Islet macrophages drive islet vascular remodeling and compensatory hyperinsulinemia in the early stages of diabetes

{beta}-cells respond to peripheral insulin resistance by increasing circulating insulin in early type-2 diabetes (T2D). Isletremodeling supports this compensation but the drivers of this process remain poorly understood. Infiltrating macrophages have been implicated in late stage T2D but relatively little is known on isletresident macrophages, especially in early T2D. We hypothesize that isletresident macrophages contribute to isletvascular remodeling and hyperinsulinemia, the failure of which results in a rapid progression to T2D. Using genetic and diet-induced models of compensatory hyperinsulinemiawe show that its depletion significantly compromises isletremodeling in terms of size, vascular density and insulin secretion capacity. Depletion of isletmacrophages reduces VEGF-A secretion from both human and mouse isletsex vivo and the impact of reduced VEGF-A functionally translates to delayed re-vascularization upon transplantation in vivo. Hence, we show a new role of isletresident macrophages in the context of early T2D and suggest that there is considerable utility in harnessing isletmacrophages to promote isletremodeling and isletinsulin secretion capacity.nnHighlightsO_LIThe compensatory hyperinsulinemic phase of type-2 diabetes is accompanied with significant pancreatic isletremodeling.nC_LIO_LIBona fide isletresident macrophages are increased during the diabetic compensation phase by largely in situ proliferation.nC_LIO_LIAblating macrophages severely compromises the isletremodeling process and exacerbates glycemic control in vivo.nC_LIO_LIMouse and human isletmacrophages contribute VEGF-A to the isletenvironment.nC_LIO_LISpecific removal of isletmacrophages delays isletvascularization in compensatory hyperinsulinemic mice.nC_LI