We have collaborated with the Hara, Ahlgren and Sorenson laboratories in formulating a quantitative understanding of various aspects of islet development from their data. Although the islets of Langerhans occupy only about 1% volume of the pancreas, they play a critical role in the homeostasis of blood glucose. Islets have three major endocrine cell types. Alpha and beta cells secrete glucagon and insulin for counteracting low and high glucose levels, respectively. Delta cells secrete somatostatin which inhibits both glucagon and insulin secretion. Islets range in size from clusters of a few cells to several thousand cells. Furthermore, different species have different islet architectures. Rodent islets have a characteristic structure where beta cells are located in the islet core, while alpha and delta cells are distributed on the islet mantle. In human islets, on the other hand, non-beta cells are also distributed within the islet core. In spite of this anatomical knowledge, we still do not understand the design principles of islet architecture: the functional importance of islet size, and cell arrangement. Our analysis of endocrine cell arrangements in about 20,000 individual human islets showed that human islets are not a random mixture of endocrine cells, but that beta-cells prefer to be in contact with each other as in rodent islets. This is relevant to islet physiology in that the coupling beta-beta contacts observed in T2D may reduce essential couplings between beta-cells resulting in inefficient insulin secretion. Our study of islet architecture has led us to hypothesize that islet morphology differences between species may be due to species-specific endocrine cell fractions, rather than species-specific cell-cell adhesion properties. We have carried out model simulations that support our hypothesis. We are collaborating with the Foty laboratory (UMDNJ) to confirm this experimentally in endocrine cell lines. We are modeling cell-cell interactions to predict alterations in islet function that follow from changes in islet composition. We are continuing our collaborations with the Hara and Ahlgren (Ume) laboratories to model the dynamics of islet size distributions under various conditions, such as pregnancy and obesity.
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