the Wellcome Trust and the Swedish Research Council.

PLH was funded by Fondation privée of the University Hospitals of Geneva and the NIDDK grant DK We thank the Mouse Metabolic Evaluation Facility MEF from the Center for Integrative Genomics for performing tissue glucose uptake measurements.

Center for Integrative Genomics, University of Lausanne, , Lausanne, Switzerland. Oxford Centre for Diabetes, Endocrinology, and Metabolism, University of Oxford, Churchill Hospital, Oxford, OX3 7LE, UK.

Department of Clinical Science, UMAS, Division of Islet Cell Physiology, Lund, Sweden. Department of Genetic Medicine and Development, , Geneva, Switzerland. You can also search for this author in PubMed Google Scholar.

Nature : — Wendt A , Birnir B , Buschard K , Gromada J , Salehi A , Sewing S , Rorsman P , Braun M Glucose inhibition of glucagon secretion from rat α-cells is mediated by GABA released from neighboring β-cells. Diabetes 53 : — Gerich JE , Charles MA , Grodsky GM Characterization of the effects of arginine and glucose on glucagon and insulin release from the perfused rat pancreas.

J Clin Invest 54 : — Berthoud HR , Fox EA , Powley TL Localization of vagal preganglionics that stimulate insulin and glucagon secretion. Am J Physiol : R — R Maruyama H , Hisatomi A , Orci L , Grodsky GM , Unger RH Insulin within islets is a physiologic glucagon release inhibitor.

J Clin Invest 74 : — Samols E , Stagner JI , Ewart RB , Marks V The order of islet microvascular cellular perfusion is B-A-D in the perfused rat pancreas.

J Clin Invest 82 : — Samols E , Stagner JI Intra-islet regulation. Ishihara H , Maechler P , Gjinovci A , Herrera PL , Wollheim CB Islet β-cell secretion determines glucagon release from neighbouring α-cells.

Nat Cell Biol 5 : — J Physiol : — Borg WP , During MJ , Sherwin RS , Borg MA , Brines ML , Shulman GI Ventromedial hypothalamic lesions in rats suppress counter-regulatory responses to hypoglycemia. J Clin Invest 93 : — Borg MA , Sherwin RS , Borg WP , Tamborlane WV , Shulman GI Local ventromedial hypothalamus glucose perfusion blocks counterregulation during systemic hypoglycemia in awake rats.

J Clin Invest 99 : — Taborsky Jr GJ , Ahren B , Mundinger TO , Mei Q , Havel PJ Autonomic mechanism and defects in the glucagon response to insulin-induced hypoglycaemia.

Diabetes Nutr Metab 15 : — Raju B , Cryer PE Loss of the decrement in intraislet insulin plausibly explains loss of the glucagon response to hypoglycemia in insulin-deficient diabetes: documentation of the intraislet insulin hypothesis in humans. Diabetes 54 : — Aguilar-Bryan L , Bryan J Molecular biology of adenosine triphosphate-sensitive potassium channels.

Endocr Rev 20 : — Seghers V , Nakazaki M , DeMayo F , Aguilar-Bryan L , Bryan J Sur1 knockout mice. A model for K ATP channel-independent regulation of insulin secretion. J Biol Chem : — Miki T , Nagashima K , Tashiro F , Kotake K , Yoshitomi H , Tamamoto A , Gonoi T , Iwanaga T , Miyazaki J , Seino S Defective insulin secretion and enhanced insulin action in K ATP channel-deficient mice.

Proc Natl Acad Sci USA 95 : — Shiota C , Larsson O , Shelton KD , Shiota M , Efanov AM , Hoy M , Lindner J , Kooptiwut S , Juntti-Berggren L , Gromada J , Berggren PO , Magnuson MA Sulfonylurea receptor type 1 knock-out mice have intact feeding-stimulated insulin secretion despite marked impairment in their response to glucose.

Nat Neurosci 4 : — Lam TK , Pocai A , Gutierrez-Juarez R , Obici S , Bryan J , Aguilar-Bryan L , Schwartz GJ , Rossetti L Hypothalamic sensing of circulating fatty acids is required for glucose homeostasis.

Nat Med 11 : — Pocai A , Lam TK , Gutierrez-Juarez R , Obici S , Schwartz GJ , Bryan J , Aguilar-Bryan L , Rossetti L Hypothalamic K ATP channels control hepatic glucose production.

Shiota C , Rocheleau JV , Shiota M , Piston DW , Magnuson MA Impaired glucagon secretory responses in mice lacking the type 1 sulfonylurea receptor. Endocrinology : — Pipeleers DG , Schuit FC , Van Schravendijk CF , Van de Winkel M Interplay of nutrients and hormones in the regulation of glucagon release.

Roe JH , Dailey RE Determination of glycogen with the anthrone reagent. Anal Biochem 15 : — Hussain K , Bryan J , Christesen HT , Brusgaard K , Aguilar-Bryan L , Serum glucagon counter-regulatory hormonal response to hypoglycemia is blunted in congenital hyperinsulinism.

Diabetes , in press. Iozzo P , Geisler F , Oikonen V , Maki M , Takala T , Solin O , Ferrannini E , Knuuti J , Nuutila P Insulin stimulates liver glucose uptake in humans: an 18F-FDG PET study.

J Nucl Med 44 : — Petersen KF , Laurent D , Rothman DL , Cline GW , Shulman GI Mechanism by which glucose and insulin inhibit net hepatic glycogenolysis in humans. J Clin Invest : — Nenquin M , Szollosi A , Aguilar-Bryan L , Bryan J , Henquin JC Both triggering and amplifying pathways contribute to fuel-induced insulin secretion in the absence of sulfonylurea receptor-1 in pancreatic β-cells.

Diabetes 50 : — Bancila V , Cens T , Monnier D , Chanson F , Faure C , Dunant Y , Bloc A Two SUR1-specific histidine residues mandatory for zinc-induced activation of the rat K ATP channel. Prost AL , Bloc A , Hussy N , Derand R , Vivaudou M Zinc is both an intracellular and extracellular regulator of KATP channel function.

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. Stagner JI , Samols E The vascular order of islet cellular perfusion in the human pancreas.

Diabetes 41 : 93 — Diabetologia 47 : — Gopel S , Zhang Q , Eliasson L , Ma XS , Galvanovskis J , Kanno T , Salehi A , Rorsman P Capacitance measurements of exocytosis in mouse pancreatic α-, β- and δ-cells within intact islets of Langerhans.

J Physiol Lond : — Diabetes 53 : S — S Liu YJ , Vieira E , Gylfe E A store-operated mechanism determines the activity of the electrically excitable glucagon-secreting pancreatic α-cell. Cell Calcium 35 : — Ma X , Zhang Y , Gromada J , Sewing S , Berggren PO , Buschard K , Salehi A , Vikman J , Rorsman P , Eliasson L Glucagon stimulates exocytosis in mouse and rat pancreatic α-cells by binding to glucagon receptors.

Mol Endocrinol 19 : — Oxford University Press is a department of the University of Oxford. It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide. Sign In or Create an Account. Navbar Search Filter Endocrinology This issue Endocrine Society Journals Clinical Medicine Endocrinology and Diabetes Medicine and Health Books Journals Oxford Academic Mobile Enter search term Search.

Endocrine Society Journals. Advanced Search. Search Menu. Article Navigation. Close mobile search navigation Article Navigation. Volume Article Contents Materials and Methods. Journal Article. Regulation of Glucagon Secretion at Low Glucose Concentrations: Evidence for Adenosine Triphosphate-Sensitive Potassium Channel Involvement.

Alvaro Muñoz , Alvaro Muñoz. Oxford Academic. Min Hu. Khalid Hussain. Joseph Bryan. Lydia Aguilar-Bryan. Arun S. Rajan, One Baylor Plaza, BCMA B, Houston, Texas PDF Split View Views. Cite Cite Alvaro Muñoz, Min Hu, Khalid Hussain, Joseph Bryan, Lydia Aguilar-Bryan, Arun S. Select Format Select format.

ris Mendeley, Papers, Zotero. enw EndNote. bibtex BibTex. txt Medlars, RefWorks Download citation. Permissions Icon Permissions. Close Navbar Search Filter Endocrinology This issue Endocrine Society Journals Clinical Medicine Endocrinology and Diabetes Medicine and Health Books Journals Oxford Academic Enter search term Search.

Open in new tab Download slide. TABLE 1. Insulin and glucagon secretion from WT and Sur1KO islets. Open in new tab. First Published Online August 25, and M. contributed equally to this work.

Google Scholar Crossref. Search ADS. Google Scholar PubMed. OpenURL Placeholder Text. Hypoglycaemia: the limiting factor in the glycaemic management of type I and type II diabetes.

N Engl J Med. Glucose-inhibition of glucagon secretion involves activation of GABAA-receptor chloride channels.

Glucose inhibition of glucagon secretion from rat α-cells is mediated by GABA released from neighboring β-cells. Characterization of the effects of arginine and glucose on glucagon and insulin release from the perfused rat pancreas. Localization of vagal preganglionics that stimulate insulin and glucagon secretion.

The order of islet microvascular cellular perfusion is B-A-D in the perfused rat pancreas. Islet β-cell secretion determines glucagon release from neighbouring α-cells.

Ventromedial hypothalamic lesions in rats suppress counter-regulatory responses to hypoglycemia. Local ventromedial hypothalamus glucose perfusion blocks counterregulation during systemic hypoglycemia in awake rats. Autonomic mechanism and defects in the glucagon response to insulin-induced hypoglycaemia.

Loss of the decrement in intraislet insulin plausibly explains loss of the glucagon response to hypoglycemia in insulin-deficient diabetes: documentation of the intraislet insulin hypothesis in humans.

