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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

Banting and Best Diabetes Centre, Department of Medicine, Toronto General Hospital, University of Toronto, Ontario, Canada

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.

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