diaendoСахарный диабетDiabetes mellitus2072-03512072-0378Endocrinology research centre10.14341/DM12234diaendo-12234Research ArticleОригинальные исследованияOriginal StudiesАссоциация инсулинорезистентности и неалкогольной жировой болезни печениAssociation of insulin resistance and non-alcoholic fatty liver diseasehttps://orcid.org/0000-0002-5371-8708МишинаЕкатерина ЕвгеньевнаMishinaEkaterina E.

Аспирант, научный сотрудник

eLibrary SPIN: 2115-7697

117036, г. Москва, ул. Дмитрия Ульянова, д. 11

MD, PhD student, research associate

eLibrary SPIN: 2115-7697

11, Dm. Ulyanova street, Moscow, 117036

eka-mi@rambler.ruhttps://orcid.org/0000-0001-5825-3287МайоровАлександр ЮрьевичMayorovAlexander Y.

Доктор медицинских наукeLibrary SPIN: 4275-7779Москва

MD, PhD

eLibrary SPIN: 4275-7779

Moscow

education@endocrincentr.ruhttps://orcid.org/0000-0003-2346-1216БогомоловПавел ОлеговичBogomolovPavel O.

Кандидат медицинских наук

eLibrary SPIN: 7261-9960

Москва

MD, PhD

eLibrary SPIN: 7261-9960

Moscow

bpo73@list.ruhttps://orcid.org/0000-0001-7640-638XЛюсинаЕкатерина ОлеговнаLiusinaEkaterina O.

Кандидат медицинских наук, сстарший научный сотрудник

eLibrary SPIN: 1772-5678

Москва

MD, PhD, senior research associate

eLibrary SPIN: 1772-5678

Moscow

eka-lusina@yandex.ruhttps://orcid.org/0000-0002-5041-3466БуеверовАлексей ОлеговичBueverovAlexey O.

Доктор медицинских наук, ведущий научный сотрудник

eLibrary SPIN: 1299-0293

Москва

MD, PhD, leading research associate

eLibrary SPIN: 1299-0293

Moscow

 

bcl72@yandex.ruНациональный медицинский исследовательский центр эндокринологииРоссияEndocrinology Research CentreRussian FederationМосковский областной научно-исследовательский клинический институт имени М.Ф. ВладимирскогоRussian FederationMoscows regional Research Clinical institute n.a. M.F. VladimirskiyRussian FederationМосковский областной научно-исследовательский клинический институт имени М.Ф. Владимирского; Первый Московский государственный медицинский университет имени И.М. Сеченова (Сеченовский университет)Russian FederationMoscows regional Research Clinical institute n.a. M.F. Vladimirskiy; I.M. Sechenov First Moscow State Medical University (Sechenov University)Russian Federation202022092020235412423Copyright © Мишина Е.Е., Майоров А.Ю., Богомолов П.О., Люсина Е.О., Буеверов А.О., 20212021Мишина Е.Е., Майоров А.Ю., Богомолов П.О., Люсина Е.О., Буеверов А.О.Mishina E.E., Mayorov A.Y., Bogomolov P.O., Liusina E.O., Bueverov A.O.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.dia-endojournals.ru/jour/article/view/12234ОБОСНОВАНИЕ

ОБОСНОВАНИЕ. Количество пациентов с хроническими нарушениями обмена веществ, такими как ожирение, сахарный диабет 2 типа (СД2) и неалкогольная жировая болезнь печени (НАЖБП), растет с угрожающей скоростью во всем мире как в развитых, так и в развивающихся странах. В мире распространенность НАЖБП приближается к 25%. Среди пациентов с СД2 у 70–80% диагностируется НАЖБП. Инсулинорезистентность (ИР) признана одним из основных патогенетических факторов развития самого распространенного хронического заболевания печени — НАЖБП.

ЦЕЛЬ

ЦЕЛЬ. Данная поисковая работа направлена на определение вклада степени ИР в прогрессирование НАЖБП; сравнение золотого стандарта определения ИР (клэмп-тест) и по математической модели (HOMA-IR).

