Insufficient release of insulin from the pancreatic islet β cell is a critical defect in type 2 diabetes (T2D). Pancreatic islets are highly vascularized, and this vasculature is essential for nutrient supply to islet cells, insulin delivery to peripheral tissues and as a rich source of signals that support β-cell function. In human T2D and animal models, islet vasculopathy manifests as endothelial inflammation and capillary dilation and fragmentation. Moreover, induction of these islet vascular abnormalities in vitro is sufficient to impair insulin release and/or induce β-cell death. We have identified human islet amyloid polypeptide (hIAPP) aggregation as a mediator of islet vasculopathy. hIAPP-derived amyloid deposits accumulate in the extracellular matrix between β cells and islet capillaries in almost all patients with T2D. We now show that hIAPP aggregation results in islet endothelial cell cytotoxicity and inflammation, capillary dilation and loss. Using, RNA-Seq we identified Clec14a as a potential molecular mediator of hIAPP-induced islet endothelial damage. Clec14a is a member of the vascular C-type lectin family, whose pancreatic expression is restricted to endothelial cells. Clec14a deficiency has been shown to result in microvascular destabilization, inflammation and cell death in several tissues but has never been studied in the pancreas. We will now determine if loss of Clec14a exacerbates the islet endothelial response to hIAPP in vitro and increases susceptibility to hIAPP-induced islet vasculopathy and exacerbates β-cell dysfunction in vivo. Capillary-associated pericytes play a critical role in normal microvascular homeostasis. In several tissues, including islets, pericytes regulate capillary tone and blood flow. Pericyte coverage is also necessary for endothelial integrity, pericyte-endothelial interactions prevent endothelial inflammation and vessel leakage. This interaction, in non-islet tissues, is governed both by paracrine signals and cell-cell contact, of which Clec14a is just one mediator. Disruption of endothelial-pericyte interactions underlies the vascular instability and inflammation that drives development of diabetic retinopathy and renal fibrosis. Pericyte detachment/loss also occurs in T2D islets. However, the mechanisms that govern islet endothelial-pericyte attachment, how these are disrupted in T2D and the consequent impact on β-cell function have not been studied. This proposal will address this major knowledge gap. Our preliminary data show that hIAPP aggregation leads to islet pericyte detachment and degeneration. Our data and others’ show this includes a direct toxic effect of hIAPP on microvascular pericytes, resulting in loss of key signals that govern endothelial cell-pericyte cross-talk. This proposal will address the hypothesis that disruption of islet endothelial cell-pericyte interactions, mediated in part by Clec14a deficiency, underlies hIAPP-induced islet vasculopathy and contributes to β-cel...