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Dual SGLT1/SGLT2 Inhibitor Phlorizin Ameliorates Non-Alcoholic Fatty Liver Disease and Hepatic Glucose Production in Type 2 Diabetic Mice

Authors David-Silva A, Esteves JV, Morais MRPT, Freitas HS, Zorn TM, Correa-Giannella ML, Machado UF

Received 16 December 2019

Accepted for publication 29 February 2020

Published 17 March 2020 Volume 2020:13 Pages 739—751

DOI https://doi.org/10.2147/DMSO.S242282

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 4

Editor who approved publication: Dr Antonio Brunetti


Aline David-Silva,1 João Victor Esteves,1 Mychel Raony PT Morais,2 Helayne Soares Freitas,1 Telma Maria Zorn,2 Maria Lucia Correa-Giannella,3 Ubiratan Fabres Machado1

1Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil; 2Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil; 3Laboratório de Carboidratos e Radioimunoensaio, LIM-18, Hospital das Clinicas HCFMUSP, Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo, Brazil

Correspondence: Ubiratan Fabres Machado
Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, Av. Prof. Lineu Prestes 1524, São Paulo, SP 05508-900, Brazil
Tel +55 11 30917494
Email ubiratan@icb.usp.br

Purpose: NAFLD is a hepatic component of type 2 diabetes mellitus (T2D), in which impaired hepatic glucose production plays an important role. Inhibitors of sodium glucose transporter 2 (SGLT2) reduce glycemia and exert beneficial effects on diabetic complications. Recently, dual SGLT1/2 inhibition has been proposed to be more effective in reducing glycemia. We hypothesized that improving hepatic glucose metabolism induced by SGLT1/2 inhibition could be accompanied by beneficial effects on NAFLD progression.
Methods: Glycemic homeostasis, hepatic glucose production and NAFLD features were investigated in obese T2D mice, treated with SGLT1/2 inhibitor phlorizin for 1 week.
Results: T2D increased glycemia; insulinemia; hepatic expression of phosphoenolpyruvate carboxykinase (PEPCK), glucose-6-phosphatase (G6Pase) and glucose transporter 2 (Slc2a2 gene); hepatocyte nuclear factors 1A/4A/3B-binding activity in Slc2a2; endogenous glucose production; liver weight, plasma transaminase concentration as well as hepatic inflammation markers, and induced histological signals of non-alcoholic steatohepatitis (NASH, according to NASH-CRN Pathology Committee System). Phlorizin treatment restored all these parameters (mean NASH score reduced from 5.25 to 2.75 P< 0.001); however, plasma transaminase concentration was partially reverted and some hepatic inflammation markers remained unaltered.
Conclusion: NAFLD accompanies altered hepatic glucose metabolism in T2D mice and that greatly ameliorated through short-term treatment with the dual SGLT1/2 inhibitor. This suggests that altered hepatic glucose metabolism participates in T2D-related NAFLD and highlights the pharmacological inhibition of SGLTs as a useful approach not only for controlling glycemia but also for mitigating development and/or progression of NAFLD.

Keywords: GLUT2, PEPCK, G6Pase, phlorizin, NASH

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