glucagon receptors

Summary

Summary: Cell surface receptors that bind glucagon with high affinity and trigger intracellular changes which influence the behavior of cells. Activation of glucagon receptors causes a variety of effects; the best understood is the initiation of a complex enzymatic cascade in the liver which ultimately increases the availability of glucose to body organs.

Top Publications

  1. Liang Y, Osborne M, Monia B, Bhanot S, Gaarde W, Reed C, et al. Reduction in glucagon receptor expression by an antisense oligonucleotide ameliorates diabetic syndrome in db/db mice. Diabetes. 2004;53:410-7 pubmed
    ..However, alpha-cell glucagon levels were increased significantly. Our studies support the concept that antagonism of glucagon receptors could be an effective approach for controlling blood glucose in diabetes.
  2. Chen D, Liao J, Li N, Zhou C, Liu Q, Wang G, et al. A nonpeptidic agonist of glucagon-like peptide 1 receptors with efficacy in diabetic db/db mice. Proc Natl Acad Sci U S A. 2007;104:943-8 pubmed
    ..Thus, Boc5 behaved as a full GLP-1 mimetic in vitro and in vivo. The chemical genus represented by Boc5 may prompt the exploration of orally available GLP-1R agonists with potential utility in diabetes and obesity. ..
  3. Cani P, Holst J, Drucker D, Delzenne N, Thorens B, Burcelin R, et al. GLUT2 and the incretin receptors are involved in glucose-induced incretin secretion. Mol Cell Endocrinol. 2007;276:18-23 pubmed
    ..In conclusion, both incretins secretion depends on mechanisms involving their own receptors and GLP-1 further requires GLUT2. ..
  4. Runge S, Thøgersen H, Madsen K, Lau J, Rudolph R. Crystal structure of the ligand-bound glucagon-like peptide-1 receptor extracellular domain. J Biol Chem. 2008;283:11340-7 pubmed publisher
    ..The structure provides for the first time detailed molecular insight into ligand binding of the human GLP-1 receptor, an established target for treatment of type 2 diabetes. ..
  5. Greig N, Mattson M, Perry T, Chan S, Giordano T, Sambamurti K, et al. New therapeutic strategies and drug candidates for neurodegenerative diseases: p53 and TNF-alpha inhibitors, and GLP-1 receptor agonists. Ann N Y Acad Sci. 2004;1035:290-315 pubmed
    ..Stimulation of the glucagon-like peptide-1 receptor (GLP-1R) in brain is associated with neurotrophic functions that, additionally, can protect cells against excess glutamate and other toxic insults. ..
  6. Guo L, Liu J, Xia Z. Geniposide inhibits CoCl2-induced PC12 cells death via the mitochondrial pathway. Chin Med J (Engl). 2009;122:2886-92 pubmed
    ..Geniposide protects PC12 cells from CoCl(2) involved in mitochondrial mediated apoptosis, and GLP-1R might play a critical role in the neuroprotection of geniposide in PC12 cells. ..
  7. Irwin N, Flatt P, Patterson S, Green B. Insulin-releasing and metabolic effects of small molecule GLP-1 receptor agonist 6,7-dichloro-2-methylsulfonyl-3-N-tert-butylaminoquinoxaline. Eur J Pharmacol. 2010;628:268-73 pubmed publisher
    ..These results provide evidence to support the development and potential use of low molecular weight GLP-1 receptor agonists for the treatment of type 2 diabetes. ..
  8. Bucinskaite V, Tolessa T, Pedersen J, Rydqvist B, Zerihun L, Holst J, et al. Receptor-mediated activation of gastric vagal afferents by glucagon-like peptide-1 in the rat. Neurogastroenterol Motil. 2009;21:978-e78 pubmed publisher
    ..GLP-2 receptors appear not be functionally expressed on vagal afferents. ..
  9. Baggio L, Drucker D. Biology of incretins: GLP-1 and GIP. Gastroenterology. 2007;132:2131-57 pubmed
    ..Recently approved therapeutic agents based on potentiation of incretin action provide new physiologically based approaches for the treatment of type 2 diabetes. ..

