Cardiovascular biology of the GIP receptor

Glucose-dependent insulinotropic polypeptide (GIP) is a gut hormone secreted primarily from enteroendocrine K cells in the duodenum and proximal jejunum following nutrient ingestion, primarily acting on islet beta-cells to potentiate insulin secretion in a glucose-dependent manner. New discoveries of GIP receptor (GIPR) biology in adipose tissue, as well as findings that co-agonists for the glucagon-like peptide-1 receptor (GLP-1R) and GIPR induce greater weight loss than that seen with GLP-1R agonists alone, has led to continued interest in manipulating GIPR activity for the treatment of obesity/type 2 diabetes mellitus (T2DM). As cardiovascular diseases represent the number one cause of death in people with T2DM, there has also been growing interest in understanding the cardiovascular actions of the GIP/GIPR axis. Although controversy surrounds whether GIPR agonism or antagonism will induce weight loss in obesity/T2DM, such actions undoubtedly will impact cardiovascular function and outcomes since obesity is a major risk factor for cardiovascular disease. Furthermore, GIPR agonism is associated with reduced progression of atherosclerotic lesions in preclinical studies. Conversely, genetic deletion of GIPR activity within cardiac myocytes of the heart results in robust protection against experimental myocardial infarction. Nonetheless, interrogation of the GIP/GIPR axis on cardiac function in humans will involve the systemic actions of the GIPR within the myocardium and other systems (e.g. adipose tissue, vasculature), which will influence the long-term future of GIPR modification for the treatment of obesity/T2DM.