Beyond the pancreas: contrasting cardiometabolic actions of GIP and GLP1

Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP1) exhibit incretin activity, meaning that they potentiate glucose-dependent insulin secretion. The emergence of GIP receptor (GIPR)–GLP1 receptor (GLP1R) co-agonists has fostered growing interest in the actions of GIP and GLP1 in metabolically relevant tissues. Here, we update concepts of how these hormones act beyond the pancreas. The actions of GIP and GLP1 on liver, muscle and adipose tissue, in the control of glucose and lipid homeostasis, are discussed in the context of plausible mechanisms of action. Both the GIPR and GLP1R are expressed in the central nervous system, wherein receptor activation produces anorectic effects enabling weight loss. In preclinical studies, GIP and GLP1 reduce atherosclerosis. Furthermore, GIPR and GLP1R are expressed within the heart and immune system, and GLP1R within the kidney, revealing putative mechanisms linking GIP and GLP1R agonism to cardiorenal protection. We interpret the clinical and mechanistic data obtained for different agents that enable weight loss and glucose control for the treatment of obesity and type 2 diabetes mellitus, respectively, by activating or blocking GIPR signalling, including the GIPR–GLP1R co-agonist tirzepatide, as well as the GIPR antagonist–GLP1R agonist AMG-133. Collectively, we update translational concepts of GIP and GLP1 action, while highlighting gaps, areas of uncertainty and controversies meriting ongoing investigation. This Review highlights the extrapancreatic actions of the incretin hormones gastric inhibitory polypeptide and glucagon-like peptide 1. These peptides are active on tissues with cardiometabolic relevance, such as liver, adipose tissue, muscle, the immune, kidney, heart, blood vessels and the central nervous system. Key points Glucagon-like peptide 1 (GLP1) receptor and glucose-dependent insulinotropic polypeptide (GIP) receptor are widely expressed in multiple organs beyond the pancreas. GIP and GLP1 reduce appetite by signalling through their receptors that are expressed in multiple regions of the central nervous system. GIP suppresses macrophage-dependent inflammation, whereas GLP1 reduces gut inflammation through its receptor on intraepithelial lymphocytes. Both GLP1 and GIP act indirectly on white adipose tissue, whereas GIP directly regulates fat and amino acid metabolism and inflammation within brown adipose tissue. GIP and GLP1 are neuroprotective in preclinical models of ne