CART (cocaine- and amphetamine-regulated transcript) is an anorexigenic peptide widely expressed in the central and peripheral nervous systems as well as in islet endocrine cells and nerve fibers. CART knock out mice display impaired glucose-stimulated insulin secretion in vivo and in vitro, together with impaired glucose elimination and reduced expression of GLUT-2 and PDX-1. In addition, a mutation in the human CART gene cosegregates with obesity and type 2 diabetes. CART regulates islet hormone secretion from isolated rat islets and is upregulated in the beta cells of type 2 diabetic rodents. More recently, we have studied the effect of CART on insulin secretion in vivo in mice. In addition, we have examined CART expression in human pancreas and GI-tract. Furthermore, we have studied regulation of beta cell CART expression in vivo in rats as well as in clonal beta cells. Peripherally administered CART lowers plasma glucose and enhances glucose stimulated insulin secretion after an intra-venous glucose tolerance test (IVGTT) in mice. CART increases glucose stimulated insulin secretion from isolated mouse islets stimulated with an array of secretagogues. CART is markedly upregulated in the beta cells of rats made type-2 diabetic with daily injections of dexamethasone; this is prevented by daily insulin treatment. The gene expression and protein levels of CART in INS-1 (832/13) cells seem to be regulated by both glucose and glucocorticoids. Interestingly, CART mRNA and protein are expressed also in human islet cells and in nerve fibers innervating the islets. Furthermore, CART is a constituent of the gastrin producing G-cells in the antrum of the stomach as well as of endocrine cells in the upper small intestine, paving the way for CART as an incretin hormone. In conclusion, CART may play important roles in glucose homeostasis and in the pathophysiology of type 2 diabetes.