GIP

GIP is one of the two main incretin hormones (along with GLP-1) that are released from enteroendocrine K cells in the proximal small intestine following oral nutrient intake, particularly fats and carbohydrates. It acts on pancreatic beta cells via the GIP receptor (a GPCR coupled to Gs protein) to increase cAMP and augment glucose-stimulated insulin secretion—this is the basis of the 'incretin effect,' explaining why oral glucose produces a greater insulin response than IV glucose at the same blood glucose level. Unlike its name suggests, GIP has only weak and clinically insignificant effects on inhibiting gastric acid secretion and gastric emptying (the more potent inhibitor is GLP-1). In type 2 diabetes, the insulinotropic effect of GIP is significantly blunted (beta cell resistance to GIP), while GLP-1 effects are relatively preserved, which is why GLP-1-based therapies (GLP-1 agonists) are more clinically useful than GIP-based monotherapy. However, newer dual GIP/GLP-1 receptor agonists (e.g., tirzepatide) have been developed and show enhanced efficacy for glycemic control and weight loss in type 2 diabetes, leveraging both incretin pathways synergistically. GIP secretion is stimulated by fat and glucose in the gut lumen, and it also has some role in fat metabism, promoting lipogenesis in adipose tissue, linking it to obesity pathophysiology. Understanding the incretin system is high-yield for USMLE Step 1 (GI physiology, endocrine pathways) and Step 2 (diabetes pharmacology, particularly the mechanism of DPP-4 inhibitors and GLP-1/GIP receptor agonists).