title: Chronic exposure to GLP-1R agonists promotes homologous GLP-1 receptor desensitization in vitro but does not attenuate GLP-1R-dependent glucose homeostasis in vivo.
abstract: Glucagon-like peptide-1 (GLP-1) stimulates glucose-dependent insulin secretion and inhibits food intake, gastric emptying, and glucagon secretion, actions that promote reduction of fasting and postprandial glycemia in subjects with type 2 diabetes. The rapid degradation of native GLP-1 has engendered interest in more stable longer-acting GLP-1 receptor agonists such as exendin-4 (Ex-4); however, the potential consequences of sustained GLP-1 receptor activation leading to receptor desensitization has not been extensively studied. We have now examined a range of GLP-1 receptor-dependent responses following treatment with Ex-4 using INS-1 cells in vitro and both wild-type control and MT-Ex-4 transgenic mice in vivo. Although both GLP-1 and Ex-4 acutely desensitized GLP-1 receptor-dependent cAMP accumulation in INS-1 cells, Ex-4 produced more sustained receptor desensitization, relative to GLP-1, in both acute (5-120 min) and chronic (24-72 h) experiments. PMA (4-phorbol 12-myristate 13-acetate) but not glucagon, glucose-dependent insulinotropic polypeptide (GIP), or epinephrine produced heterologous desensitization in vitro. MT-Ex-4 transgenic mice exhibited a reduced glycemic response to oral but not intraperitoneal glucose challenge following acute Ex-4 administration. In contrast, no differences in glycemic excursion or plasma insulin were observed after 1 week of twice-daily Ex-4 administration to wild-type versus MT-Ex-4 mice. Similarly, the levels of insulin, pdx-1, and GLP-1 receptor mRNA transcripts were comparable in wild-type and MT-Ex-4 transgenic mice after 1 week of Ex-4 administration. However, repeated Ex-4 administration significantly reduced food intake in MT-Ex-4 but not in wild-type mice. These findings illustrate that although Ex-4 is more potent than native GLP-1 in producing GLP-1 receptor desensitization in vitro, chronic exposure to Ex-4 in normal or transgenic mice is not associated with significant downregulation of GLP-1 receptor-dependent responses coupled to glucose homeostasis in vivo.
authors.affiliation: Banting and Best Diabetes Centre, University of Toronto, Toronto General Hospital, 200 Elizabeth St., MBRW 4R-402, Toronto, Ontario Canada M5G 2C4. d.drucker@utoronto.ca.
authors.forename: Laurie L
authors.initials: LL
authors.lastname: Baggio
authors.forename: Jung-Guk
authors.initials: JG
authors.lastname: Kim
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Drucker
mesh_terms: D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D005934:Glucagon / Q000494:pharmacology*; D052216:Glucagon-Like Peptide 1; D000067757:Glucagon-Like Peptide-1 Receptor; D005947:Glucose / Q000378:metabolism*; D007515:Islets of Langerhans / Q000187:drug effects / Q000502:physiology*; D007700:Kinetics; D051379:Mice; D010446:Peptide Fragments / Q000494:pharmacology*; D011498:Protein Precursors / Q000494:pharmacology*; D018027:Receptors, Glucagon / Q000819:agonists* / Q000502:physiology*
chemical_list: C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D010446:Peptide Fragments; D011498:Protein Precursors; D018027:Receptors, Glucagon; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D000242:Cyclic AMP; D005947:Glucose