510-P: Protection of Kidney and Pancreas in Diabetes via Rescuing Disruption of STRA6-Retinol Cascade by SGLT2 Inhibitor, not Sulfonylurea

Abstract

Sodium glucose co-transporter 2 (SGLT2) inhibitors have been proved to be beneficial for cardiovascular and renal outcome in diabetic patients. Our study demonstrated that disruption of intracellular retinol signaling is associated with diabetic nephropathy. Retinoid homeostasis, regulated by RBP4/STRA6/CRBP1/LRAT/RARs pathway, is also very crucial in cell biological function of pancreas and islets. This study aimed to demonstrate whether SGLT2 inhibitor or sulfonylurea could protect pancreas and kidney from diabetes-related injury. Diabetic db/db mice were treated with empagliflozin or glibenclamide for 4 weeks at their age of 8 weeks. This study analyzed RBP4/STRA6/CRBP1/LRAT/RARs signals and p-JNK, caspase in both pancreas and kidney, and functional markers of pancreatic β-cells (insulin, MafA, Pdx1, and NKX6.1) in pancreas of wild type, db/db, glibenclamide-treated db/db and empagliflozin-treated db/db mice. Significant reduction of insulin, MafA, Pdx1 and NKX6.1 protein and mRNA in pancreas of db/db mice were found and could be rescued in empagliflozin-treated db/db mice, but not in glibenclamide-treated db/db mice. STRA6, CRBP1, LRAT and RARβ protein and mRNA levels were reduced, while p-JNK and caspase expression increased in pancreas and kidneys of db/db mice. These changes were recovered in empagliflozin-treated db/db mice, but not in glibenclamide-treated db/db mice. The concentration of retinol, and retinoic acid, measured by HPLC, were also conserved in pancreas of empagliflozin-treated db/db mice, not in glibenclamide-treated db/db mice. In conclusion, this study indicates that empagliflozin, but not glibenclamide, exerts protective effects on pancreas and kidneys from diabetes through retrieving the disruption of STRA6-retinol signals in db/db mice. Disclosure S. Shin: None. Funding Taiwan Ministry of Science and Technology