Incretin actions beyond the pancreas: lessons from knockout mice

Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are intestinal hormones secreted in response to ingestion of various nutrients. These incretins stimulate insulin secretion from pancreatic beta cells in a glucose-dependent fashion. GIP and GLP-1 actions are mediated by specific receptors, the GIP receptor (GIPR) and the GLP-1 receptor (GLP-1R), which are expressed in pancreatic beta cells and various other tissues and organs. Investigations using mice deficient in GIPR and/or GLP-1R have clarified roles of the incretins in enhancement of glucose-dependent insulin secretion from beta cells as well as divergent biological activities with therapeutic implications for diabetes-related complications, such as cardiovascular diseases, retinopathy, nephropathy and neuropathy, and comorbidities, such as cognitive impairment, bone fracture and obesity. We review here recent findings on the extra-pancreatic effects of GIP and GLP-1 from the perspective of diabetes treatment.