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Horm Metab Res 2004; 36(11/12): 766-770
DOI: 10.1055/s-2004-826161
Review
© Georg Thieme Verlag KG Stuttgart · New York

Physiology of GLP-1 - Lessons from Glucoincretin Receptor Knockout Mice

B.  Thorens1
  • 1 Department of Physiology, University of Lausanne, Lausanne, Switzerland
Further Information

Publication History

Received 20 July 2004

Accepted after revision 4 August 2004

Publication Date:
18 January 2005 (online)

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Abstract

GLP-1 has both peripheral and central actions, as this hormone is secreted by gut endocrine cells and brainstem neurons projecting into the hypothalamus and other brain regions. GLP-1 has multiple regulatory functions participating in the control of glucose homeostasis, β-cell proliferation and differentiation, food intake, heart rate and even learning. GLP-1 action depends on binding to a specific G-coupled receptor linked to activation of the adenylyl cyclase pathway. Analysis of mice with inactivation of the GLP-1 receptor gene has provided evidence that absence of GLP-1 action in the mouse, despite this hormone potent physiological effects when administered in vivo, only leads to mild abnormalities in glucose homeostasis without any change in body weight. However, a critical role for this hormone and its receptor was demonstrated in the function of the hepatoportal vein glucose sensor, in contrast to that of the pancreatic β-cells, although absence of both GLP-1 and GIP receptors leads to a more severe phenotype characterized by a β-cell-autonomous defect in glucose-stimulated insulin secretion. Together, the studies of these glucoincretin receptor knockout mice provide evidence that these hormones are part of complex regulatory systems where multiple redundant signals are involved.

