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Endocr Rev. 2019 Sep 12. pii: bnz002. doi: 10.1210/endrevbnz002. [Epub ahead of print]

Glucose-Dependent Insulinotropic Polypeptide Receptor Therapies For The Treatment Of Obesity, Do Agonists = Antagonists?

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Amgen Research, Department of Cardiometabolic Disorders, Thousand Oaks CA, USA.
Amgen Research, Department of Comparative Biology and Safety Sciences, Thousand Oaks, CA, USA.
Department of Endocrinology, Diabetes and Geriatric Medicine, Akita University Graduate School of Medicine, Akita, Japan.


Glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) is associated with obesity in human genome-wide association studies (GWAS). Similarly, mouse genetic studies indicate that loss of function alleles and GIP overexpression both protect from high-fat diet (HFD)-induced weight gain. Together, these data provide compelling evidence to develop therapies targeting GIPR for the treatment of obesity. Further, both antagonists and agonists alone prevent weight gain, but result in remarkable weight loss when co-dosed or molecularly combined with glucagon-like peptide-1 (GLP-1) analogs preclinically. Here, we review the current literature on GIPR, including biology, human and mouse genetics, and pharmacology of both agonists and antagonists, discussing the similarities and differences between the two approaches. Despite opposite approaches being investigated preclinically and clinically, there may be viability of both agonists and antagonists for the treatment of obesity and we expect this area to continue to evolve with new clinical data and molecular and pharmacological analyses of GIPR function.


GIP; GIPR; GLP-1; agonists; antagonists; obesity


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