B-Cell survival plays a pivotal role in preventing the pathogenesis of diabetes and thus, there are intensive efforts to understand the molecular mechanisms by which B-cell growth and function is regulated. This research focuses on defining those signaling proteins essential to mediation of glucose-dependent growth and function in these cells and in particular is concerned with the most proximal proteins to the IGF-1 receptor, which are represented by the family of IRS proteins. IRS proteins, particular IRS-2, mediate the score of effects of insulin-like growth factor-1 and glucose on b-cell growth and function via influencing protein complex formation and hence, signal transmission. The heterogeneity of IRS proteins is mainly apparent in the number and design of their docking sites for SH-2 containing proteins which provides some explanation for the diversification of their respective signaling pathways and biological endpoints. From preliminary data, it appears that the ratios of IRS protein expression are instrumental in predicting certain phenotypic differences, such as degree of differentiation and rate of growth, among B-cell populations. This hypothesis will be examined in a model of reverting the less differentiated phenotype INS-1cells to a more highly differentiated, glucose-responsive B-cell population. This research is intended to characterize in B-cells the biological endpoints affected by differences in IRS protein expression and to further examine IRS-mediated signaling events and protein complex formation, and lastly, to define the functional consequences associated with changes in IRS protein levels in B-cells. These experiments will progress towards the development of a model B-cell population, which is suitable to test for transplantation therapies, and anticipated to provide novel drug targets in which to prevent the gradual decline in B-cell mass and function occurring in type II diabetes.
