Treatment of Hyperglycemia with Empagliflozin, With or Without Metformin, Improves Islet Endothelial Cell Health and Insulin Secretion in db/db Diabetic Mice

Islet endothelial dysfunction occurs in diabetic mice and results in impaired insulin release in vitro. Previously, we found that 12-week treatment of db/db mice with the SGLT2 inhibitor empagliflozin (EMPA) improved islet endothelial dysfunction. Here, we determined if this occurs with shorter treatment duration, is associated with increased insulin release and whether EMPA combined with metformin (MET) provides additional benefit. 6-week old male diabetic C57BL/KsJ.db/db mice and littermate controls (db/+;+/+) were treated with EMPA (20 mg/kg/d in diet), MET (0.5 g/kg/d in water), EMPA+MET, or vehicle (VEH) for 6 weeks. A subset of mice (n=3-5) underwent IV glucose tolerance tests to determine insulin release. mRNA levels of cell adhesion molecules E-selectin (Sele) and vascular cell adhesion molecule 1 (Vcam1), proinflammatory cytokine interleukin-6 (Il6) and vasoconstrictor endothelin-1 (Edn1), were assessed. EMPA treatment lowered plasma glucose, increased insulin release and improved islet endothelial health (Table). MET had a similar effect, but was less effective than EMPA, while EMPA+MET was more effective in improving endothelial function but did not further increase insulin release. Improving islet endothelial health with EMPA may have beneficial effects on beta-cell function in human type 2 diabetes.