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

Autor(es)

David-Silva, Aline ^[1] ; Esteves, Joao Victor ^[1] ; Morais, Mychel Raony P. T. ^[2] ; Freitas, Helayne Soares ^[1] ; Zorn, Telma Maria ^[2] ; Correa-Giannella, Maria Lucia ^[3] ; Machado, Ubiratan Fabres ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Inst Biomed Sci, Dept Physiol & Biophys, Av Prof Lineu Prestes 1524, BR-05508900 Sao Paulo, SP - Brazil

^[2] Univ Sao Paulo, Inst Biomed Sci, Dept Cell & Dev Biol, Sao Paulo - Brazil

^[3] Univ Sao Paulo, Hosp Clin HCFMUSP, Lab Carboidratos & Radioimunoensaio, LIM 18, Fac Med, Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: DIABETES METABOLIC SYNDROME AND OBESITY-TARGETS AND THERAPY; v. 13, p. 739-751, 2020.
• Citações Web of Science: 0

Resumo

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 (Sle2a2 gene); hepatocyte nuclear factors 1A/4A/3B-binding activity in Sle2a2; 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. (AU)

• Processo FAPESP: 16/15603-0 - Desvendando mecanismos envolvidos no controle glicêmico e nas complicações crônicas do Diabetes mellitus: contribuições à saúde humana
• Beneficiário: Ubiratan Fabres Machado
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 11/09463-8 - Regulação transcricional do gene slc2a2 em fígado de animais com esteato-hepatite não alcoólica.
• Beneficiário: Aline David Silva
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 17/19449-9 - Regulação epigenética, mediada por microRNAs, da proteína GLUT4 (gene Slc2a4) em músculo esquelético de camundongos portadores de diabetes mellitus tipo 2
• Beneficiário: João Victor Del Conti Esteves
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado