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

Abstract

β-cells respond to peripheral insulin resistance by increasing circulating insulin in early type-2 diabetes (T2D). Islet remodeling 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 islet resident macrophages, especially in early T2D. We hypothesize that islet resident macrophages contribute to islet vascular remodeling and hyperinsulinemia, the failure of which results in a rapid progression to T2D. Using genetic and dietinduced models of compensatory hyperinsulinemia we show that its depletion significantly compromises islet remodeling in terms of size, vascular density and insulin secretion capacity. Depletion of islet macrophages reduces VEGF-A secretion from both human and mouse islets ex vivo and the impact of reduced Highlights• The compensatory hyperinsulinemic phase of type-2 diabetes is accompanied with significant pancreatic islet remodeling.• Bona fide islet resident macrophages are increased during the diabetic compensation phase by largely in situ proliferation.• Ablating macrophages severely compromises the islet remodeling process and exacerbates glycemic control in vivo.• Mouse and human islet macrophages contribute VEGF-A to the islet environment.• Specific removal of islet macrophages delays islet vascularization in compensatory hyperinsulinemic mice.