When released from within islets, local concentrations of GIP and particularly GLP-1 are likely to be much greater than the low circulating levels of the hormones and without significant exposure to degradation by DPPIV. MRK 016 Administration of multiple low doses of streptozotocin resulted in severe insulitis, marked destruction of beta-cells, depletion of pancreatic and plasma insulin, elevation of glucagon and severe diabetes. This is consistent with the observed actions of the toxin to induce lymphocytic infiltration and insulitis rather than simply inducing chemical destruction of beta cells as occurs when administered as a large single dose. The marked loss of beta cells resulted in remaining islets being marginally smaller, irregularly shaped and exhibiting substantially increased alphacell mass and pancreatic glucagon content. Interestingly, a subpopulation of alpha cells predominantly expressed GLP-1, supporting the idea that an increase in local production of GLP-1 may be involved in compensation for beta cell loss. There was also a substantial increase in TUNEL staining beta cells and, in contrast to other reports, little evidence of Ki-67 positive betacell regeneration, MSOP giving rise to markedly decreased Ki-67 to TUNEL ratio. The possible involvement of GLP-1 and GIP in this compensatory islet response was evaluated further using GLP-1R KO and GIPR KO mice maintained on the C57BL/6 background. Compared with wild-type C57BL/6 controls, incretin receptor KO mice displayed characteristic changes of islet morphology and beta-cell mass as described previously. GLP-1 and GIP were expressed in islet alpha cells of all groups of mice. Treatment of incretin receptor KO mice with multiple low dose streptozotocin resulted in a slightly greater severity of islet damage than normal mice treated with the toxin. This was reflected by decreased islet numbers in GLP-1R KO mice and decreases in islet size and beta cell area together with increased alpha cell mass in both transgenic mouse models. Knock-out of GLP-1R also resulted in increased pancreatic GLP-1 without change of pancreatic glucagon or circulating hormone levels, suggesting that insulin deficiency and/ or receptor deletion affects cellular GLP-1 production from the proglucagon precursor. In contrast, circulating GIP was decreased in in both groups of receptor knock-out mice without affecting tissue stores. Irrespective of these changes, deletion of receptors for either incretin hormone did not greatly affect the course of severe insulin deficient diabetes. This likely reflects the severe hyperglycaemia and substantial level of damage inflicted on beta cells, as witnessed by lack of beta cell regeneration and markedly decreased Ki67/TUNEL ratios in control diabetic C57BL/6 mice. The metabolic and islet cell responses to hydrocortisone treatment were quite different to those induced by multiple low doses of streptozotocin.