МЕТОДЫ

МЕТОДЫ. Проведено наблюдательное одномоментное открытое сравнительное исследование по принципу «случай-контроль». Объектами исследования стали пациенты с избыточной массой тела и ожирением, у которых ранее не было диагностировано нарушений углеводного обмена, без вторичных причин накопления жира в печени. В процессе обследования были проведены клинико-лабораторные исследования, получены индексы ИР (М-индекс, HOMA-IR индекс), поставлен диагноз нарушения углеводного обмена (или его отсутствия), проведена биопсия печени, верифицированы морфологический и клинический диагнозы.

РЕЗУЛЬТАТЫ

РЕЗУЛЬТАТЫ. В анализ включены сведения о 60 пациентах, они разделены на 3 группы: без НАЖБП (7 человек), со стеатозом (18 человек), с неалкогольным стеатогепатитом (НАСГ) (35 человек). Группы были сопоставимы по возрасту, полу, индексу массы тела (ИМТ), гликированному гемоглобину. При оценке степени ИР методом гиперинсулинемического эугликемического клэмп-теста у 19 человек выявлена тяжелая степень ИР, у 28 человек — средняя степень, у 8 — легкая степень, у 5 человек не выявлено ИР. В трех исследуемых группах медиана ИР соответствовала средней степени и значимо не различалась. При сравнении золотого стандарта определения ИР и с помощью математической модели (HOMA-IR) выявлена обратная значимая корреляция (p=0,0001).

ЗАКЛЮЧЕНИЕ

ЗАКЛЮЧЕНИЕ. В ходе проведенного исследования не выявлено корреляционной взаимосвязи между степенью ИР и степенью выраженности НАЖБП. Данный результат свидетельствует о наличии других патогенетических факторов, влияющих на прогрессирование НАЖБП.

BACKGROUND

BACKGROUND: The number of patients with chronic metabolic disorders such as obesity, type 2 diabetes mellitus (T2D) and non-alcoholic fatty liver disease (NAFLD) is growing at an alarming rate worldwide in both developed and developing countries. In the world, the prevalence of NAFLD is approaching 25%. Among patients with T2D, 70–80% are diagnosed with NAFLD. Insulin resistance (IR) is recognized as one of the main pathogenetic factors in the development of the most common chronic liver disease — NAFLD.

AIM

AIM: Our search work was aimed at determining the contribution of the degree of IR to the progression of NAFLD; compare the gold standard for the determination of IR (clamp) and the mathematical model (HOMA-IR).

METHODS

METHODS: An observational one-stage open comparative study was conducted on the basis of the case-control principle. The objects of the study were overweight and obese patients who had not previously been diagnosed carbohydrate metabolism disorders, without secondary causes of fat accumulation in the liver. During the examination, clinical and laboratory studies were carried out, IR indices (M-index, HOMA-IR index) were obtained, a diagnosis of carbohydrate metabolism disturbance (or its absence) was made, a liver biopsy was made, morphological and clinical diagnoses were made.

RESULTS

RESULTS: The analysis included information about 60 patients, they are divided into 3 groups: without NAFLD (7 people), with steatosis (18 people), with non-alcoholic steatohepatitis (NASH) (35 people), groups are comparable by age, gender, and body mass index (BMI), glycated hemoglobin. When assessing the degree of IR using the hyperinsulinemic euglycemic clamp test, 19 showed a severe degree of IR, 28 had a moderate degree, 8 had a mild degree, and 5 had no IR. In the three studied groups, the median IR corresponded to an average degree and did not significantly differ. When comparing the gold standard for determining IR and the mathematical model (HOMA-IR) in the studied groups, an negative significant correlation was revealed (p = 0,0001).

CONCLUSIONS

CONCLUSIONS: In the course of our study, no correlation was found between the degree of IR and the severity of NAFLD. This result allows us to think about other pathogenetic factors that affect the progression of NAFLD.