More Information

Publications62

  1. Holst J. The physiology of glucagon-like peptide 1. Physiol Rev. 2007;87:1409-39 pubmed
    ..Decreased secretion of GLP-1 may contribute to the development of obesity, and exaggerated secretion may be responsible for postprandial reactive hypoglycemia. ..
  2. Saraceni C, Broderick T. Effects of glucagon-like peptide-1 and long-acting analogues on cardiovascular and metabolic function. Drugs R D. 2007;8:145-53 pubmed
    ..However, long-term pharmacological doses of GLP-1 have shown prolonged and beneficial actions on cardiovascular homeostasis in the adjuvant treatment of metabolic disease. ..
  3. Miranda L, Winters K, Gegg C, Patel A, Aral J, Long J, et al. Design and synthesis of conformationally constrained glucagon-like peptide-1 derivatives with increased plasma stability and prolonged in vivo activity. J Med Chem. 2008;51:2758-65 pubmed publisher
    ..Importantly, PEGylated GLP-1 peptide 23 exhibited sustained in vivo efficacy with respect to blood glucose reduction and decreased body weight for several days in nonhuman primates. ..
  4. Maida A, Lovshin J, Baggio L, Drucker D. The glucagon-like peptide-1 receptor agonist oxyntomodulin enhances beta-cell function but does not inhibit gastric emptying in mice. Endocrinology. 2008;149:5670-8 pubmed publisher
    ..These findings may have implications for therapeutic efforts using OXM as a long-acting GLP-1R agonist for the treatment of metabolic disorders. ..
  5. Al Sabah S, Donnelly D. The positive charge at Lys-288 of the glucagon-like peptide-1 (GLP-1) receptor is important for binding the N-terminus of peptide agonists. FEBS Lett. 2003;553:342-6 pubmed
  6. Williams D, Baskin D, Schwartz M. Evidence that intestinal glucagon-like peptide-1 plays a physiological role in satiety. Endocrinology. 2009;150:1680-7 pubmed publisher
    ..We conclude that GLP-1 released from the intestine in response to ingested nutrients is a physiologically active satiety signal. ..
  7. Baggio L, Huang Q, Brown T, Drucker D. Oxyntomodulin and glucagon-like peptide-1 differentially regulate murine food intake and energy expenditure. Gastroenterology. 2004;127:546-58 pubmed
    ..Hence ligand-specific activation of a common GLP-1R increases the complexity of gut-central nervous system pathways regulating energy homeostasis and metabolic expenditure. ..
  8. Teng M, Johnson M, Thomas C, Kiel D, Lakis J, Kercher T, et al. Small molecule ago-allosteric modulators of the human glucagon-like peptide-1 (hGLP-1) receptor. Bioorg Med Chem Lett. 2007;17:5472-8 pubmed
    ..These findings serve as a valuable starting point for the discovery of more drug-like small molecule agonists for the hGLP-1 receptor. ..
  9. Hansotia T, Baggio L, Delmeire D, Hinke S, Yamada Y, Tsukiyama K, et al. Double incretin receptor knockout (DIRKO) mice reveal an essential role for the enteroinsular axis in transducing the glucoregulatory actions of DPP-IV inhibitors. Diabetes. 2004;53:1326-35 pubmed
  10. Nystrom T, Gonon A, Sjoholm A, Pernow J. Glucagon-like peptide-1 relaxes rat conduit arteries via an endothelium-independent mechanism. Regul Pept. 2005;125:173-7 pubmed
    ..In conclusion, we now report a direct vascular action of GLP-1, relaxing conduit vessels independently of NO and the endothelium. ..
  11. Nauck M, Meier J. Glucagon-like peptide 1 and its derivatives in the treatment of diabetes. Regul Pept. 2005;128:135-48 pubmed
    ..It is hoped that this new class of drugs interacting with the GLP-1 or other incretin receptors, the so-called "incretin mimetics", will broaden our armamentarium of antidiabetic medications in the nearest future. ..