Molecular biology of adenosine triphosphate-sensitive potassium channels. Sur1 knockout mice. Defective insulin secretion and enhanced insulin action in K ATP channel-deficient mice. Sulfonylurea receptor type 1 knock-out mice have intact feeding-stimulated insulin secretion despite marked impairment in their response to glucose.

Hypothalamic sensing of circulating fatty acids is required for glucose homeostasis. Hypothalamic K ATP channels control hepatic glucose production. Impaired glucagon secretory responses in mice lacking the type 1 sulfonylurea receptor. Interplay of nutrients and hormones in the regulation of insulin release.

Interplay of nutrients and hormones in the regulation of glucagon release. Serum glucagon counter-regulatory hormonal response to hypoglycemia is blunted in congenital hyperinsulinism. Mechanism by which glucose and insulin inhibit net hepatic glycogenolysis in humans.

Both triggering and amplifying pathways contribute to fuel-induced insulin secretion in the absence of sulfonylurea receptor-1 in pancreatic β-cells. Two SUR1-specific histidine residues mandatory for zinc-induced activation of the rat K ATP channel. Zinc is both an intracellular and extracellular regulator of KATP channel function.

β-Cell secretory products activate α-cell ATP-dependent potassium channels to inhibit glucagon release. Capacitance measurements of exocytosis in mouse pancreatic α-, β- and δ-cells within intact islets of Langerhans. A store-operated mechanism determines the activity of the electrically excitable glucagon-secreting pancreatic α-cell.

Glucagon stimulates exocytosis in mouse and rat pancreatic α-cells by binding to glucagon receptors. Issue Section:. Download all slides. Views 4, More metrics information. Total Views 4, Email alerts Article activity alert. Advance article alerts. New issue alert. Receive exclusive offers and updates from Oxford Academic.

More on this topic Evidence that the Physiological Pulse Frequency of Glucagon Secretion Optimizes Glucose Production by Perifused Rat Hepatocytes. Effects of an Enkephalin Analog on Pancreatic Endocrine Function and Glucose Homeostasis in Normal and Diabetic Dogs.

Reversal of Defective Glucagon Responses to Hypoglycemia in Insulin-Dependent Autoimmune Diabetic BB Rats.

Modulation of adenosine triphosphate-sensitive potassium channel and voltage-dependent calcium channel by activin A in HIT-T15 cells.

Related articles in PubMed Resolution and quantification of carbohydrates by enantioselective comprehensive two-dimensional gas chromatography. The diagnostic value of cognitive assessment indicators for mild cognitive impairment MCI.

Chondroitin Sulfate-Derived Micelles for Adipose Tissue-Targeted Delivery of Celastrol and Phenformin to Enhance Obesity Treatment. Glucagon-Like Peptide-1 Receptor Agonists During Electroconvulsive Therapy: Case Report With Evolving Concerns and Management Considerations. Citing articles via Web of Science Latest Most Read Most Cited Sirt3 regulates proliferation and progesterone production in Leydig cells via suppression of reactive oxygen species.

AURKA enhances the glycolysis and development of ovarian endometriosis through ERβ. Effects of the cortisol milieu on tumor-infiltrating immune cells TIICs in corticotroph tumors. mTOR regulates mineralocorticoid receptor transcriptional activity by ULK1- dependent and independent mechanisms.

Adrenal Abcg1 Controls Cholesterol Flux and Steroidogenesis. More from Oxford Academic.

Sarah L. GkucagonAlexander Frueh Glucagon secretion, Margarita V. Focus and concentration supplementsHaiqiang DouLidia Argemi-MuntadasAlexander HamiltonSrcretion Glucagon secretionPeter Glucagon secretionBenjamin DaviesThomas MoritzLena EliassonPatrik RorsmanJakob G. Knudsen; Glucose Controls Glucagon Secretion by Regulating Fatty Acid Oxidation in Pancreatic α-Cells. Diabetes 1 October ; 72 10 : — Whole-body glucose homeostasis is coordinated through secretion of glucagon and insulin from pancreatic islets.

Alvaro Citrus aurantium medicinal uses, Min Hu, Khalid Hussain, Joseph Bryan, Lydia Aguilar-Bryan, Arun S. Glucagon is a swcretion counterregulatory hormone that opposes the action of secretipn in secretipn glycemia. The cellular mechanisms by which pancreatic α-cell glucagon Glucaogn occurs in response to hypoglycemia are poorly known.

Gpucagon this study, we examined hypoglycemia-induced glucagon secretion in vitro in isolated islets and in vivo Glucabon Sur1KO mice lacking neuroendocrine-type K ATP channels and paired wild-type Glucagon secretion controls.

Glucagoh mice fed ad libitum secrteion normal glucagon seccretion and Glucagon secretion hepatic Glucagon secretion in response to secrefion glucagon but G,ucagon a blunted glucagon response Hydration for sports injury prevention insulin-induced hypoglycemia.

Glucagon sedretion from Glucagon secretion and WT islets is increased secertion 2. WT islets increase glucagon secretion approximately fold when challenged Glucwgon 0. approximately Glucagon secretion. Consistent Glycagon a Glucagob interaction between Glucagon secretion Revolutionary weight loss channels and Glucxgon zinc-insulin, WT Glucagon hormone role exhibit secrstion inverse correlation between β-cell secretion and glucagon Glucagoh.

Glibenclamide stimulated insulin secretion and reduced glucagon release in WT wecretion but was without effect on secretiln from Sur1KO Glucwgon. The sefretion indicate that loss of α-cell K ATP channels uncouples glucagon release from inhibition by β-cells and reveals a role for Increased explosive strength ATP channels in the regulation of glucagon release by low glucose.

THE Wecretion OF glucagon, a small secretino hormone secreted by Herbal remedies for heart health α-cells, is Glucagon secretion by hypoglycemia and zecretion by hyperglycemia, insulin, and somatostatin.

In combination with insulin, glucagon Citrus aurantium for respiratory health the rate of gluconeogenesis and glycogenolysis Gllucagon the liver and thus plays a key Glucagon secretion in the counterregulatory response to hypoglycemia 1.

Sevretion inhibition of glucagon release after a meal Rye bread benefits often blunted and contributes to Glucahon hyperglycemia by accelerating secrretion in type 2 diabetes 2.

The stimulation of glucagon Glucagoh by insulin-induced hypoglycemia Herbal weight loss solutions the counterregulatory response is impaired in type aecretion diabetes and in advanced stages of Glucagon secretion 2 diabetes 34.

This reduced secretion predisposes individuals Glucagoj repeated hypoglycemic episodes that secrretion lead to coma or neurological injury 5. Large clinical studies including the Diabetes Control and Complications Maintaining healthy digestion 6 and the U.

Prebiotics for better digestion study 7 advocate aggressive management using an intensive Glucagn regiment to achieve Glucwgon and reduce complications, but this strategy has been associated with an increased secretoin of hypoglycemic episodes 6 during which impaired glucagon secretion constitutes a significant barrier wecretion the prevention of, and recovery from, hypoglycemia 48.

The control of glucagon secretion is multifactorial, reportedly Hydration and recovery strategies in youth sports by γ-aminobutyric acid 910 Glucagoh, low Glucagon secretion 11and Anti-aging ingredients innervation 12 and by intra-islet insulin 13 — 15 or cosecreted zinc 16 Glucaagon, Although all are potential regulators, the mechanism s escretion which falling blood glucose controls glucagon secretion is not well understood.

One school Glucagon secretion thought holds that low glucose sensing in the brain, particularly neurons in the hypothalamus Athletic performance nutrition19Natural flavonoid sources autonomic pathways that stimulate glucagon release 20implying Glucagon secretion innervation of pancreatic islets sscretion required Other evidence suggests that local intra-islet control mechanisms are involved and that glucose secrerion insulin levels, either directly or indirectly via Fuel for performance secretion, affect α-cell secrteion release independently Gucagon central Nutrition for weight loss autonomic control 1522 Secretiln studies provide evidence for intra-islet control, demonstrating that glucagon release Nutritional health supplements stimulated strongly by a Glufagon of falling plasma Glucsgon and insulin levels 22 — A similar mechanism has been suggested to Gluxagon in α-cells stimulated Glucagom pyruvate, a fuel that Glucxgon readily enter α-cells via monocarboxylate transporters srcretion present in β-cells 16 and thus selectively increase the metabolic rate of α-cells.

We have used K ATP channel-null Sur1KO mice to study the role of K ATP channels in glucagon secretion. SUR1 and K IR 6. Here we evaluate the ability of mouse islets to secrete glucagon in response to a hypoglycemic challenge and use Sur1KO islets to establish a role for K ATP channels in the glucagon secretory response to hypoglycemia.

Experiments were performed on mice using protocols approved by the Institutional Animal Care and Use Committee of Baylor College of Medicine and carried out in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals. Sur1KO mice were generated by homologous recombination as described previously A 6-h fast was initiated between and h; experiments were done between and h.

Experiments with fed mice were done between and h. Data points were obtained from mice euthanized at the time points as indicated in the figure legends. Short-acting human insulin 0. Human glucagon 0. In perfusion experiments, K ATP channels were blocked with glibenclamide 1 μ m Sigma Chemical Co.

Insulin and glucagon were dissolved in 0. The final dimethyl sulfoxide concentration was 0. Pancreatic islets were isolated by intraductal injection of 1. Amino acids were included to simulate conditions in vivo ; antibiotics were included to prevent bacterial growth.

Islets were washed twice with KRB and preincubated at 37 C with gentle shaking. After 30 min, the medium was replaced with KRB containing 1.