Key words

GLP-1 receptor - GIP receptor - β-cells - Insulin secretion - Diabetes

References

  • 1 Vrang N, Phifer C B, Corkern M M, Berthoud H R. Gastric distension induces c-Fos in medullary GLP-1/2-containing neurons.  Am J Physiol Regul Integr Comp Physiol. 2003;  285 R470 - 478. Epub 2003 Apr 24
    PubMedSearch in Google Scholar
  • 2 Thorens B, Larsen P J. Gut-derived signaling molecules and vagal afferents in the control of glucose and energy homeostasis.  Curr Opin Clin Nutr Metab Care. 2004;  7 471-847
    PubMedSearch in Google Scholar
  • 3 During M J, Cao L, Zuzga D S, Francis J S, Fitzsimons H L, Jiao X, Bland R J, Klugmann M, Banks W A, Drucker D J, Haile C N. Glucagon-like peptide-1 receptor is involved in learning and neuroprotection.  Nat Med. 2003;  9 1173 - 1179. Epub 2003 Aug 17
    PubMedSearch in Google Scholar
  • 4 Thorens B. Expression cloning of the pancreatic beta cell receptor for the gluco-incretin hormone glucagon-like peptide I.  Proc Natl Acad Sci USA. 1992;  89 8641-8645
    CrossrefPubMedSearch in Google Scholar
  • 5 Mayo K E, Miller L J, Bataille D, Dalle S, Goke B, Thorens B, Drucker D J. International Union of Pharmacology. XXXV. The glucagon receptor family.  Pharmacol Rev. 2003;  55 167-194
    CrossrefPubMedSearch in Google Scholar
  • 6 Scrocchi L A, Brown T J, MacLusky N, Brubaker P L, Auerbach A B, Joyner A L, Drucker D J. Glucose intolerance but normal satiety in mice with a null mutation in the glucagon-like peptide-1 receptor gene.  Nature Medicine. 1996;  2 1254-1258
    CrossrefPubMedSearch in Google Scholar
  • 7 Scrocchi L A, Drucker D J. Effects of aging and a high-fat diet on body weight and glucose tolerance in glucagon-like peptide-1 receptor -/- mice.  Endocrinology. 1998;  139 3127-3132
    CrossrefPubMedSearch in Google Scholar
  • 8 Scrocchi L A, Hill M E, Saleh J, Perkins B, Drucker D J. Elimination of glucagon-like peptide 1R signaling does not modify weight gain and islet adaptation in mice with combined disruption of leptin and GLP-1 action.  Diabetes. 2000;  49 1552-1560
    PubMedSearch in Google Scholar
  • 9 MacLusky N J, Cook S, Scrocchi L, Shin J, Kim J, Vaccarino F, Asa S L, Drucker D J. Neuroendocrine function and response to stress in mice with complete disruption of glucagon-like peptide-1 receptor signaling.  Endocrinology. 2000;  141 752-762
    CrossrefPubMedSearch in Google Scholar
  • 10 Flamez D, Van Breusegem A, Scrocchi L A, Quartier E, Pipeleers D, Drucker D J, Schuit F. Mouse pancreatic b-cells exhibit preserved glucose competence after disruption of the glucagon-like peptide-1 receptor gene.  Diabetes. 1998;  47 646-652
    PubMedSearch in Google Scholar
  • 11 Pederson R A, Satkunarajah M, McIntosh C H, Scrocchi L A, Flamez D, Schuit F, Drucker D J, Wheeler M B. Enhanced glucose-dependent insulinotropic polypeptide secretion and insulinotropic action in glucagon-like peptide 1 receptor -/- mice.  Diabetes. 1998;  47 1046-1052
    PubMedSearch in Google Scholar
  • 12 Flamez D, Gilon P, Moens K, van Breusegem A, Delmeire D, Scrocchi L A, Henquin J C, Drucker D J, Schuit F. Altered cAMP and Ca2+ signaling in mouse pancreatic islets with glucagon-like peptide-1 receptor null phenotype.  Diabetes. 1999;  48 1979-1986
    PubMedSearch in Google Scholar
  • 13 Rolin B, Larsen M O, Gotfredsen C F, Deacon C F, Carr R D, Wilken M, Knudsen L B. The long-acting GLP-1 derivative NN2211 ameliorates glycemia and increases beta-cell mass in diabetic mice.  Am J Physiol Endocrinol Metab. 2002;  283 E745-E752
    PubMedSearch in Google Scholar
  • 14 Tourrel C, Bailbe D, Lacorne M, Meile M-J, Kergoat M, Portha B. Persistent improvement of type 2 diabetes in the Goto-Kakizaki rat model by expansion of the b-cell mass during the prediabetic period with glucagon-like peptide-1 or exendin-4.  Diabetes. 2002;  51 1443-1452
    PubMedSearch in Google Scholar
  • 15 Tourrel C, Bailbe D, Meile M J, Kergoat M, Portha B. Glucagon-like peptide-1 and exendin-4 stimulate beta-cell neogenesis in streptozotocin-treated newborn rats resulting in persistently improved glucose homeostasis at adult age.  Diabetes. 2001;  50 1562-1570
    CrossrefPubMedSearch in Google Scholar
  • 16 Xu G, Stoffers D A, Habener J F, Bonner-Weir S. Exendin-4 stimulates both b-cell replication and neogenesis, resulting in increased b-cell mass and improved glucose tolerance in diabetic rats.  Diabetes. 1999;  48 2270-2276
    CrossrefPubMedSearch in Google Scholar
  • 17 Zhou J, Pineyro M A, Wang X, Doyle M E, Egan J M. Exendin-4 differentiation of a human pancreatic duct cell line into endocrine cells: involvement of PDX-1 and HNF3beta transcription factors.  J Cell Physiol. 2002;  192 304-314
    CrossrefPubMedSearch in Google Scholar
  • 18 Zhou J, Wang X, Pineyro M A, Egan J M. Glucagon-like peptide 1 and exendin-4 convert pancreatic AR42J cells into glucagon- and insulin-producing cells.  Diabetes. 1999;  48 2358-2366
    CrossrefPubMedSearch in Google Scholar
  • 19 Egan J M, Bulotta A, Hui H, Perfetti R. GLP-1 receptor agonists are growth and differentiation factors for pancreatic islet beta cells.  Diabetes Metab Res Rev. 2003;  19 115-123
    CrossrefPubMedSearch in Google Scholar