  12. Aulinger B, D ALESSIO D. Glucagon-like peptide 1: continued advances, new targets and expanding promise as a model therapeutic. Curr Opin Endocrinol Diabetes Obes. 2007;14:68-73 pubmed
  13. Bavec A, Jiang Y, Langel U, Zorko M. Role of cysteine 341 and arginine 348 of GLP-1 receptor in G-protein coupling. Mol Biol Rep. 2007;34:53-60 pubmed
    ..Moreover, these two amino acids from the third intracellular loop might represent an important novel targets for covalent modification by downstream regulators in signaling through GLP-1 receptor. ..
  14. Beinborn M, Worrall C, McBride E, Kopin A. A human glucagon-like peptide-1 receptor polymorphism results in reduced agonist responsiveness. Regul Pept. 2005;130:1-6 pubmed
    ..A genetic link between the T149M variant and increased susceptibility to type 2 diabetes remains to be established. ..
  15. Hansotia T, Maida A, Flock G, Yamada Y, Tsukiyama K, Seino Y, et al. Extrapancreatic incretin receptors modulate glucose homeostasis, body weight, and energy expenditure. J Clin Invest. 2007;117:143-52 pubmed
    ..These findings extend our understanding of how endogenous incretin circuits regulate glucose homeostasis independent of the beta cell via control of adipokine secretion and energy expenditure. ..
  16. Flock G, Baggio L, Longuet C, Drucker D. Incretin receptors for glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide are essential for the sustained metabolic actions of vildagliptin in mice. Diabetes. 2007;56:3006-13 pubmed
  17. Bertilsson G, Patrone C, Zachrisson O, Andersson A, Dannaeus K, Heidrich J, et al. Peptide hormone exendin-4 stimulates subventricular zone neurogenesis in the adult rodent brain and induces recovery in an animal model of Parkinson's disease. J Neurosci Res. 2008;86:326-38 pubmed
  18. Drucker D, Nauck M. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet. 2006;368:1696-705 pubmed
    ..However, long-term clinical studies are needed to determine the benefits of targeting the incretin axis for the treatment of type 2 diabetes. ..
  19. Liu J, Yin F, Zheng X, Jing J, Hu Y. Geniposide, a novel agonist for GLP-1 receptor, prevents PC12 cells from oxidative damage via MAP kinase pathway. Neurochem Int. 2007;51:361-9 pubmed
    ..All these data demonstrate that geniposide, an agonist for GLP-1 receptor, regulates expression of anti-oxidative proteins including HO-1 and Bcl-2 by activating the transcriptor of p90RSK via MAPK signaling pathway in PC12 cells. ..
  20. Ding X, Saxena N, Lin S, Gupta N, Gupta N, Anania F. Exendin-4, a glucagon-like protein-1 (GLP-1) receptor agonist, reverses hepatic steatosis in ob/ob mice. Hepatology. 2006;43:173-81 pubmed
    ..In conclusion, Exendin-4 appears to effectively reverse hepatic steatosis in ob/ob mice by improving insulin sensitivity. Our data suggest that GLP-1 proteins in liver have a novel direct effect on hepatocyte fat metabolism. ..
  21. Lin F, Wang R. Molecular modeling of the three-dimensional structure of GLP-1R and its interactions with several agonists. J Mol Model. 2009;15:53-65 pubmed publisher
    ..Before the complete structure of GLP-1R is determined through experimental means, our model may serve as a valuable reference for characterizing the interactions between GLP-1R and its agonists. ..
  22. Ban K, Noyan Ashraf M, Hoefer J, Bolz S, Drucker D, Husain M. Cardioprotective and vasodilatory actions of glucagon-like peptide 1 receptor are mediated through both glucagon-like peptide 1 receptor-dependent and -independent pathways. Circulation. 2008;117:2340-50 pubmed publisher
    ..Our data suggest that the extent to which GLP-1 is metabolized to GLP-1(9-36) may have functional implications in the cardiovascular system. ..
  23. Knudsen L, Kiel D, Teng M, Behrens C, Bhumralkar D, Kodra J, et al. Small-molecule agonists for the glucagon-like peptide 1 receptor. Proc Natl Acad Sci U S A. 2007;104:937-42 pubmed
    ..Also, the compound stimulates insulin release from perfused rat pancreas in a manner additive with GLP-1 itself. These compounds may lead to the identification or design of orally active GLP-1 agonists. ..