Aprotinin 5. Louis, MO. Determinations were done in duplicate for the number of different islet preparations indicated in the figure legends. Islets were transferred to a column of Bio-Gel P Bio-Rad and perfused 0. The glucose concentration was raised to Samples were collected at the indicated time points, aprotinin was added, and the samples were handled as described above.

Glucose values were determined from tail vein blood samples using a Free-Style glucometer Therasense, Alameda, CA. Charles, MO. Plasma insulin was measured in 5. Liver glycogen content was determined using the anthrone reaction 35 normalized to protein content determined using the BCA bicinchoninic acid assay Pierce Biotechnology, Inc.

Values are expressed as micrograms glycogen per microgram protein. Graphics as well as statistical analyses were performed using GraphPad Prism GraphPad Software, San Diego, CA.

To compare their counterregulatory responses, insulin was administered to fed WT and Sur1KO animals to induce hypoglycemia. The initial blood glucose values were the same in both animals, but administration of insulin 0. Blood glucose values returned to normal in the control animals within approximately 90 min, whereas the Sur1KO mice exhibited a slower rate of recovery Fig.

Although their initial plasma values were equivalent, 15 min of hypoglycemia prompted a 2-fold increase in glucagon level in Sur1KO mice vs. an approximately 5-fold increase in control animals Fig. Similar observations have been made in patients with persistent hyperinsulinism of infancy 36 and another Sur1KO mouse model The initial hepatic glycogen contents were the same in both animals, and insulin produced a comparable transient increase in glycogen content during the first 15 min, presumably as a consequence of increased insulin-dependent glucose uptake 37 or because of a greater hepatic glycogen cycling as a result of inhibition of glycogenolysis This transient increase was followed by a marked decline in glycogen content in both animals, although the rate of glycogen use was reduced in the Sur1KO animals Fig.

The results extend a study using K IR 6. Sur1KO mice have an impaired glucagon response to insulin-induced hypoglycemia. A, Changes in blood glucose after ip injection of insulin 0. To determine whether differential hormone sensitivity could account for the impaired response, glucagon 0.

WT mice exhibited a transient, less than 2-fold, increase in blood glucose that returned to the control value within 60 min, whereas the Sur1KO animals displayed a greater, sustained hyperglycemia Fig.

The hepatic glycogen contents of 6-h-fasted WT and Sur1KO mice were not significantly different, and exogenous glucagon dramatically depleted glycogen stores in both animals to an equivalent level within 90 min Fig.

The plasma insulin levels were significantly lower in Sur1KO vs. WT mice Fig. The results imply the hepatic response to exogenous glucagon is not impaired in the knockout animals and that the prolonged hyperglycemia observed in the Sur1KO mice is a consequence of their previously reported lack of first-phase insulin release when glucose is elevated 26 WT and Sur1KO mice respond to exogenous glucagon.

A, Blood glucose changes after injection of 0. A previous study reported that glucagon release from K IR 6. This report focused on the central nervous system CNS component, concluding it is impaired.

To assess the secretory capacity of Sur1KO α-cells further, isolated islets were tested in both static and perifusion assays. When tested under hypoglycemic conditions 2 h in 1. control islets Fig. Isolated Sur1KO islets have an attenuated response to low glucose.

Perifusion assays show that the Sur1KO α-cells respond to changes in glucose level, but their response is blunted. Figure 3B illustrates the normal biphasic insulin response of WT islets to a stepwise change in glucose concentration.

Figure 3D shows that switching WT islets from low to high glucose 2. In contrast, glucagon secretion from Sur1KO islets was reduced from After exposure to high glucose, a low-glucose challenge produced a marked approximately fold increase of glucagon release in WT islets The equivalent switch with Sur1KO islets produced an increase in glucagon secretion Note, however, that although the increased glucagon release from WT islets correlates with a monotonic fall in insulin secretion over the first 10 min, the period when the rise in glucagon release is maximal, the Sur1KO islets actually increase their rate of insulin secretion, reaching a peak value of 7.

The results show that the glucagon response to low glucose is attenuated and that there is an uncoupling of the communication between α- and β-cells in the Sur1KO islets.

The values for insulin and glucagon at the ends of the perifusion experiments after 30 min in 0. The values are means ± se.

P values comparing WT vs. Glibenclamide strongly stimulates insulin secretion from WT islets in 0. Glibenclamide does not affect insulin or glucagon release from Sur1KO islets lacking K ATP channels Fig.

Note that the levels of glucagon secretion from WT islets treated with glibenclamide mimic the impaired release observed for Sur1KO islets compare Fig. The results are consistent with the partial suppression of glucagon release by β-cell secretory products acting via K ATP channels Glibenclamide Glib stimulates insulin and inhibits glucagon release in WT but not Sur1KO islets in low glucose.

A, Response of WT islets. B, Response of Sur1KO islets. The perifusion protocol is the same as shown in Fig. In addition, nifedipine reduces the elevated, basal insulin secretion from Sur1KO islets Fig.

These observations confirm our earlier reports that nifedipine will suppress persistent insulin release from Sur1KO islets 26 ,

: Glucagon secretion

Frontiers | Glucagon secretion and signaling in the development of diabetes In addition to effects on alpha cell proliferation, some studies have suggested that pharmacologic activation of GABA A receptor by artemisinins or GABA may alter alpha cell identity and trans-differentiate adult alpha cells to beta-like cells 78 — 80 , and have led to clinical trials investigating GABA receptor agonists as protection against the development of diabetes. Further characterization of the link between electrophysiological signatures and the genes regulating the dynamics of granule exocytosis will reveal new mechanisms of alpha cell dysfunction in diabetes. Excitation wavelength nm. Malonyl-CoA is a byproduct of the Krebs cycle downstream of glycolysis and an allosteric inhibitor of Carnitine palmitoyltransferase I CPT1 , a mitochondrial enzyme important for bringing fatty acids into the intermembrane space of the mitochondria for β-oxidation. In mice and rats, SSTR2 also predominates in the α-cell and SSTR5 in the β-cell population Hunyady et al. Glucose-Inhibition of Glucagon Secretion Involves Activation of GABAA-Receptor Chloride Channels. Perfused dog stomach provides a unique tool for investigating α-cell function in absence of endogenously released insulin.
How is glucagon controlled?

Thus, glucagon and insulin are part of a feedback system that keeps blood glucose levels stable. Glucagon increases energy expenditure and is elevated under conditions of stress.

Glucagon is a amino acid polypeptide. The polypeptide has a molecular mass of daltons. The hormone is synthesized and secreted from alpha cells α-cells of the islets of Langerhans , which are located in the endocrine portion of the pancreas.

Glucagon is produced from the preproglucagon gene Gcg. Preproglucagon first has its signal peptide removed by signal peptidase , forming the amino acid protein proglucagon. In intestinal L cells , proglucagon is cleaved to the alternate products glicentin 1—69 , glicentin-related pancreatic polypeptide 1—30 , oxyntomodulin 33—69 , glucagon-like peptide 1 72— or , and glucagon-like peptide 2 — In rodents, the alpha cells are located in the outer rim of the islet.

Human islet structure is much less segregated, and alpha cells are distributed throughout the islet in close proximity to beta cells. Glucagon is also produced by alpha cells in the stomach.

Recent research has demonstrated that glucagon production may also take place outside the pancreas, with the gut being the most likely site of extrapancreatic glucagon synthesis. Glucagon generally elevates the concentration of glucose in the blood by promoting gluconeogenesis and glycogenolysis.

Glucose is stored in the liver in the form of the polysaccharide glycogen, which is a glucan a polymer made up of glucose molecules. Liver cells hepatocytes have glucagon receptors. When glucagon binds to the glucagon receptors, the liver cells convert the glycogen into individual glucose molecules and release them into the bloodstream, in a process known as glycogenolysis.

As these stores become depleted, glucagon then encourages the liver and kidney to synthesize additional glucose by gluconeogenesis. Glucagon turns off glycolysis in the liver, causing glycolytic intermediates to be shuttled to gluconeogenesis. Glucagon also regulates the rate of glucose production through lipolysis.

Glucagon induces lipolysis in humans under conditions of insulin suppression such as diabetes mellitus type 1. Glucagon production appears to be dependent on the central nervous system through pathways yet to be defined.

In invertebrate animals , eyestalk removal has been reported to affect glucagon production. Excising the eyestalk in young crayfish produces glucagon-induced hyperglycemia. Glucagon binds to the glucagon receptor , a G protein-coupled receptor , located in the plasma membrane of the cell.

The conformation change in the receptor activates a G protein , a heterotrimeric protein with α s , β, 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 cAMP , which activates protein kinase A cAMP-dependent protein kinase.

This enzyme, in turn, activates phosphorylase kinase , which then phosphorylates glycogen phosphorylase b PYG b , converting 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 s , in hepatocytes.

Malonyl-CoA is a byproduct of the Krebs cycle downstream of glycolysis and an allosteric inhibitor of Carnitine palmitoyltransferase I CPT1 , a 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 tumors , such as glucagonoma , symptoms 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.

What links here Related changes Upload file Special pages Permanent link Page information Cite this page Get shortened URL Download QR code Wikidata item. Download as PDF Printable version.

In other projects. Wikimedia Commons. Peptide hormone. This article is about the natural hormone. The major part of the concentration of somatostatin in blood is due to somatostatin release from the gut. Thus, the increase in local somatostatin and release of somatostatin delivery to the pancreas may both play a role in diabetes Figure 2.

It was previously demonstrated that in perifused islets and in infused isolated pancreas that the SSTR antagonist can greatly increase the response of α-cells to arginine. However, responses to insulin-induced hypoglycemia have not been tested.

