Regulation of spatial organization and cell-cell communication in the islet of Langerhans

The most important determinant in whether a person will develop type 2 diabetes or gestational diabetes is whether their islets of Langerhans are able to compensate for the increase demand for insulin brought about by peripheral insulin resistance. In successful compensatory islet expansion (that can mitigate the develop- ment of diabetes), islets retain their three-dimensional architecture, endocrine cell-cell communication, and in- tra-islet regulation of hormone secretion. Failure of compensatory islet expansion is a key event in the etiology of type 2 diabetes and gestational diabetes. Accordingly, abnormal islet architecture and dysregulated hor- mone secretion are hall-marks of all types of diabetes mellitus. How islets orchestrate the changes in tissue architecture and in cell-cell communication during compensatory expansion, and why they fail to do so in dia- betes, is unclear. This is important, because approaches to promoting compensatory islet expansion by focus- ing on β cell proliferation alone, without tackling other aspects of islet tissue remodeling, have not been suffi- ciently effective so far. This application focuses on the Slit-Robo signaling pathway as a critical regulatory mechanism in remodeling islet organization and intra-islet cell-cell communication, the failure of which is a lim- iting factor for compensatory islet expansion. Specific Aim 1 will test the hypothesis that down-regulation of Robo2 receptors in beta cells is essential for compensatory islet expansion. Specific Aim 2 will determine how down-regulation of Robo2 in beta cells causes alpha cells dyregulation. Specific Aim 3 will test the hypothesis that Slit-Robo mediated crosstalk between pancreatic stroma and endocrine cells is involved in compensatory islet expansion. Understanding the role of Slit-Robo signaling in regulating islet dynamics during life events could potentially be leveraged in the future to promote successful compensatory islet expansion and intra-islet control of hormone secretion in obesity, insulin resistance, and pregnancy.