  24. Lopez de Maturana R, Treece Birch J, Abidi F, Findlay J, Donnelly D. Met-204 and Tyr-205 are together important for binding GLP-1 receptor agonists but not their N-terminally truncated analogues. Protein Pept Lett. 2004;11:15-22 pubmed
    ..This suggests that the locus is important for the formation of the binding site for the N-terminal residues of peptide agonists. ..
  25. Liu J, Zheng X, Yin F, Hu Y, Guo L, Deng X, et al. Neurotrophic property of geniposide for inducing the neuronal differentiation of PC12 cells. Int J Dev Neurosci. 2006;24:419-24 pubmed
    ..All these results show that activation of GLP-1 receptor by geniposide to induce the neuronal differentiation of PC12 cells involves in MAPK signaling cascade. ..
  26. Baggio L, Huang Q, Brown T, Drucker D. A recombinant human glucagon-like peptide (GLP)-1-albumin protein (albugon) mimics peptidergic activation of GLP-1 receptor-dependent pathways coupled with satiety, gastrointestinal motility, and glucose homeostasis. Diabetes. 2004;53:2492-500 pubmed
    ..These findings illustrate that peripheral administration of a larger peptide-albumin recombinant protein mimics GLP-1R-dependent activation of central and peripheral pathways regulating energy intake and glucose homeostasis in vivo. ..
  27. Al Sabah S, Donnelly D. A model for receptor-peptide binding at the glucagon-like peptide-1 (GLP-1) receptor through the analysis of truncated ligands and receptors. Br J Pharmacol. 2003;140:339-46 pubmed
    ..6. We describe a peptide-receptor binding model to account for these data. ..
  28. Underwood C, Garibay P, Knudsen L, Hastrup S, Peters G, Rudolph R, et al. Crystal structure of glucagon-like peptide-1 in complex with the extracellular domain of the glucagon-like peptide-1 receptor. J Biol Chem. 2010;285:723-30 pubmed publisher
    ..The data support the existence of differences in the binding modes of GLP-1 and exendin-4 on the full-length GLP-1 receptor. ..
  29. Murage E, Schroeder J, Beinborn M, Ahn J. Search for alpha-helical propensity in the receptor-bound conformation of glucagon-like peptide-1. Bioorg Med Chem. 2008;16:10106-12 pubmed publisher
    ..Based on these findings, a highly potent bicyclic GLP-1 analogue was synthesized which is the most conformationally constrained GLP-1 analogue reported to date. ..
  30. Bharucha K, Tarr P, Zipursky S. A glucagon-like endocrine pathway in Drosophila modulates both lipid and carbohydrate homeostasis. J Exp Biol. 2008;211:3103-10 pubmed publisher
    ..Taken together, our results indicate that a single endocrine pathway contributes to both lipid and carbohydrate catabolism in the Drosophila fat body...
  31. Qureshi S, Rios Candelore M, Xie D, Yang X, Tota L, Ding V, et al. A novel glucagon receptor antagonist inhibits glucagon-mediated biological effects. Diabetes. 2004;53:3267-73 pubmed
    ..Taken together, these data suggest that Cpd 1 is a potent glucagon receptor antagonist that has the capability to block the effects of glucagon in vivo. ..
  32. During M, Cao L, Zuzga D, Francis J, Fitzsimons H, Jiao X, et al. Glucagon-like peptide-1 receptor is involved in learning and neuroprotection. Nat Med. 2003;9:1173-9 pubmed
    ..Systemic administration of [Ser(2)]exendin(1-9) in wild-type animals prevents kainate-induced apoptosis of hippocampal neurons. Brain GLP-1R represents a promising new target for both cognitive-enhancing and neuroprotective agents. ..