In order to test the hypothesis about the importance of somatostatin in diabetic rats, a specific antagonist SSTR2 of the somatostatin receptor of α-cells was injected. It was demonstrated that infusion of this antagonist can fully normalize glucagon responses to insulin-induced hypoglycemia in diabetic rats [Figure 3 , from ref.

Yue et al. A patent Vranic et al. This could permit diabetic patients to adhere more strictly to an intensive insulin treatment and lessen the risk of diabetic complications.

Figure 2. In the normal physiology, the α-cell is under the tonic inhibitory influence of insulin and therefore somatostatin inhibition of α-cell may be of minor or no importance Singh et al. This is in contrast to diabetic islets in diabetes, where α-cell may be more sensitive to insulin and in addition, both circulating and pancreatic somatostatin, are increased.

It is generally believed that hypoglycemia is a strong stimulator of glucagon release from the α-cell. However, in islets in-vitro the effect of hypoglycemia is not consistent. This difference may reflect the fact that between in-vitro and in-vivo systems, in-vivo the islets have abundant blood flow, which brings to the islet other factors such as amino acids i.

We hypothesize therefore, that hypoglycemia has an effect only when amino acids or other substances found in blood, are present. In absence of the tonic effect of insulin, somatostatin is the only endogenous inhibitor of glucagon release and insulin exerts a strong inhibitory effect on the α-cell.

Therefore, when an antagonist blocks the α-cell receptors, despite the inhibitory effect of injected insulin, the α-cell can release normal amounts of glucagon Vranic, The figure is modified from that we previously reported Vranic, Figure 3.

In diabetic D rats, plasma glucagon increases only marginally during a glucose clamp at 2. B The response of glucagon to hypoglycemia was the same as in normal N rats.

C The data is also shown as area under the curve AUC analysis. The data is modified from that we reported in ref. The SSTR2a is highly specific for glucagon and only marginally for insulin, and it's structure is H-Fpa-cyclo[DCys-PAL-DTrp-Lys-Tle-Cys]-Nal-NH2 Yue et al.

Most importantly, infusion of the SSTR2 antagonist in absence of insulin did not affect the blood concentration of insulin, glucagon, epinephrine, or blood-sugar Yue et al. The efficacy of the SSTR2 antagonist with two different doses of the antagonist and of insulin was tested.

It is particularly interesting that in normal rats the antagonist did not improve or even decrease the response of glucagon to insulin-induced hypoglycemia.

One could speculate that in normal rats, the high doses of antagonist even have some agonist properties, and confirmed that in normal rats, somatostatin is not a major inhibitor of hypoglycemia-induced glucagon release.

The response of corticosterone was also normalized. Corticosterone in contrast to glucagon is important for hypoglycemias of longer duration, since the effects of cortisol are mainly exerted through genetic mechanisms.

This could also be of importance for glucagon release because cortisol has some effect on the α-cells' control. Interestingly, delivery of the SSTR2 antagonist did not further increase pancreatic glucagon and somatostatin, or plasma somatostatin. One of the key questions was whether the SSTR2 antagonist can actually prevent hypoglycemia.

On the first day insulin alone, and on the second day, either insulin alone or an infusion of antagonist was started in the same rat, before the insulin-induced hypoglycemia Vranic et al. The reason for such designs is that even one episode of hypoglycemia sensitizes the endocrine and metabolic system so that you would expect that on the second day the rats would need a different amount of insulin.

In order to avoid this problem, diabetic rats were injected for 3 days with insulin, in order to avoid further effect of antecedent hypoglycemia. After the injection of insulin, rats became hypoglycemic, but with the SSTR2 antagonist, hypoglycemia was avoided.

Without the antagonist, glucagon response was abolished, but with the antagonist, glucagon response was restored Yue et al. These STZ-induced diabetic rats were not treated with insulin since they still have some residual insulin in the blood and in the pancreas.

In contrast, BB rats are totally insulin-deprived, thus requiring insulin treatment, and therefore this model is more similar to human T1D; both caused by immune destruction of the β-cells. The in-vivo to in-vitro responses to hypoglycemia and arginine in controls and in diabetic BB rats were compared Qin et al.

In the in-vivo experiments, the glucose was clamped at 2. In contrast to the controls, the glucagon response was greatly diminished, but it was normalized during the infusion of the SSTR2 antagonist. With glucagon response normalized, the BB rats did not need glucose infusion to maintain the clamp, while without the antagonist they needed a large amount of glucose infused because of the glucagon deficiency.

Interestingly, we used for the first time pancreatic slices to assess the effect of hypoglycemia and arginine.

Surprisingly, hypoglycemia per se did not increase glucagon release. However, glucagon release was enhanced when arginine was infused Qin et al. The difference between in-situ and in-vitro experiments is that pancreatic slices are not controlled by the nervous system and are not exposed to hormones or metabolites such as, arginine that stimulate glucagon release.

It was questioned whether somatostatin plays a role during hypoglycemia because somatostatin-secreting δ-cells are downstream of glucagon-secreting α-cells in the islet microcirculation of non-diabetic rats Samols et al. However, δ-cells in diabetic rats are also distributed in central portions of islet cells because the architecture of islet cell type is altered Adeghate, , suggesting that paracrine actions of islet hormones are altered in diabetes such that somatostatin release upstream of α-cells may affect glucagon secretion.

The arrangement of human endocrine islet cells is likewise more disperse throughout the islet, which provides evidence for the proximity of δ-cells and α-cells Cabrera et al. Furthermore, paracrine signaling may also occur via diffusion within the islet interstitium, independent of blood flow.

The remaining question to be answered is to explore factors in blood that are necessary to sensitize the responses of α-cell to hypoglycemia and the mechanism of the potential sensitization of α-cells to insulin in diabetes. These results indicate that SSTR2 blockade Rossowski et al.

This strategy could lead to prevention of hypoglycemia in insulin-treated diabetics. Considerable work investigating glucagon secretion and α-cell signaling in healthy islets have been done as discussed above.

However, there has been relatively little progress in assessing the perturbation of α-cellular physiology and paracrine dysregulation during diabetes, which will require more innovative approaches.

One approach is the pancreatic slice preparation Huang et al. The slice preparation has very recently enabled us to begin to assess α-cell dysfunction in T1D wherein the very small islet mass and inflammation would have rendered it impossible to reliably isolate and examine the α-cell Huang et al.

This, along with the larger glucagon granules found on E. carrying larger amount of glucagon cargo, would trigger more glucagon release, thus explaining the basis of hyperglucagonemia in T1D Huang et al. Future studies employing the pancreas slice preparation will enable the elucidation of paracrine regulation within normal and diabetic islets.

Another approach is genetic manipulation of candidate proteins within α-cells by α-cell-specific knockout mouse models Gustavsson et al. Ideally, these clever approaches could be combined. From a clinical point of view, the mechanism whereby in T2D there is excessive response to glucagon during meals, and whether pharmacological intervention can prevent this problem.

A key question is also whether it is possible to prevent hypoglycemia in insulin-treated diabetics. So far, the evidence was obtained only in STZ-treated and BB rats. Patrick E. MacDonald receives research funding for his work on α-cells from Merck.

Herbert Y. Gaisano and Mladen Vranic have no financial or commercial relationships. This work was supported by a grant to Herbert Y. Gaisano from the Canadian Diabetes Association OGHG. MacDonald holds an Alberta Innovates-Health Sciences Scholarship and the Canada Research Chair in Islet Biology.

Adeghate, E. Distribution of calcitonin-gene-related peptide, neuropeptide-Y, vasoactive intestinal polypeptide, cholecystokinin-8, substance P and islet peptides in the pancreas of normal and diabetic rats. Neuropeptides 33, — Pubmed Abstract Pubmed Full Text CrossRef Full Text.

Altarejos, J. CREB and the CRTC co-activators: sensors for hormonal and metabolic signals. Cell Biol. Amatruda, J. Porte Jr. Sherwin, and A. Baron New York, NY: McGraw-Hill , 97— Andersson, S. Glucose-dependent docking and SNARE protein-mediated exocytosis in mouse pancreatic alpha-cell.

Pflugers Arch. Barg, S. Mechanisms of exocytosis in insulin-secreting B-cells and glucagon-secreting A-cells. Tight coupling between electrical activity and exocytosis in mouse glucagon-secreting alpha-cells. Diabetes 49, — Barns, A. Ketoacidosis in pancreatectomized man. Baukrowitz, T. PIP2 and PIP as determinants for ATP inhibition of KATP channels.

Science , — Boden, G. Glucagon deficiency and hyperaminoacidemia after total pancreatectomy. Bokvist, K. Bolli, G. Abnormal glucose counter-regulation in insulin-dependent diabetes mellitus.

Interaction of anti-insulin antibodies and impaired glucagon and epinephrine secretion. Diabetes 32, — Pubmed Abstract Pubmed Full Text. Braun, M. Somatostatin release, electrical activity, membrane currents and exocytosis in human pancreatic delta cells.

Diabetologia 52, — Butler, P. Contribution to postprandial hyperglycemia and effect on initial splanchnic glucose clearance on glucose intolerant or NIDDM patients.

Diabetes 40, 73— Cabrera, O. The unique cytoarchitecture of human pancreatic islets has implications for islet cell function. Glutamate is a positive autocrine signal for glucagon release.

Cell Metab. Cejvan, K. Intra-islet somatostatin regulates glucagon release via type 2 somatostatin receptors in rats. Diabetes 52, — Cryer, P. Hypoglycemia: the limiting factor in the glycemic management of Type I and Type II diabetes.

Diabetologia 4, — da Silva Xavier, G. Per-arnt-sim PAS domain-containing protein kinase is downregulated in human islets in type 2 diabetes and regulates glucagon secretion. Diabetologia 54, — Dagogo-Jack, S.

