Ghrelin and CART. Two new islet peptides. Expression, regulation and function

Sammanfattning: Until recently, the islets of Langerhans were thought to harbour four main cell types characterised with respect to principal hormone product. Here we show that the novel hormone ghrelin is expressed in a fifth islet cell type, the islet ghrelin cell, in humans and rodents. The cells are developmentally regulated in that they are numerous around birth and fewer in the adult. The islet ghrelin cells have unique ultrastructural features that distinguish them from the other islet cells. Further, we demonstrate that ghrelin inhibits GSIS from clonal beta cells. In addition, we show that the neuropeptide CART is expressed in several islet cell types during rat development, but only in delta cells and nerves in normal adult animals. Further, CART is robustly upregulated in the beta cells of several rodent models of type-2 diabetes. We also show that CART augments cAMP-mediated GSIS from clonal beta cells and from isolated rat islets via increased intracellular cAMP and the PKA-dependent pathway. On the other hand, in the absence of cAMP-elevating agents CART inhibits secretion of insulin, glucagon and somatostatin. Further emphasizing a role for CART in the islets, CART KO mice display impaired GSIS in vivo and in vitro together with impaired glucose elimination and reduced expression of beta cell function markers. Although CART KO mice have normal food intake they develop a late onset increased body weight. Importantly, islet dysfunction is apparent already in young, still lean animals.