  33. Liu J, Yin F, Guo L, Deng X, Hu Y. Neuroprotection of geniposide against hydrogen peroxide induced PC12 cells injury: involvement of PI3 kinase signal pathway. Acta Pharmacol Sin. 2009;30:159-65 pubmed publisher
    ..These results demonstrate that the PI3K signaling pathway is involved in the neuroprotection of geniposide in PC12 cells against the oxidative damage induced by H(2)O(2) in PC12 cells. ..
  34. Winzell M, Brand C, Wierup N, Sidelmann U, Sundler F, Nishimura E, et al. Glucagon receptor antagonism improves islet function in mice with insulin resistance induced by a high-fat diet. Diabetologia. 2007;50:1453-62 pubmed
    ..Chronic glucagon receptor antagonism in HFD-fed mice improves islet sensitivity to glucose and increases insulin secretion, suggesting improvement of key defects underlying impaired glucose tolerance and type 2 diabetes. ..
  35. Bray G. Exenatide. Am J Health Syst Pharm. 2006;63:411-8 pubmed
    ..Exenatide offers a novel treatment option for patients with type 2 diabetes mellitus who are refractory to metformin or sulfonylurea therapy or both. ..
  36. Yusta B, Baggio L, Estall J, Koehler J, Holland D, Li H, et al. GLP-1 receptor activation improves beta cell function and survival following induction of endoplasmic reticulum stress. Cell Metab. 2006;4:391-406 pubmed
    ..These findings demonstrate that GLP-1R signaling directly modulates the ER stress response leading to promotion of beta cell adaptation and survival. ..
  37. Schirra J, Nicolaus M, Roggel R, Katschinski M, Storr M, Woerle H, et al. Endogenous glucagon-like peptide 1 controls endocrine pancreatic secretion and antro-pyloro-duodenal motility in humans. Gut. 2006;55:243-51 pubmed
    ..GLP-1 tonically inhibits antroduodenal motility and mediates the postprandial inhibition of antral and stimulation of pyloric motility. We therefore suggest GLP-1 as a true incretin hormone and enterogastrone in humans. ..
  38. Preitner F, Ibberson M, Franklin I, Binnert C, Pende M, Gjinovci A, et al. Gluco-incretins control insulin secretion at multiple levels as revealed in mice lacking GLP-1 and GIP receptors. J Clin Invest. 2004;113:635-45 pubmed
  39. Feldkaemper M, Burkhardt E, Schaeffel F. Localization and regulation of glucagon receptors in the chick eye and preproglucagon and glucagon receptor expression in the mouse eye. Exp Eye Res. 2004;79:321-9 pubmed
  40. Knauf C, Cani P, Kim D, Iglesias M, Chabo C, Waget A, et al. Role of central nervous system glucagon-like Peptide-1 receptors in enteric glucose sensing. Diabetes. 2008;57:2603-12 pubmed publisher
    ..We conclude that the gut-glucose sensor modulates peripheral glucose metabolism through a nutrient-sensitive mechanism, which requires brain GLP-1Rc signaling and is impaired during diabetes. ..
  41. Hansotia T, Drucker D. GIP and GLP-1 as incretin hormones: lessons from single and double incretin receptor knockout mice. Regul Pept. 2005;128:125-34 pubmed
    ..Hence, incretin receptor signaling exerts physiologically relevant actions critical for glucose homeostasis, and represents a pharmacologically attractive target for development of agents for the treatment of Type 2 diabetes. ..
  42. Hayes M, Bradley L, Grill H. Endogenous hindbrain glucagon-like peptide-1 receptor activation contributes to the control of food intake by mediating gastric satiation signaling. Endocrinology. 2009;150:2654-9 pubmed publisher
    ..We conclude that endogenous NTS GLP-1R activation driven by gastric satiation signals contributes to the control of normal feeding. ..
  43. Li Y, Perry T, Kindy M, Harvey B, Tweedie D, Holloway H, et al. GLP-1 receptor stimulation preserves primary cortical and dopaminergic neurons in cellular and rodent models of stroke and Parkinsonism. Proc Natl Acad Sci U S A. 2009;106:1285-90 pubmed publisher
    ..Our findings demonstrate that Ex-4 can protect neurons against metabolic and oxidative insults, and they provide preclinical support for the therapeutic potential for Ex-4 in the treatment of stroke and PD. ..