Hypoglycemia-associated autonomic failure in insulin dependent diabetes mellitus. De Marinis, Y. Detimary, P. 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.

Doi, K. Identical biological effects of pancreatic glucagon and a purified moiety of canine gastric glucagon. Drucker, D.

Biologic actions and therapeutic potential of the proglucagon-derived peptides. Duchen, M. Substrate-dependent changes in mitochondrial function, intracellular free calcium concentration and membrane channels in pancreatic beta-cells. Dufer, M. Methyl pyruvate stimulates pancreatic beta-cells by a direct effect on KATP channels, and not as a mitochondrial substrate.

Dunning, B. Alpha cell function in health and disease: influence of glucagon-like peptide Diabetologia 48, — The role of alpha-cell dysregulation in fasting and postprandial hyperglycemia in type 2 diabetes and therapeutic implications. Fanelli, C. Long-term recovery from unawareness, deficient counterregulation and lack of cognitive dysfunction during hypoglycemia following institution of rational intensive therapy in IDDM.

Diabetologia 37, — Franklin, I. Beta-cell secretory products activate alpha-cell ATP-dependent potassium channels to inhibit glucagon release. Diabetes 54, — GABA in the endocrine pancreas: its putative role as an islet cell paracrine-signalling molecule. Fu, A. Role of AMPK in pancreatic beta cell function.

PMID: Gaisano, H. Pancreatic islet alpha-cell commands itself: secrete more glucagon! Gauthier, B. Synaptotagmins bind calcium to release insulin. Gerich, J. Glucose counterregulation and its impact on diabetes mellitus.

Diabetes 37, — Lack of glucagon response to hypoglycaemia in diabetes: evidence for an intrinsic pancreatic alpha cell defect. Gopel, S. Gromada, J. Alpha-cells of the endocrine pancreas: 35 years of research but the enigma remains.

Somatostatin inhibits exocytosis in rat pancreatic alpha-cells by G i2 -dependent activation of calcineurin and depriming of secretory granules. Diabetes 53, S—S Gupta, V. The defective glucagon response from transplanted intrahepatic pancreatic islets during hypoglycemia is transplantation site-determined.

Diabetes 46, 28— Gustavsson, N. Hatton, T. Glucagon-like immunoreactants in extracts of the rat hypothalamus. Endocrinology , — Biosynthesis of glucagon IRG in canine gastric mucosa. Diabetes 34, 38— Hauge-Evans, A. Somatostatin secreted by islet δ-cells fulfils multiple roles as a paracrine regulator of islet function.

Diabetes 58, — Hayashi, M. 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.

Heimberg, H. The glucose sensor protein glucokinase is expressed in glucagon producing alpha cells.

Henquin, J. Hierarchy of the beta-cell signals controlling insulin secretion. Hocart, S. Highly potent cyclic disulfide antagonists of somatostatin. Holst, J. Circulating glucagon after total pancreatectomy in man.

Diabetologia 25, — Hope, K. Diabetes 53, — Huang, Y. Electrophysiological identification of mouse islet α-cells: from isolated single α-cells to in situ assessment within pancreas slices. Islets 3, — Unperturbed alpha-cell function examined in mouse pancreatic tissue slices. In situ electrophysiological examination of pancreatic alpha-cells in the streptozotocin-induced diabetes model revealing the cellular basis of glucagon hypersecretion.

Diabetes in press. Inouye, K. Effects of recurrent hyperinsulinemia with and without hypoglycemia on counterregulation in diabetic rats. Ishihara, H. Islet beta-cell secretion determines glucagon release from neighbouring alpha-cells.

Ito, A. Adhesion molecule CADM1 contributes to gap junctional communication among pancreatic islet alpha-cells and prevents their excessive secretion of glucagon.

Islets 4. Kanno, T. Cellular function in multicellular system for hormone-secretion: electrophysiological aspect of studies on alpha-, beta- and delta-cells of the pancreatic islet. Kawamori, D. Insulin signaling in alpha cells modulates glucagon secretion in vivo.

Kim, A. Islet architecture: a comparative study. Islets 1, — Le Marchand, S. Glucose suppression of glucagon secretion: metabolic and calcium responses from alpha-cells in intact mouse pancreatic islets.

Leclerc, I. AMP-activated protein kinase regulates glucagon secretion from mouse pancreatic alpha cells. Lee, Y. Glucagon receptor knockout prevents insulin-deficient type 1 diabetes in mice.

Diabetes 60, — Lefebvre, P. Factors controlling gastric-glucagon release. Glucose and insulin in the regulation of glucagon release from the isolated perfused dog stomach. Leung, Y. Electrophysiological characterization of pancreatic islet cells in the mouse insulin promoter-green fluorescent protein mouse.

Liu, D. Inhibitory effect of circulating insulin on glucagon secretion during hypoglycemia in type 1 diabetic patients. Diabetes Care 15, 59— Ludvigsen, E. Regulation of insulin and glucagon secretion from rat pancreatic islets in vitro by somatostatin analogues.

Luyckx, A. Lefebre Berlin, NY: Springer Verlag. Ma, X. Glucagon stimulates exocytosis in mouse and rat pancreatic {alpha} cells by binding to glucagon receptors.

MacDonald, P. A K ATP channel-dependent pathway within alpha cells regulates glucagon release from both rodent and human islets of Langerhans. PLoS Biol. doi: Marliss, E. Intense exercise has unique effects on both insulin release and its role in glucoregulation: implications for diabetes.

Diabetes 51 Suppl. Matsuyama, T. Plasma glucose, insulin pancreatic and enteroglucagon levels in normal and depancreatized dogs. Mertz, R. Activation of stimulus-secretion coupling in pancreatic beta-cells by specific products of glucose metabolism. Evidence for privileged signaling by glycolysis.

Mojsov, S. Insulinotropin: glucagon-like peptide I co-encoded in the glucagon gene is a potent stimulator of insulin release in the perfused rat pancreas.

Moller, D. New drug targets for type 2 diabetes and the metabolic syndrome. Nature , — Morita, S. Measurement and partial characterization of immunoreactive glucagon in gastrointestinal tissues of dogs.

Diabetes 25, — Muller, W. Glucagon immunoreactivities and amino acid profile in plasma of duodenopancreatectomized patients. Extrapancreatic glucagon and glucagon-like imunoreactivity in depancreatized dogs: a quantitative assessment of secretion rates and anatomical delineation of sources.

Munoz, A. Regulation of glucagon secretion at low glucose concentrations: evidence for adenosine triphosphate-sensitive potassium channel involvement. Newgard, C. Cellular engineering and gene therapy strategies for insulin replacement in diabetes.

Diabetes 43, — Olofsson, C. Palmitate stimulation of glucagon secretion in mouse pancreatic alpha-cells results from activation of L-type calcium channels and elevation of cytoplasmic calcium. Olsen, H.

Glucose stimulates glucagon release in single rat alpha-cells by mechanisms that mirror the stimulus-secretion coupling in beta-cells. Orci, L. Hypertrophy and hyperplasia of somatostatin-containing D-cells in diabetes.

Papachristou, D. Tissue-specific alterations in somatostatin mRNA accumulation in streptozocin-induced diabetes. Diabetes 38, — Patel, Y.

Top bar navigation

Thus, glucagon and insulin are part of a feedback system that keeps blood glucose levels stable. Glucagon increases energy expenditure and is elevated under conditions of stress.

Glucagon is a amino acid polypeptide. The polypeptide has a molecular mass of daltons. The hormone is synthesized and secreted from alpha cells α-cells of the islets of Langerhans , which are located in the endocrine portion of the pancreas.

Glucagon is produced from the preproglucagon gene Gcg. Preproglucagon first has its signal peptide removed by signal peptidase , forming the amino acid protein proglucagon.

In intestinal L cells , proglucagon is cleaved to the alternate products glicentin 1—69 , glicentin-related pancreatic polypeptide 1—30 , oxyntomodulin 33—69 , glucagon-like peptide 1 72— or , and glucagon-like peptide 2 — In rodents, the alpha cells are located in the outer rim of the islet.

Human islet structure is much less segregated, and alpha cells are distributed throughout the islet in close proximity to beta cells. Glucagon is also produced by alpha cells in the stomach.

Recent research has demonstrated that glucagon production may also take place outside the pancreas, with the gut being the most likely site of extrapancreatic glucagon synthesis.

Glucagon generally elevates the concentration of glucose in the blood by promoting gluconeogenesis and glycogenolysis. Glucose is stored in the liver in the form of the polysaccharide glycogen, which is a glucan a polymer made up of glucose molecules. Liver cells hepatocytes have glucagon receptors.

When glucagon binds to the glucagon receptors, the liver cells convert the glycogen into individual glucose molecules and release them into the bloodstream, in a process known as glycogenolysis. As these stores become depleted, glucagon then encourages the liver and kidney to synthesize additional glucose by gluconeogenesis.

Glucagon turns off glycolysis in the liver, causing glycolytic intermediates to be shuttled to gluconeogenesis. Glucagon also regulates the rate of glucose production through lipolysis. Glucagon induces lipolysis in humans under conditions of insulin suppression such as diabetes mellitus type 1.

Glucagon production appears to be dependent on the central nervous system through pathways yet to be defined.

In invertebrate animals , eyestalk removal has been reported to affect glucagon production. Excising the eyestalk in young crayfish produces glucagon-induced hyperglycemia. Glucagon binds to the glucagon receptor , a G protein-coupled receptor , located in the plasma membrane of the cell.

The conformation change in the receptor activates a G protein , a heterotrimeric protein with α s , β, 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 cAMP , which activates protein kinase A cAMP-dependent protein kinase.

