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Does glucose-dependent insulinotropic polypeptide receptor blockade as well as agonism have a role to play in management of obesity and diabetes?
Lafferty, Ryan A; Flatt, Peter R; Gault, Victor A; Irwin, Nigel.
Affiliation
  • Lafferty RA; Diabetes Research Centre, Schools of Biomedical Sciences and Pharmacy & Pharmaceutical Sciences, Ulster University, Coleraine, Northern Ireland, UK.
  • Flatt PR; Diabetes Research Centre, Schools of Biomedical Sciences and Pharmacy & Pharmaceutical Sciences, Ulster University, Coleraine, Northern Ireland, UK.
  • Gault VA; Diabetes Research Centre, Schools of Biomedical Sciences and Pharmacy & Pharmaceutical Sciences, Ulster University, Coleraine, Northern Ireland, UK.
  • Irwin N; Diabetes Research Centre, Schools of Biomedical Sciences and Pharmacy & Pharmaceutical Sciences, Ulster University, Coleraine, Northern Ireland, UK.
J Endocrinol ; 262(2)2024 Aug 01.
Article in En | MEDLINE | ID: mdl-38861364
ABSTRACT
Recent approval of the dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, tirzepatide, for the management of type 2 diabetes mellitus (T2DM) has reinvigorated interest in exploitation of GIP receptor (GIPR) pathways as a means of metabolic disease management. However, debate has long surrounded the use of the GIPR as a therapeutic target and whether agonism or antagonism is of most benefit in management of obesity/diabetes. This controversy appears to be partly resolved by the success of tirzepatide. However, emerging studies indicate that prolonged GIPR agonism may desensitise the GIPR to essentially induce receptor antagonism, with this phenomenon suggested to be more pronounced in the human than rodent setting. Thus, deliberation continues to rage in relation to benefits of GIPR agonism vs antagonism. That said, as with GIPR agonism, it is clear that the metabolic advantages of sustained GIPR antagonism in obesity and obesity-driven forms of diabetes can be enhanced by concurrent GLP-1 receptor (GLP-1R) activation. This narrative review discusses various approaches of pharmacological GIPR antagonism including small molecule, peptide, monoclonal antibody and peptide-antibody conjugates, indicating stage of development and significance to the field. Taken together, there is little doubt that interesting times lie ahead for GIPR agonism and antagonism, either alone or when combined with GLP-1R agonists, as a therapeutic intervention for the management of obesity and associated metabolic disease.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Receptors, Gastrointestinal Hormone / Diabetes Mellitus, Type 2 / Glucagon-Like Peptide-1 Receptor / Obesity Limits: Animals / Humans Language: En Journal: J Endocrinol Year: 2024 Document type: Article Country of publication: Reino Unido

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Receptors, Gastrointestinal Hormone / Diabetes Mellitus, Type 2 / Glucagon-Like Peptide-1 Receptor / Obesity Limits: Animals / Humans Language: En Journal: J Endocrinol Year: 2024 Document type: Article Country of publication: Reino Unido