GIP and GLP-1 were clearly expressed in islet alpha cells of pregnant mice and there was a substantial increase in peripherally located cell populations expressing only GIP or GLP-1. Consistent with these changes pancreatic levels of both GIP and GLP-1 were increased together with up-regulation of alpha cell PC1/3, as observed previously. These changes were not accompanied by increases in GLP-1/glucagon colocalization but this could reflect a suspected increase of alpha cells expressing only GLP-1, hence giving a lower value for the colocalization coefficient. Similarly pregnancy increased intestinal contents of both incretin hormones and the numbers of intestinal K- and L-cells. Consistent with negative intra-islet regulation by increased beta cell numbers and insulin content, plasma glucagon levels were decreased by pregnancy. The changes considered above indicate significant adaptation of islets in pregnancy and suggest that they may be partly due to intra-islet production of GLP-1 and GIP which exerts local effects on beta cell function, including stimulation of beta cell proliferation and inhibition of apoptosis. The observed increase of circulating GIP suggests possible involvement of K-cell derived GIP but contrary to such a view, the pregnancy-induced changes in the islets of GIPR KO mice were similar to pregnant C57BL/6 mice. This included prominent increases in islet area, beta cell area and pancreatic insulin content together with decreased islet GIP/glucagon colocalization and no increase in the population of cells solely expressing GLP-1. Thus it appears that intestinal or islet derived GIP plays little role in islet adaptation to pregnancy. However, in marked contrast, pregnant GLP-1R KO mice exhibited no adaptive changes in any of these islet parameters and displayed an actual decrease of islet numbers. Consistent with decreased beta cell mass, the ratio of Ki67/TUNEL positive insulin positive cells in pregnant GLP-1R KO mice did not favour proliferation. Since circulating GLP-1 was unchanged in these animals, loss of islet compensation is more likely to be due to abolition of the intra-islet effects of islet-derived GLP-1. Furthermore in GLP-1RKO mice, pregnancy was not associated with increases in populations of islet cells purely expressing GLP-1 or GIP and there was a decrease in numbers of alpha cells coexpressing GIP and glucagon. Pancreatic GLP-1, GIP and insulin were actually decreased and the pregnancy-induced increases in intestinal GLP-1 and GIP together with L-cell hyperplasia were abolished. Taken together, these data reveal an essential role of GLP-1 in islet compensation to pregnancy, suggesting crucial involvement of changes in proglucagon processing in islet cells leading to local generation of GLP-1. Clearly generation of transgenic mice with targeted knockout of beta cell GLP-1 receptor could be useful to separate out any indirect effects.