Cluster of differentiation 93 (CD93) is a glycoprotein expressed in activated endothelial cells. The extracellular portion of CD93 can be secreted as a soluble form (sCD93) under inflammatory conditions. As diabetic nephropathy (DN) is a well-known inflammatory disease, we hypothesized that sCD93 would be a new biomarker for DN. We prospectively enrolled 97 patients with type 2 diabetes and evaluated the association between serum sCD93 and DN prevalence. The association between CD93 and development of DN was investigated using human umbilical cord endothelial cells (HUVECs) in vitro and diabetic db/db mice in vivo. Subjects with higher sCD93 levels had a lower estimated glomerular filtration rate (eGFR). The sCD93 level was an independent determinant of both the albumin-to-creatinine ratio (ACR) and the eGFR. The risk of prevalent DN was higher in the high sCD93 group (adjusted odds ratio 7.212, 95% confidence interval 1.244–41.796, p = 0.028). In vitro, CD93 was highly expressed in HUVECs and both CD93 expression and secretion were upregulated after lipopolysaccharides (LPS) stimulation. In vivo, peritoneal and urine sCD93 levels and the renal glomerular expression of CD93 were significantly higher in the db/db mice than in the control db/m+ mice. These results suggest the potential of sCD93 as a candidate biomarker associated with DN.

Islets are highly vascularized for prompt insulin secretion. Although angiopoietin-1 (Ang1) is a wellknown angiogenic factor, its role in glucose homeostasis remains largely unknown. The objective of this study was to investigate whether and how Ang1 contributes to glucose homeostasis in response to metabolic challenge. We used inducible systemic Ang1 knockout (Ang1 sys2/2) and b-cellspecific Ang1 knockout (Ang1 b-cell2/2) mice fed a high-fat diet for 24 weeks. Although the degree of insulin sensitivity did not differ between Ang1 sys2/2 and Ang1 sys+/+ mice, serum insulin levels were lower in Ang1 sys2/2 mice, resulting in significant glucose intolerance. Similar results were observed in Ang1 b-cell2/2 mice, suggesting a critical role of b-cell-derived Ang1 in glucose homeostasis. There were no differences in b-cell area or vasculature density, but glucosestimulated insulin secretion was significantly decreased, and PDX-1 expression and GLUT2 localization were altered in Ang1 b-cell2/2 compared with Ang1 b-cell+/+ mice. These effects were associated with less pericyte coverage, disorganized endothelial cell ultrastructure, and enhanced infiltration of inflammatory cells and upregulation of adhesion molecules in the islets of Ang1 b-cell2/2 mice. In conclusion, b-cell-derived Ang1 regulates insulin secretion and glucose homeostasis by stabilizing the blood vessels in the islet and may be a novel therapeutic target for diabetes treatment in the future.