Cocaine- and amphetamine-regulated transcript (CART) is an anorexigenic peptide widely expressed in the central, peripheral, and enteric nervous systems. CART is also expressed in endocrine cells, including beta-cells during rat development and delta-cells of adult rats. We examined the effect of CART 55-102 on islet hormone secretion, using INS-1(832/13) cells and isolated rat islets. In addition, islet CART expression was examined in two rat models of type 2 diabetes: Goto-Kakizaki (GK) rats and dexamethasone (DEX)-treated rats. At high glucose, CART potentiated cAMP-enhanced insulin secretion via the cAMP/protein kinase A-dependent pathway. In the absence of cAMP-elevating agents, CART was without effect on INS-1 cells but modestly inhibited secretion of insulin, glucagon, and somatostatin from isolated islets. CART was markedly upregulated in the beta-cells of both diabetes models. Thus, in DEX-treated rats, islet CART mRNA expression, and the number of CART-immunoreactive beta-cells were 10-fold higher than in control rats. In GK rats, the relative number of CART-expressing beta-cells was 30-fold higher than in control rats. We conclude that CART is a regulator of islet hormone secretion and that CART is upregulated in the beta-cells of type 2 diabetic rats.