#2601 THE MOLECULAR EFFECT OF SGLT2I ON THE AUTOPHAGY PATHWAY IN TYPE II DIABETES MELLITUS AND ITS VASCULAR COMPLICATIONS

Abstract

Abstract Background and Aims Type II Diabetes mellitus (T2DM) is a severe metabolic disorder characterized by chronic hyperglycemia and its subsequent glucose toxicity that lead to irreversible damages in several organs such as Diabetic Nephropathy (DN) [1]. Autophagy is involved in catabolic processes and plays a key role in the degradation of damaged intracellular proteins in order to maintain intracellular homeostasis and cell integrity. Studies showed that autophagy-related protein 5 (ATG5) and Light chain 3-II (LC3-II) play a critical role in a variety of disease processes, like DN [3]. Empagliflozin (EMPA) is sodium glucose transporter inhibitor (SGLT2i) which represents a new class of glucose lowering drugs and is recommended in T2DM [4]. We hypothesized that EMPA effects renal integrity and function via the autophagy mechanism. The proposed research aim to investigate the molecular effect of SGLT2i on the expression of ATG5 and its downstream collaborator LC3-II in diabetic mice model [5]. Methods 8-week-old male mice: C57BL/6 Wild Type (Con), BTBR ob/ob (DM) and BTBR ob/ob treated with EMPA (1mg/kg/day P.O.) (DM+EMPA) were followed for 12 consecutive weeks for their weight, blood glucose and renal function. After sacrifice lysate from renal cortex were analyzed by Western blot and immunohistochemistry for ATG5, LC3B and fibronectin expression. Results Blood glucose level in DM mice was higher than Con, and lower in DM+EMPA. DM+EMPA mice drunk, urinated more and exerted more glucose than DM mice, yet had less protein in their urine. WB and IHC analyses revealed that renal ATG5 and LC3-II levels were reduced in DM mice compared with Con and DM+EMPA mice. Fibronectin expression was increased in DM compared to Con mice, and DM+EMPA mice. Conclusions EMPA treatment preserved DM mice renal dysfunction. Our data suggest that there is a link between DM and ATG5/LC3-II dysregulation and subsequent DN. EMPA preserves ATG5/LC3-II in DM mice. Our findings may be translated into clinical practice approach and may lead to further studies to address DM and vascular complications by selective modulation of ATG5/LC3-II expression with SGLT2i treatment.