This enzyme, in turn, activates phosphorylase kinase , which then phosphorylates glycogen phosphorylase b PYG b , converting 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 s , in hepatocytes.

Malonyl-CoA is a byproduct of the Krebs cycle downstream of glycolysis and an allosteric inhibitor of Carnitine palmitoyltransferase I CPT1 , a mitochondrial enzyme important for bringing fatty acids into the intermembrane space of the mitochondria for β-oxidation.

Determinations were done in duplicate for the number of different islet preparations indicated in the figure legends. Islets were transferred to a column of Bio-Gel P Bio-Rad and perfused 0. The glucose concentration was raised to Samples were collected at the indicated time points, aprotinin was added, and the samples were handled as described above.

Glucose values were determined from tail vein blood samples using a Free-Style glucometer Therasense, Alameda, CA. Charles, MO. Plasma insulin was measured in 5. Liver glycogen content was determined using the anthrone reaction 35 normalized to protein content determined using the BCA bicinchoninic acid assay Pierce Biotechnology, Inc.

Values are expressed as micrograms glycogen per microgram protein. Graphics as well as statistical analyses were performed using GraphPad Prism GraphPad Software, San Diego, CA. To compare their counterregulatory responses, insulin was administered to fed WT and Sur1KO animals to induce hypoglycemia.

The initial blood glucose values were the same in both animals, but administration of insulin 0. Blood glucose values returned to normal in the control animals within approximately 90 min, whereas the Sur1KO mice exhibited a slower rate of recovery Fig.

Although their initial plasma values were equivalent, 15 min of hypoglycemia prompted a 2-fold increase in glucagon level in Sur1KO mice vs. an approximately 5-fold increase in control animals Fig. Similar observations have been made in patients with persistent hyperinsulinism of infancy 36 and another Sur1KO mouse model The initial hepatic glycogen contents were the same in both animals, and insulin produced a comparable transient increase in glycogen content during the first 15 min, presumably as a consequence of increased insulin-dependent glucose uptake 37 or because of a greater hepatic glycogen cycling as a result of inhibition of glycogenolysis This transient increase was followed by a marked decline in glycogen content in both animals, although the rate of glycogen use was reduced in the Sur1KO animals Fig.

The results extend a study using K IR 6. Sur1KO mice have an impaired glucagon response to insulin-induced hypoglycemia. A, Changes in blood glucose after ip injection of insulin 0.

To determine whether differential hormone sensitivity could account for the impaired response, glucagon 0. WT mice exhibited a transient, less than 2-fold, increase in blood glucose that returned to the control value within 60 min, whereas the Sur1KO animals displayed a greater, sustained hyperglycemia Fig.

The hepatic glycogen contents of 6-h-fasted WT and Sur1KO mice were not significantly different, and exogenous glucagon dramatically depleted glycogen stores in both animals to an equivalent level within 90 min Fig. The plasma insulin levels were significantly lower in Sur1KO vs.

WT mice Fig. The results imply the hepatic response to exogenous glucagon is not impaired in the knockout animals and that the prolonged hyperglycemia observed in the Sur1KO mice is a consequence of their previously reported lack of first-phase insulin release when glucose is elevated 26 , WT and Sur1KO mice respond to exogenous glucagon.

A, Blood glucose changes after injection of 0. A previous study reported that glucagon release from K IR 6. This report focused on the central nervous system CNS component, concluding it is impaired. To assess the secretory capacity of Sur1KO α-cells further, isolated islets were tested in both static and perifusion assays.

When tested under hypoglycemic conditions 2 h in 1. control islets Fig. Isolated Sur1KO islets have an attenuated response to low glucose. Perifusion assays show that the Sur1KO α-cells respond to changes in glucose level, but their response is blunted. Figure 3B illustrates the normal biphasic insulin response of WT islets to a stepwise change in glucose concentration.

Figure 3D shows that switching WT islets from low to high glucose 2. In contrast, glucagon secretion from Sur1KO islets was reduced from After exposure to high glucose, a low-glucose challenge produced a marked approximately fold increase of glucagon release in WT islets The equivalent switch with Sur1KO islets produced an increase in glucagon secretion Note, however, that although the increased glucagon release from WT islets correlates with a monotonic fall in insulin secretion over the first 10 min, the period when the rise in glucagon release is maximal, the Sur1KO islets actually increase their rate of insulin secretion, reaching a peak value of 7.

The results show that the glucagon response to low glucose is attenuated and that there is an uncoupling of the communication between α- and β-cells in the Sur1KO islets. The values for insulin and glucagon at the ends of the perifusion experiments after 30 min in 0.

The values are means ± se. P values comparing WT vs. Glibenclamide strongly stimulates insulin secretion from WT islets in 0. Glibenclamide does not affect insulin or glucagon release from Sur1KO islets lacking K ATP channels Fig.

Note that the levels of glucagon secretion from WT islets treated with glibenclamide mimic the impaired release observed for Sur1KO islets compare Fig. The results are consistent with the partial suppression of glucagon release by β-cell secretory products acting via K ATP channels Glibenclamide Glib stimulates insulin and inhibits glucagon release in WT but not Sur1KO islets in low glucose.

A, Response of WT islets. B, Response of Sur1KO islets. The perifusion protocol is the same as shown in Fig. In addition, nifedipine reduces the elevated, basal insulin secretion from Sur1KO islets Fig.

These observations confirm our earlier reports that nifedipine will suppress persistent insulin release from Sur1KO islets 26 , Table 1 summarizes the insulin and glucagon secretion values at 30 min after switching the glucose concentration from The Sur1KO islets have an increased output of insulin and a decreased output of glucagon in response to hypoglycemic challenge compared with WT islets.

Glibenclamide does not affect hormone secretion from Sur1KO islets after 30 min of incubation, whereas blocking L-type calcium channels with nifedipine effectively inhibits insulin secretion in both WT and Sur1KO islets.

Nifedipine Nif inhibits glucagon secretion from both WT and Sur1KO islets in low glucose. The impaired response cannot be attributed to reduced hormonal sensitivity because exogenous glucagon equivalently depletes glycogen reserves in both animals, and the modest glucagon response in Sur1KO animals does mobilize hepatic glycogen albeit more slowly than in the control animals.

Counterregulation involves both central and peripheral control of glucagon secretion. The results extend the analysis reported for K IR 6. The results do not preclude a role for a central hypothalamic counterregulatory response to low glucose levels in vivo. However, in contrast to previous work 29 , we conclude that isolated islets, free from CNS input, are capable of responding to low glucose with a glucagon secretory response and that this response is compromised in Sur1KO islets.

In amino acid-containing media, low glucose stimulates glucagon release from both WT and Sur1KO islets, whereas high glucose inhibits secretion. In both situations, the WT islets show the greater response with both stronger inhibition and stimulation, but the Sur1KO islets clearly exhibit glucose-dependent effects on glucagon release that are independent of K ATP channels.

This idea is supported by the generally strong inverse correlation seen in control islets between insulin and glucagon release and by the observation that stimulation of insulin secretion with glibenclamide effectively blocks the glucagon secretion from WT islets elicited by extreme hypoglycemia 0.

Surprisingly, although the loss of α-cell K ATP channels appears to uncouple glucagon release from the inhibitory effects of β-cell secretion, it does not produce hyperglucagonemia.

It is worth reiterating, however, that the strong inverse correlation between insulin and glucagon release is missing in the Sur1KO islets. This can be seen clearly, for example, in Fig. The results support the idea that α-cells have a two-tier control system in which α-cell glucagon secretion is tightly coupled to release of zinc-insulin by β-cells via K ATP channels but have an underlying K ATP -independent regulatory mechanism that is regulated by fuel metabolism.

The nature of the underlying mechanism is not understood but may be similar to the control s regulating insulin release in K ATP -null β-cells 39 , Therefore, we attempted to inhibit insulin secretion from Sur1KO islets with nifedipine in an effort to mimic the fall in insulin seen in WT islets and test the idea that falling insulin and falling glucose would enhance glucagon secretion in the absence of K ATP channels.

The suppression of glucagon release from Sur1KO islets is more pronounced than the controls possibly as a consequence of tonic inactivation of N- and T-type calcium channels as suggested previously On the other hand, glucagon secretion in response to epinephrine is reported to involve the activation of store-operated currents 48 , emphasizing the importance of intracellular calcium changes.

The observation that isolated islets can mount a counterregulatory response to low glucose does not diminish the importance of CNS control of glycemia. The role s for hypothalamic K ATP channels in counterregulation and control of hepatic gluconeogenesis are well established 30 , In summary, pancreatic islets can sense and respond directly to changes in ambient glucose and mount a counterregulatory response in vitro , secreting glucagon in response to hypoglycemia, independent of CNS regulation.

Sur1KO mice exhibit a blunted glucagon response to insulin-induced hypoglycemia in vivo , suggesting an important role for K ATP channels in counterregulation. Additional clinical and laboratory studies are required to understand the detailed interactions between pancreatic α- and β-cells and the role of their dialog in glucose homeostasis.

This work was supported by Juvenile Diabetes Research Foundation International to A. and to J. Jiang G , Zhang BB Glucagon and regulation of glucose metabolism.

Am J Physiol Endocrinol Metab : E — E Google Scholar. Shah P , Basu A , Basu R , Rizza R Impact of lack of suppression of glucagon on glucose tolerance in humans. Am J Physiol : E — E Cryer PE Hypoglycaemia: the limiting factor in the glycaemic management of type I and type II diabetes.

Diabetologia 45 : — Cryer PE Diverse causes of hypoglycemia-associated autonomic failure in diabetes. N Engl J Med : — Malouf R , Brust JC Hypoglycemia: causes, neurological manifestations, and outcome. Ann Neurol 17 : — The Diabetes Control and Complications Trial Research Group. prospective diabetes study Overview of 6 years therapy of type II diabetes: a progressive disease.