  • 20 Abraham E J, Leech C A, Lin J C, Zulewski H, Habener J F. Insulinotropic hormone glucagon-like peptide-1 differentiation of human pancreatic islet-derived progenitor cells into insulin-producing cells.  Endocrinology. 2002;  143 3152-3161
    CrossrefPubMedSearch in Google Scholar
  • 21 Movassat J, Beattie G M, Lopez A D, Hayek A. Exendin 4 up-regulates expression of PDX 1 and hastens differentiation and maturation of human fetal pancreatic cells.  J Clin Endocrinol Metab. 2002;  87 4775-4781
    CrossrefPubMedSearch in Google Scholar
  • 22 De Leon D D, Deng S, Madani R, Ahima R S, Drucker D J, Stoffers D A. Role of endogenous glucagon-like peptide-1 in islet regeneration after partial pancreatectomy.  Diabetes. 2003;  52 365-371
    PubMedSearch in Google Scholar
  • 23 Farilla L, Hui H, Bertolotto C, Kang E, Bulotta A, di Mario U, Perfetti R. Glucagon-like peptide-1 promotes islet cell growth and inhibits apoptosis in Zucker diabetic rats.  Endocrinology. 2002;  143 4397-4408
    CrossrefPubMedSearch in Google Scholar
  • 24 Li Y, Hansotia T, Yusta B, Ris F, Halban P A, Drucker D J. Glucagon-like peptide-1 receptor signaling modulates beta cell apoptosis.  J Biol Chem. 2003;  278 471-478
    CrossrefPubMedSearch in Google Scholar
  • 25 Gardemann A, Strulik H, Jungermann K. A portal-arterial glucose concentration gradient as a signal for an insulin-dependent net glucose uptake in perfused rat liver.  FEBS letters. 1986;  202 255-259
    CrossrefPubMedSearch in Google Scholar
  • 26 Hamilton-Wessler M, Bergman R N, Halter J B, Watanabe R M, Donovan C M. The role of liver glucosensors in the integrated sympathetic response induced by deep hypoglycemia in dogs.  Diabetes. 1994;  43 1052-1060
    PubMedSearch in Google Scholar
  • 27 Hevener A L, Bergman R N, Donovan C M. Novel glucosensor for hypoglycemic detection localized to the portal vein.  Diabetes. 1997;  46 1521-1525
    PubMedSearch in Google Scholar
  • 28 Hevener A L, Bergman R N, Donovan C M. Hypoglycemic detection does not occur in the hepatic artery or liver.  Diabetes. 2001;  50 399-403
    PubMedSearch in Google Scholar
  • 29 Burcelin R, Crivelli V, Perrin C, da Costa A, Mu J, Kahn B B, Birnbaum M J, Kahn C R, Vollenweider P, Thorens B. GLUT4, AMP kinase, but not the insulin receptor, are required for hepatoportal glucose sensor-stimulated muscle glucose utilization.  J Clin Invest. 2003;  111 1555-1562
    CrossrefPubMedSearch in Google Scholar
  • 30 Niijima A. Afferent impulse discharges from glucoreceptors in the liver of the guinea pig.  annals New York Academy of Sciences. 1969;  157 690-700
    PubMedSearch in Google Scholar
  • 31 Niijima A. Glucose-sensitive afferent nerve fibres in the hepatic branch of the vagus nerve in the guinea-pig.  Journal of Physiology. 1982;  332 315-323
    PubMedSearch in Google Scholar
  • 32 Nakabayashi H, Nishizawa M, Nakagawa A, Takeda R, Niijima A. Vagal hepatopancreatic reflex effect evoked by intraportal appearance of tGLP-1.  American Journal of Physiology. 1996;  271 E808-E813
    PubMedSearch in Google Scholar
  • 33 Nishizawa M, Nakabayashi H, Uchida K, Nakagawa A, Niijima A. The hepatic vagal nerve is receptive to incretin hormone glucagon-like peptide-1, but not to glucose-dependent insulinotropic polypeptide, in the portal vein.  Journal of the Autonomic Nervous System. 1996;  61 149-154
    CrossrefPubMedSearch in Google Scholar
  • 34 Balkan B, Li X. Portal GLP-1 administration in rats augments the insulin response to glucose via neuronal mechanisms.  American Journal of Physiology. 2000;  279 R1449-R1454
    PubMedSearch in Google Scholar
  • 35 Burcelin R, DaCosta A, Drucker D, Thorens B. Glucose competence of the hepatoporal vein sensor requires the presence of an activated GLP-1 receptor.  Diabetes. 2001;  50 1720-1728
    PubMedSearch in Google Scholar
  • 36 Preitner F, Ibberson M, Franklin I, Binnert C, Pende M, Gjinovici A, Hansotia T, Drucker D J, Wollheim C B, Burcelin R, Thorens B. Gluco-incretin control insulin secretion at multiple levels as revealed in mice lacking GLP-1 and GIP receptors. J. Clin.  Invest.. 2004;  113 635-645
    CrossrefPubMedSearch in Google Scholar
  • 37 Rolin B, Deacon C F, Carr R D, Ahren B. The major glucagon-like peptide-1 metabolite, GLP-1-(9-36) -amide, does not affect glucose or insulin levels in mice.  Eur J Pharmacol. 2004;  494 283-288
    CrossrefPubMedSearch in Google Scholar
  • 38 Burcelin R, Dolci W, Thorens B. Glucose sensing by the hepatoportal sensor is GLUT2-dependent. In vivo analysis in GLUT2-null mice.  Diabetes. 2000;  49 1643-1648
    PubMedSearch in Google Scholar
  • 39 Ahren B. Sensory nerves contribute to insulin secretion by glucagon-like peptide-1 in mice.  Am J Physiol Regul Integr Comp Physiol. 2004;  286 R269-R272
    PubMedSearch in Google Scholar
  • 40 Hansotia T, Baggio L L, Delmeire D, Hinke S A, Yamada Y, Tsukiyama K, Seino Y, Holst J J, Schuit F, Drucker D J. 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 1326-1335
    PubMedSearch in Google Scholar

B. Thorens

Department of Physiology, University of Lausanne

27 rue du Bugnon · CH-1005 Lausanne · Switzerland

Phone: +41 (21) 692 53 90

Fax: +41 (21) 692 53 55

Email: Bernard.Thorens@unil.ch