GLP-1 and GIP are generated within islets and exert possible unsuspected roles in the functional regulation of beta cells and other islet cell types. Their involvement in the regulation of beta cell mass is possibly more intriguing given the paucity of agents with such effects and the loss of beta cells in both type 1 and type 2 diabetes. Pregnancy is one of the very few situations associated with physiological and reversible expansion of beta cell mass not only in animals, which show remarkable plasticity of insulin secreting cells, but also in humans. Given the positive actions of the two incretins on beta cell mass, resulting from reciprocal effects on beta cell proliferation and death, we examined the role GLP-1 and GIP in islet adaptation to pregnancy using incretin receptor knockout mice. The results reveal an important role of GLP-1 in pregnancy-induced increases in beta cell mass, mediated largely by local GLP-1 production in alpha cells. In contrast, GIPR KO mice demonstrated intact mechanisms of islet adaptation to pregnancy, suggesting that islet or K-cell derived GIP is not essential for pregnancy-associated expansion of beta cell mass. Pregnancy increases metabolic needs and hence alters maternal metabolism by enhancing nutrient absorption and pancreatic beta cell function to match increased demand. Earlier reports on pregnancy-induced beta cell compensation revealed that lactogenic hormones stimulate beta cell proliferation and suppress apoptosis, thereby increasing beta cell mass. This is supported by observations in prolactin receptor knockout mice which displayed an inability to increase beta cell mass during pregnancy. Several reports also claim that lactogenic hormones increase serotonin biosynthesis in beta cells which in turn exerts proliferative effects on beta cells. In contrast, the involvement of gut hormones which normally play a key role in the regulation of beta cell function and survival has been largely overlooked. Interestingly, Sugiyama et al. observed that beta cell proliferation was not affected in pregnant glucagon-GFP knock-in mice lacking global proglucagon derived peptides, including glucagon, GLP-1, GLP-2 and oxyntomodulin. However, recent studies have shown that these mice display important compensatory changes even in the non-pregnant state, including markedly increased circulating GIP with substantial ectopic expression of GIP in islet beta cells. Thus, a positive role of GIP on beta cell mass may be particularly important in these animals. Accordingly, further studies are required using more specific receptor knockout models without functional GLP-1 or GIP receptors to assess the true role of incretin hormones in islet cell adaptations to pregnancy. Our study using GLP-1R and GIPR knockout animal models revealed that receptor knockout did not affect islet area and beta cell area but increased alpha cell area without affecting pancreatic glucagon content in GIP.