Prospective Diabetes Study Group. Diabetes 44 : — Bolli GB , Fanelli CG Physiology of glucose counterregulation to hypoglycemia. Endocrinol Metab Clin North Am 28 : — Rorsman P , Berggren PO , Bokvist K , Ericson H , Mohler H , Ostenson CG , Smith PA Glucose-inhibition of glucagon secretion involves activation of GABAA-receptor chloride channels.

Nature : — Wendt A , Birnir B , Buschard K , Gromada J , Salehi A , Sewing S , Rorsman P , Braun M Glucose inhibition of glucagon secretion from rat α-cells is mediated by GABA released from neighboring β-cells. Paradoxical Stimulation of Glucagon Secretion by High Glucose Concentrations.

Gylfe E. Ups J Med Sci — Whalley NM, Pritchard LE, Smith DM. White a. Processing of Proglucagon to GLP-1 in Pancreatic α-Cells: Is This a Paracrine Mechanism Enabling GLP-1 to Act on β-Cells?

Asadi F, Dhanvantari S. Plasticity in the Glucagon Interactome Reveals Novel Proteins That Regulate Glucagon Secretion in α-TC Cells. Front Endocrinol Lausanne Omar-Hmeadi M, Lund PE, Gandasi NR, Tengholm A, Barg S.

Paracrine Control of α-Cell Glucagon Exocytosis is Compromised in Human Type-2 Diabetes. Nat Commun — Le Marchand SJ, Piston DW. Glucose Suppression of Glucagon Secretion: Metabolic and Calcium Responses From Alpha-Cells in Intact Mouse Pancreatic Islets.

Quoix N, Cheng-xue R, Mattart L, Zeinoun Z, Guiot Y, Beauvois M, et al. Ramracheya R, Ward C, Shigeto M, Walker JN, Amisten S, Zhang Q, et al. Membrane Potential-Dependent Inactivation of Voltage-Gated Ion Channels in α-Cells Inhibits Glucagon Secretion From Human Islets.

Zhang Q, Ramracheya R, Lahmann C, Tarasov A, Bengtsson M, Braha O, et al. Role of KATP Channels in Glucose-Regulated Glucagon Secretion and Impaired Counterregulation in Type 2 Diabetes. Zhang Q, Dou H, Rorsman P. J Physiol — Liu Y-J, Vieira E, Gylfe E. A Store-Operated Mechanism Determines the Activity of the Electrically Excitable Glucagon-Secreting Pancreatic α-Cell.

Cell Calcium — Tian G, Tepikin AV, Tengholm A, Gylfe E. Watts M, Sherman A. Modeling the Pancreatic α-Cell: Dual Mechanisms of Glucose Suppression of Glucagon Secretion. Biophys J — PloS One 7:e Elliott AD, Ustione A, Piston DW.

Somatostatin and Insulin Mediate Glucose-Inhibited Glucagon Secretion in the Pancreatic α-Cell by Lowering cAMP.

Am J Physiol Endocrinol Metab E— Yu Q, Shuai H, Ahooghalandari P, Gylfe E, Tengholm A. Glucose Controls Glucagon Secretion by Directly Modulating cAMP in Alpha Cells.

Hughes JW, Ustione A, Lavagnino Z, Piston DW. Regulation of Islet Glucagon Secretion: Beyond Calcium. Diabetes Obes Metab — Leclerc I, Sun G, Morris C, Fernandez-Millan E, Nyirenda M, Rutter GA. AMP-Activated Protein Kinase Regulates Glucagon Secretion From Mouse Pancreatic Alpha Cells. Da Silva Xavier G, Farhan H, Kim H, Caxaria S, Johnson P, Hughes S, et al.

Per-Arnt-Sim PAS Domain-Containing Protein Kinase is Downregulated in Human Islets in Type 2 Diabetes and Regulates Glucagon Secretion. Sun G, da Silva Xavier G, Gorman T, Priest C, Solomou A, Hodson DJ, et al.

LKB1 and Ampkα1 are Required in Pancreatic Alpha Cells for the Normal Regulation of Glucagon Secretion and Responses to Hypoglycemia. Mol Metab — Bozadjieva N, Blandino-Rosano M, Chase J, Dai XQ, Cummings K, Gimeno J, et al.

Loss of Mtorc1 Signaling Alters Pancreatic α Cell Mass and Impairs Glucagon Secretion. Kramer NB, Lubaczeuski C, Blandino-Rosano M, Barker G, Gittes GK, Caicedo A, et al. Glucagon Resistance and Decreased Susceptibility to Diabetes in a Model of Chronic Hyperglucagonemia.

Gromada J, Franklin I, Wollheim CB. Alpha-Cells of the Endocrine Pancreas: 35 Years of Research But the Enigma Remains.

Kawamori D, Kulkarni RN. Insulin Modulation of Glucagon Secretion: The Role of Insulin and Other Factors in the Regulation of Glucagon Secretion.

Islets —9. Tsuchiyama N, Takamura T, Ando H, Sakurai M, Shimizu A, Kato KI, et al. Possible Role of α-Cell Insulin Resistance in Exaggerated Glucagon Responses to Arginine in Type 2 Diabetes. Diabetes Care —7. Wendt A, Birnir B, Buschard K, Gromada J, Salehi A, Sewing S, et al.

Glucose Inhibition of Glucagon Secretion From Rat α-Cells Is Mediated by GABA Released From Neighboring β-Cells. Li C, Liu C, Nissim I, Chen J, Chen P, Doliba N, et al. Regulation of Glucagon Secretion in Normal and Diabetic Human Islets by?? Rorsman P, Berggren PO, Bokvist K, Ericson H, Möhler H, Ostenson CG SP.

Glucose-Inhibition of Glucagon Secretion Involves Activation of GABAA-Receptor Chloride Channels. Nature —6. Xu E, Kumar M, Zhang Y, Ju W, Obata T, Zhang N, et al. Intra-Islet Insulin Suppresses Glucagon Release via GABA-GABAA Receptor System. Feng AL, Xiang Y, Gui L, Kaltsidis G, Feng Q, Lu W.

Paracrine GABA and Insulin Regulate Pancreatic Alpha Cell Proliferation in a Mouse Model of Type 1 Diabetes. Jin Li J, Casteels T, Frogne T, Ingvorsen C, Honore C, Courtney M, et al. Artemisinins Target GABAA Receptor Signaling and Impair α Cell Identity. Weir GC, Bonner-Weir S.

GABA Signaling Stimulates β Cell Regeneration in Diabetic Mice. Cell —9. Ben-Othman N, Vieira A, Courtney M, Record F, Gjernes E, Avolio F, et al. Long-Term GABA Administration Induces Alpha Cell-Mediated Beta-Like Cell Neogenesis.

van der Meulen T, Lee S, Noordeloos E, Donaldson CJ, Adams MW, Noguchi GM, et al. Artemether Does Not Turn α Cells Into β Cells. Ackermann AM, Moss NG, Kaestner KH. GABA and Artesunate Do Not Induce Pancreatic α-to-β Cell Transdifferentiation In Vivo.

Combined Effect of GABA and Glucagon-Like Peptide-1 Receptor Agonist on Cytokine-Induced Apoptosis in Pancreatic β-Cell Line and Isolated Human Islets. J Diabetes — Daems C, Welsch S, Boughaleb H, Vanderroost J, Robert A, Sokal E, et al. Early Treatment With Empagliflozin and GABA Improves β -Cell Mass and Glucose Tolerance in Streptozotocin-Treated Mice.

J Diabetes Res — Human Beta Cells Produce and Release Serotonin to Inhibit Glucagon Secretion From Alpha Cells. Cell Rep — Bennet H, Balhuizen A, Medina A, Dekker Nitert M, Ottosson Laakso E, Essén S, et al.

Altered Serotonin 5-HT 1D and 2A Receptor Expression May Contribute to Defective Insulin and Glucagon Secretion in Human Type 2 Diabetes. Peptides — Yip L, Taylor C, Whiting CC, Fathman CG. Diminished Adenosine A1 Receptor Expression in Pancreatic a-Cells May Contribute to the Patholog Y of Type 1 Diabetes.

Ishihara H, Wollheim CB. Is Zinc an Intra-Islet Regulator of Glucagon Secretion? Diabetol Int — Franklin I, Gromada J, Gjinovci A, Theander S. Beta Cell Secretory Products Activate Alpha Cell ATP-Dependent Potassium Channels to Inhibit Glucagon Release.

Ravier MA, Rutter GA. Glucose or Insulin, But Not Zinc Ions, Inhibit Glucagon Secretion From Mouse Pancreatic [Alpha]-Cells. Solomou A, Philippe E, Chabosseau P, Migrenne-li S, Gaitan J, Lang J, et al. Nutr Metab Lond Solomou A, Meur G, Bellomo E, Hodson DJ, Tomas A, Li SM, et al.

Strowski MZ, Parmar RM, Blake AD, Schaeffer JM. Somatostatin Inhibits Insulin and Glucagon Secretion via Two Receptor Subtypes : An In Vitro Study of Pancreatic Islets From Somatostatin Receptor 2 Knockout Mice.

Endocrinology —7. Gromada J, Hoy M, Bushcard K, Salehi A, Rorsman P. Somatostatin Inhibits Exocytosis in Rat Pancreatic a-Cells by Gi2-Dependent Activation of Calcineurin and Depriming of Secretory Granules. Rutter GA. Regulating Glucagon Secretion: Somatostatin in the Spotlight.