  44. Sowden G, Drucker D, Weinshenker D, Swoap S. Oxyntomodulin increases intrinsic heart rate in mice independent of the glucagon-like peptide-1 receptor. Am J Physiol Regul Integr Comp Physiol. 2007;292:R962-70 pubmed
  45. Syme C, Zhang L, Bisello A. Caveolin-1 regulates cellular trafficking and function of the glucagon-like Peptide 1 receptor. Mol Endocrinol. 2006;20:3400-11 pubmed
    ..This study provides further evidence of the key role of accessory proteins in specifying the cellular behavior of G protein-coupled receptors. ..
  46. Longuet C, Sinclair E, Maida A, Baggio L, Maziarz M, Charron M, et al. The glucagon receptor is required for the adaptive metabolic response to fasting. Cell Metab. 2008;8:359-71 pubmed publisher
    ..The actions of glucagon on TG synthesis and FAO were abolished in PPARalpha-/- hepatocytes. These findings demonstrate that the Gcgr receptor is required for control of lipid metabolism during the adaptive metabolic response to fasting. ..
  47. Chow B, Moon T, Hoo R, Yeung C, MULLER M, Christos P, et al. Identification and characterization of a glucagon receptor from the goldfish Carassius auratus: implications for the evolution of the ligand specificity of glucagon receptors in vertebrates. Endocrinology. 2004;145:3273-88 pubmed
    ..shares 56, 51, 50, and 52% amino acid identities with frog Rana tigrina regulosa, mouse, rat, and human glucagon receptors, respectively...
  48. Sandoval D, Bagnol D, Woods S, D Alessio D, Seeley R. Arcuate glucagon-like peptide 1 receptors regulate glucose homeostasis but not food intake. Diabetes. 2008;57:2046-54 pubmed publisher
    ..These data suggest that the arcuate GLP-1 receptors are a key component of the GLP-1 system for improving glucose homeostasis by regulating both insulin secretion and glucose production. ..
  49. Yang Y, Zhou L, Liu S, Tang J, Li F, Li R, et al. Expression of feeding-related peptide receptors mRNA in GT1-7 cell line and roles of leptin and orexins in control of GnRH secretion. Acta Pharmacol Sin. 2005;26:976-81 pubmed
    ..Feeding and reproductive function are closely linked. Many orexigenic and anorexigenic signals may control feeding behavior as well as alter GnRH secretion through their receptors on GnRH neurons. ..
  50. Perry T, Holloway H, Weerasuriya A, Mouton P, Duffy K, Mattison J, et al. Evidence of GLP-1-mediated neuroprotection in an animal model of pyridoxine-induced peripheral sensory neuropathy. Exp Neurol. 2007;203:293-301 pubmed
    ..Our findings suggest a potential role for these peptides in the treatment of neuropathies, including that associated with type II diabetes mellitus. ..
  51. Baggio L, Huang Q, Cao X, Drucker D. An albumin-exendin-4 conjugate engages central and peripheral circuits regulating murine energy and glucose homeostasis. Gastroenterology. 2008;134:1137-47 pubmed publisher
  52. Runge S, Schimmer S, Oschmann J, Schiødt C, Knudsen S, Jeppesen C, et al. Differential structural properties of GLP-1 and exendin-4 determine their relative affinity for the GLP-1 receptor N-terminal extracellular domain. Biochemistry. 2007;46:5830-40 pubmed
    ..In view of our results it appears that the Trp-cage plays only a minor role for the interaction between Ex4 and nGLP-1R and for the differential affinity of nGLP-1R for GLP-1 and Ex4. ..
  53. Sloop K, Cao J, Siesky A, Zhang H, Bodenmiller D, Cox A, et al. Hepatic and glucagon-like peptide-1-mediated reversal of diabetes by glucagon receptor antisense oligonucleotide inhibitors. J Clin Invest. 2004;113:1571-81 pubmed
    ..Together, these studies identify a novel mechanism whereby GCGR inhibitors reverse the diabetes phenotype by the dual action of decreasing hepatic glucose production and improving pancreatic beta cell function. ..