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

  1. Laurie L. Baggio,
  2. Jung-Guk Kim and
  3. Daniel J. Drucker
  1. Banting and Best Diabetes Centre, Department of Medicine, Toronto General Hospital, University of Toronto, Ontario, Canada
  1. Address correspondence and reprint requests to Daniel J. Drucker, MD, Banting and Best Diabetes Centre, University of Toronto, Toronto General Hospital, 200 Elizabeth St., MBRW 4R-402, Toronto, Ontario Canada M5G 2C4. E-mail: d.drucker{at}


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.


  • This article is based on a presentation at a symposium. The symposium and the publication of this article were made possible by an unrestricted educational grant from Servier.

    D.J.D. is an advisory panel member and consultant for Amylin Pharmaceuticals.

    • Accepted May 6, 2004.
    • Received March 16, 2004.
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