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

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, S&atil...

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Autores principales:	David-Silva A, Esteves JV, Morais MRPT, Freitas HS, Zorn TM, Correa-Giannella ML, Machado UF
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2020
Materias:	glut2 pepck g6pase phlorizin nash. Specialties of internal medicine RC581-951
Acceso en línea:	https://doaj.org/article/af11b8b17fb8447cb14954ee70da7c4b
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spelling	oai:doaj.org-article:af11b8b17fb8447cb14954ee70da7c4b2021-12-02T15:20:16ZDual SGLT1/SGLT2 Inhibitor Phlorizin Ameliorates Non-Alcoholic Fatty Liver Disease and Hepatic Glucose Production in Type 2 Diabetic Mice1178-7007https://doaj.org/article/af11b8b17fb8447cb14954ee70da7c4b2020-03-01T00:00:00Zhttps://www.dovepress.com/dual-sglt1sglt2-inhibitor-phlorizin-ameliorates-non-alcoholic-fatty-li-peer-reviewed-article-DMSOhttps://doaj.org/toc/1178-7007Aline 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, BrazilCorrespondence: Ubiratan Fabres MachadoDepartment of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, Av. Prof. Lineu Prestes 1524, São Paulo, SP 05508-900, BrazilTel +55 11 30917494Email ubiratan@icb.usp.brPurpose: 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, NASHDavid-Silva AEsteves JVMorais MRPTFreitas HSZorn TMCorrea-Giannella MLMachado UFDove Medical Pressarticleglut2pepckg6pasephlorizinnash.Specialties of internal medicineRC581-951ENDiabetes, Metabolic Syndrome and Obesity: Targets and Therapy, Vol Volume 13, Pp 739-751 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	glut2 pepck g6pase phlorizin nash. Specialties of internal medicine RC581-951
spellingShingle	glut2 pepck g6pase phlorizin nash. Specialties of internal medicine RC581-951 David-Silva A Esteves JV Morais MRPT Freitas HS Zorn TM Correa-Giannella ML Machado UF Dual SGLT1/SGLT2 Inhibitor Phlorizin Ameliorates Non-Alcoholic Fatty Liver Disease and Hepatic Glucose Production in Type 2 Diabetic Mice
description	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, BrazilCorrespondence: Ubiratan Fabres MachadoDepartment of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, Av. Prof. Lineu Prestes 1524, São Paulo, SP 05508-900, BrazilTel +55 11 30917494Email ubiratan@icb.usp.brPurpose: 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
format	article
author	David-Silva A Esteves JV Morais MRPT Freitas HS Zorn TM Correa-Giannella ML Machado UF
author_facet	David-Silva A Esteves JV Morais MRPT Freitas HS Zorn TM Correa-Giannella ML Machado UF
author_sort	David-Silva A
title	Dual SGLT1/SGLT2 Inhibitor Phlorizin Ameliorates Non-Alcoholic Fatty Liver Disease and Hepatic Glucose Production in Type 2 Diabetic Mice
title_short	Dual SGLT1/SGLT2 Inhibitor Phlorizin Ameliorates Non-Alcoholic Fatty Liver Disease and Hepatic Glucose Production in Type 2 Diabetic Mice
title_full	Dual SGLT1/SGLT2 Inhibitor Phlorizin Ameliorates Non-Alcoholic Fatty Liver Disease and Hepatic Glucose Production in Type 2 Diabetic Mice
title_fullStr	Dual SGLT1/SGLT2 Inhibitor Phlorizin Ameliorates Non-Alcoholic Fatty Liver Disease and Hepatic Glucose Production in Type 2 Diabetic Mice
title_full_unstemmed	Dual SGLT1/SGLT2 Inhibitor Phlorizin Ameliorates Non-Alcoholic Fatty Liver Disease and Hepatic Glucose Production in Type 2 Diabetic Mice
title_sort	dual sglt1/sglt2 inhibitor phlorizin ameliorates non-alcoholic fatty liver disease and hepatic glucose production in type 2 diabetic mice
publisher	Dove Medical Press
publishDate	2020
url	https://doaj.org/article/af11b8b17fb8447cb14954ee70da7c4b
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Dual SGLT1/SGLT2 Inhibitor Phlorizin Ameliorates Non-Alcoholic Fatty Liver Disease and Hepatic Glucose Production in Type 2 Diabetic Mice

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