Xu SFS, Andersen DB, Izarzugaza JMG, Kuhre RE, Holst JJ. In the Rat Pancreas, Somatostatin Tonically Inhibits Glucagon Secretion and Is Required for Glucose-Induced Inhibition of Glucagon Secretion. Acta Physiol — Hauge-Evans AC, King AJ, Carmignac D, Richardson CC, Robinson ICAF, Low MJ, et al.

Somatostatin Secreted by Islet -Cells Fulfills Multiple Roles as a Paracrine Regulator of Islet Function. Vergari E, Knudsen JG, Ramracheya R, Salehi A, Zhang Q, Adam J, et al.

Insulin Inhibits Glucagon Release by SGLT2-Induced Stimulation of Somatostatin Secretion. Nat Commun Briant LJB, Reinbothe TM, Spiliotis I, Miranda C, Rodriguez B, Rorsman P. Δ-Cells and β-Cells Are Electrically Coupled and Regulate α-Cell Activity Via Somatostatin.

Kilimnik G, Zhao B, Jo J, Periwal V, Witkowski P, Misawa R, et al. Altered Islet Composition and Disproportionate Loss of Large Islets in Patients With Type 2 Diabetes. PloS One 6:e Ma X, Zhang Y, Gromada J, Sewing S, Berggren P-O, Buschard K, et al.

Glucagon Stimulates Exocytosis in Mouse and Rat Pancreatic α-Cells by Binding to Glucagon Receptors. Leibiger B, Moede T, Muhandiramlage TP, Kaiser D, Vaca Sanchez P, Leibiger IB, et al. Glucagon Regulates its Own Synthesis by Autocrine Signaling. Wewer Albrechtsen NJ, Kuhre RE, Hornburg D, Jensen CZ, Hornum M, Dirksen C, et al.

Circulating Glucagon Regulates Blood Glucose by Increasing Insulin Secretion and Hepatic Glucose Production. Hare KJ, Knop FK, Asmar M, Madsbad S, Deacon CF, Holst JJ, et al.

Preserved Inhibitory Potency of GLP-1 on Glucagon Secretion in Type 2 Diabetes Mellitus. J Clin Endocrinol Metab — Garg M, Ghanim H, Kuhadiya N, Green K, Hejna J, Abuaysheh S, et al.

Liraglutide Acutely Suppresses Glucagon, Lipolysis and Ketogenesis in Type 1 Diabetes. Chambers AP, Sorrell JE, Haller A, Roelofs K, Hutch CR, Kim K-S, et al. The Role of Pancreatic Preproglucagon in Glucose Homeostasis in Mice.

Habener JF, Stanojevic V. Pancreas and Not Gut Mediates the GLPInduced Glucoincretin Effect. Cell Metab —8. Fava GE, Dong EW, Wu H. Intra-Islet Glucagon-Like Peptide J Diabetes Complicat —8. Holst J, Christensen M, Lund A, De Heer J, Svendsen B, Kielgast U, et al. Regulation of Glucagon Secretion by Incretins.

Ramracheya R, Chapman C, Chibalina M, Dou H, Miranda C, González A, et al. Physiol Rep — Boss M, Bos D, Frielink C, Sandker G, Ekim S, Marciniak C, et al.

Targeted Optical Imaging of the Glucagon-Like Peptide 1 Receptor Using Exendin-4irdyecw. J Nucl Med — Roberts S, Khera E, Choi C, Navaratna T, Grimm J, Thurber GM, et al. Optoacoustic Imaging of Glucagon-Like Peptide 1 Receptor With a Near-Infrared Exendin-4 Analog. Azad BB, Rota V. Design, Synthesis and In Vitro Characterization of Glucagon-Like Peptide-1 Derivatives for Pancreatic Beta Cell Imaging by SPECT.

Bioorg Med Chem — Ast J, Arvaniti A, Fine NHF, Nasteska D, Ashford FB, Stamataki Z, et al. Super-Resolution Microscopy Compatible Fluorescent Probes Reveal Endogenous Glucagon-Like Peptide-1 Receptor Distribution and Dynamics.

Waser B, Blank A, Karamitopoulou E, Perren A, Reubi JC. Glucagon-Like-Peptide-1 Receptor Expression in Normal and Diseased Human Thyroid and Pancreas. Mod Pathol — de Heer J, Rasmussen C, Coy DH, Holst JJ.

Glucagon-Like Peptide-1, But Not Glucose-Dependent Insulinotropic Peptide, Inhibits Glucagon Secretion via Somatostatin Receptor Subtype 2 in the Perfused Rat Pancreas. Ørgaard A, Holst JJ. The Role of Somatostatin in GLPInduced Inhibition of Glucagon Secretion in Mice. Diabetologia —9.

Saponaro C, Gmyr V, Thévenet J, Moerman E, Delalleau N, Pasquetti G, et al. The GLP1R Agonist Liraglutide Reduces Hyperglucagonemia Induced by the SGLT2 Inhibitor Dapagliflozin via Somatostatin Release. Lawlor N, Youn A, Kursawe R, Ucar D, Stitzel ML. Alpha TC1 and Beta-TC-6 Genomic Profiling Uncovers Both Shared and Distinct Transcriptional Regulatory Features With Their Primary Islet Counterparts.

Sci Rep — Stamenkovic JA, Andersson LE, Adriaenssens AE, Bagge A, Sharoyko VV, Gribble F, et al. Inhibition of the Malate-Aspartate Shuttle in Mouse Pancreatic Islets Abolishes Glucagon Secretion Without Affecting Insulin Secretion.

Briant LJB, Zhang Q, Vergari E, Kellard JA, Rodriguez B, Ashcroft FM, et al. Functional Identification of Islet Cell Types by Electrophysiological Fingerprinting.

J R Soc Interface Ackermann AM, Zhang J, Heller A, Briker A, Kaestner KH. High-Fidelity Glucagon-CreER Mouse Line Generated by CRISPR-Cas9 Assisted Gene Targeting.

Quoix N, Cheng-Xue R, Guiot Y, Herrera PL, Henquin JC, Gilon P. The GluCre-ROSA26EYFP Mouse: A New Model for Easy Identification of Living Pancreatic Alpha-Cells.

FEBS Lett — Shiota C, Prasadan K, Guo P, Fusco J, Xiao X, Gittes GK. GcgCreERT2knockin Mice as a Tool for Genetic Manipulation in Pancreatic Alpha Cells.

Andersson SA, Pedersen MG, Vikman J, Eliasson L. Glucose-Dependent Docking and SNARE Protein-Mediated Exocytosis in Mouse Pancreatic Alpha-Cell. Pflugers Arch Eur J Physiol — González-Vélez V, Dupont G, Gil A, González A, Quesada I. Model for Glucagon Secretion by Pancreatic α-Cells.

Gerber SH, Sudhof TC. Molecular Determinants of Regulated Exocytosis. Gustavsson N, Wei S, Hoang DN, Lao Y, Zhang Q, Radda GK, et al. Jewell JL, Oh E, Thurmond DC. Exocytosis Mechanisms Underlying Insulin Release and Glucose Uptake : Conserved Roles for Munc18c and Syntaxin 4. Am J Physiol Regul Integr Comp Physiol R— Gandasi NR, Yin P, Riz M, Chibalina MV, Cortese G, Lund P, et al.

Xia F, Leung YM, Gaisano G, Gao X, Chen Y, Fox JEM, et al. Montefusco F, Pedersen MG. Mathematical Modelling of Local Calcium and Regulated Exocytosis During Inhibition and Stimulation of Glucagon Secretion From Pancreatic Alpha-Cells.

Yokawa S, Suzuki T, Inouye S, Inoh Y, Suzuki R, Kanamori T, et al. Visualization of Glucagon Secretion From Pancreatic α Cells by Bioluminescence Video Microscopy: Identification of Secretion Sites in the Intercellular Contact Regions.

Biochem Biophys Res Commun — Brissova M, Haliyur R, Saunders D, Shrestha S, Dai C, Blodgett DM, et al. α Cell Function and Gene Expression Are Compromised in Type 1 Diabetes. Camunas-Soler J, Dai XQ, Hang Y, Bautista A, Lyon J, Suzuki K, et al. Patch-Seq Links Single-Cell Transcriptomes to Human Islet Dysfunction in Diabetes.

Zhou Y, Liu Z, Zhang S, Zhuang R, Liu H, Liu X, et al. RILP Restricts Insulin Secretion Through Mediating Lysosomal Degradation of Proinsulin. Li H, Wei S, Cheng K, Gounko NV, Ericksen RE, Xu A, et al.

BIG3 Inhibits Insulin Granule Biogenesis and Insulin Secretion. EMBO Rep — Li H, Liu T, Lim J, Gounko NV, Hong W, Han W.

Introduction Scretion Islets Contain a Subpopulation Gkucagon Glucagon-Like Glucagon secretion Sdcretion α Cells That Glucagon secretion Secretioh in Type Glucagon secretion Diabetes. Gromada Glucagon secretion, Franklin I, Metabolic enhancer for muscle growth CB. Central Mechanisms of Glucose Sensing and Counterregulation in Defense of Hypoglycemia. 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. The rich vascularization within the islet ensures a rapid sensing of plasma glucose levels by these endocrine cells, allowing an appropriate secretory response.
Glucagon secretion means it's official. Federal Secretlon websites often end Turbocharge teamwork. gov or. Before sharing sensitive information, make sure you're on a federal government site. The site is secure.

Author: Faekus

4 thoughts on “Glucagon secretion

  1. Ich meine, dass es das sehr interessante Thema ist. Ich biete Ihnen es an, hier oder in PM zu besprechen.

Leave a comment

Yours email will be published. Important fields a marked *

Design by ThemesDNA.com