It appears that both GIP and GIP are expressed due to processing of proGIP by PC1/3 and PC2. Indeed, the major peptide form in alpha-cells might be GIP due to the relative abundance of PC2 under normal circumstances and its ability to mediate a second C-terminal cleavage of GIP ML 10302 hydrochloride liberating the truncated peptide. These two forms have identical biological effects at the GIP receptor, including promotion of insulin secretion and lowering of blood glucose. Although significant evidence for islet alpha cell production of GLP-1 and GIP has been gathered which suggests a biological role, there is no real evidence that this plays any part in the regulation of islet function. It is unlikely that isletderived GLP-1 and GIP contribute significantly to circulating incretin concentrations or the extra-pancreatic actions of the peptides, but locally released GLP-1 and GIP might exert important effects on neighboring islet cells. Thus, on the basis of known actions of the incretins, it can be hypothesized that local islet production of incretin peptides is likely to enhance betacell function and survival in response to cytotoxic attack and increased demand imposed by insulin resistance. In this paper, we have used incretin receptor knock-out mice and wild-type controls to evaluate the role of islet and intestinal Land K-cell derived GLP-1 and GIP in relation to alterations in number, morphology and function of the islets and beta-cells in animal models of beta cell insult and insulin resistance, induced by multiple low dose streptozotocin or hydrocortisone treatment. The results provide novel information on the regulation of beta cell mass, functional consequences of intra-islet expression of incretin hormones and add weight to the debate concerning strategies for exploitation of incretin receptors in relation to MG 624 obesity-diabetes. Regulation of beta-cell function is under the control of circulating nutrients, hormones, paracrine interactions and autonomic nerves innervating the pancreatic islets. Although classically considered as enteroinsular hormones, this study has examined the possibility that intra-islet production of GLP-1 or GIP, together with circulating incretins from the gut, contributes to mechanisms controlling beta-cell function, particularly the regulation of beta-cell mass and adaptive responses to beta cell toxins and insulin resistance. As with other recent studies, we readily demonstrated GLP-1 and GIP in glucagon-containing islet alpha-cells by immunohistochemistry using antisera specific for glucagon or the two incretin hormones. Comparison of molar quantities measured by ELISA revealed approximately similar amounts of GLP-1 and GIP in the pancreas, corresponding to levels approximately 25% of pancreatic glucagon.