Gurprit Bhardwaj: Molecular Endocrinology and Stem Cell Research Laboratory, Department of Biochemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat, 390021, India. Electronic address: gurprit.bhardwaj@gmail.com.
Mitul Vakani: Molecular Endocrinology and Stem Cell Research Laboratory, Department of Biochemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat, 390021, India.
Abhay Srivastava: Regenerative Medicine Program, Institute of Cardiovascular Sciences, Department of Physiology and Pathophysiology, St. Boniface Hospital Albrechtsen Research Centre, University of Manitoba, Winnipeg, MB, Canada.
Dhaval Patel: Department of Bioinformatics and Structural Biology, Indian Institute of Advanced Research, Koba, Gandhinagar, 382007, Gujarat, India.
Anju Pappachan: Department of Bioinformatics and Structural Biology, Indian Institute of Advanced Research, Koba, Gandhinagar, 382007, Gujarat, India; School of Life Sciences, Central University of Gujarat, Gandhinagar, 382030, Gujarat, India.
Prashant Murumkar: Faculty of Pharmacy, Kalabhavan Campus, The Maharaja Sayajirao University of Baroda, Vadodara, 390001, Gujarat, India.
Hemal Shah: Molecular Endocrinology and Stem Cell Research Laboratory, Department of Biochemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat, 390021, India.
Rushabh Shah: Molecular Endocrinology and Stem Cell Research Laboratory, Department of Biochemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat, 390021, India.
Sarita Gupta: Molecular Endocrinology and Stem Cell Research Laboratory, Department of Biochemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat, 390021, India. Electronic address: sglmescrl@gmail.com.
Failing pancreas and subsequent loss of pancreatic β cells worsen diabetic conditions which are further alleviated by the mounting up of glucose levels. Inhibition of sodium glucose cotransporter 2 (SGLT2) in the kidney responsible for glucose reabsorption strikingly reduces blood glucose levels. Bioactive swertisin showed a promising glucose-lowering effect. Hence, we aimed to mechanistically dissect the glucose lowering property of swertisin. A systematic in silico, in vitro, and in vivo approach was directed for target analysis of swertisin. Molecular docking was performed with Swertisn-hSGLT2 complex. Glucose uptake assay and protein expression for SGLT2 and regulatory proteins were performed under swertisin effect. Various physiological and metabolic parameters were evaluated in STZ induced BALB/c mice using swertisin treatment. SGLT2 expression was evaluated in the kidney tissue of mice. Swertisn-hSGLT2 molecularly docked complex showed similar binding energy compared to the Canagliflozin-hSGLT2 complex. Swertisin inhibited glucose uptake and decreased expression of SGLT2 in HEK293 cells. Swertisin does not affect GLUT mediated glucose transport. Swertisin treated diabetic mice demonstrated remarkable improvement in overall glucose homeostasis. Reduced expression of SGLT2 was found in kidney tissue along with reduced PKC expression which is one of the key regulators of SGLT2. Our study explored SGLT2 as a selective target of swertisin for its swift glucose-lowering action which not only inhibits SGLT2 but also reduces its expression in diabetic condition. Thus, the potential property of swertisin as a glucose-lowering agent is remarkable which points towards the likelihood of a wider avenue of diabetes therapy.