инсулинорезистентностьнеалкогольная жировая болезнь печенисахарный диабетнеалкогольный стеатогепатитожирение.insulin resistancenonalcoholic fatty liver diseasediabetes mellitusnonalcoholic steatohepatitisobesity.Работа выполнена при поддержке Российского научного фонда (проект № 17-15-01475 «Фундаментальные основы влияния инсулинорезистентности на развитие неалкогольной жировой болезни печени у пациентов с нарушениями углеводного обмена»).ReferencesMarchesini G, Day CP, Dufour JF, et al. EASL-EASD-EASO Clinical Practice Guidelines for the management of nonalcoholic fatty liver disease. J Hepatol. 2016;64(6):1388-1402. https://doi.org/10.1016/j.jhep.2015.11.004Marchesini G, Day CP, Dufour JF, et al. EASL-EASD-EASO Clinical Practice Guidelines for the management of nonalcoholic fatty liver disease. J Hepatol. 2016;64(6):1388-1402. https://doi.org/10.1016/j.jhep.2015.11.004Friedman SL, Neuschwander-Tetri BA, Rinella M, Sanyal AJ. Mechanisms of NAFLD development and therapeutic strategies. Nat Med. 2018;24(7):908-922. https://doi.org/10.1038/s41591-018-0104-9Friedman SL, Neuschwander-Tetri BA, Rinella M, Sanyal AJ. Mechanisms of NAFLD development and therapeutic strategies. Nat Med. 2018;24(7):908-922. https://doi.org/10.1038/s41591-018-0104-9International Diabetes Federation. IDF Diabetes Atlas. 2019. Available from: https://www.diabetesatlas.org/data/en/country/94/id.htmlInternational Diabetes Federation. IDF Diabetes Atlas. 2019. Available from: https://www.diabetesatlas.org/data/en/country/94/id.htmlАлгоритмы специализированной медицинской помощи больным сахарным диабетом / Под редакцией И.И. Дедова, М.В. Шестаковой, А.Ю. Майорова. 9-й выпуск (дополненный) // Сахарный диабет. — 2019. — Т. 22. — №1S1. — С. 1-144. https://doi.org/10.14341/DM221S1Standards of specialized diabetes care. Edited by Dedov I.I., Shestakova M.V., Mayorov A.Yu. 9th edition. Diabetes mellitus. 2019;22(1S1):1-144. (In Russ.). https://doi.org/10.14341/DM221S1Megyesi C, Samols E, Marks V. Glucose tolerance and diabetes in chronic liver disease. Lancet. 1967;2(7525):1051-1056.Megyesi C, Samols E, Marks V. Glucose tolerance and diabetes in chronic liver disease. Lancet. 1967;2(7525):1051-1056.Sanyal AJ, Campbell–Sargent C, Mirshahi F, et al. Nonalcoholic steatohepatitis: Association of insulin resistance and mitochondrial abnormalities. Gastroenterology. 2001;120(5):1183-1192. https://doi.org/10.1053/gast.2001.23256Sanyal AJ, Campbell–Sargent C, Mirshahi F, et al. Nonalcoholic steatohepatitis: Association of insulin resistance and mitochondrial abnormalities. Gastroenterology. 2001;120(5):1183-1192. https://doi.org/10.1053/gast.2001.23256Marchesini G, Brizi M, Bianchi G, et al. Nonalcoholic Fatty Liver Disease: A Feature of the Metabolic Syndrome. Diabetes. 2001;50(8):1844-1850. https://doi.org/10.2337/diabetes.50.8.1844Marchesini G, Brizi M, Bianchi G, et al. Nonalcoholic Fatty Liver Disease: A Feature of the Metabolic Syndrome. Diabetes. 2001;50(8):1844-1850. https://doi.org/10.2337/diabetes.50.8.1844George J, Liddle C, Samarasinghe D, et al. NASH and insulin resistance: Insulin hypersecretion and specific association with the insulin resistance syndrome. Hepatology. 2002;35(2):373-379 https://doi.org/10.1053/jhep.2002.30692.George J, Liddle C, Samarasinghe D, et al. NASH and insulin resistance: Insulin hypersecretion and specific association with the insulin resistance syndrome. Hepatology. 2002;35(2):373-379 https://doi.org/10.1053/jhep.2002.30692.Marchesini G, Brizi M, Morselli-Labate AM, et al. Association of nonalcoholic fatty liver disease with insulin resistance. Am J Med. 1999;107(5):450-455. https://doi.org/10.1016/S0002-9343(99)00271-5Marchesini G, Brizi M, Morselli-Labate AM, et al. Association of nonalcoholic fatty liver disease with insulin resistance. Am J Med. 1999;107(5):450-455. https://doi.org/10.1016/S0002-9343(99)00271-5Cцmert B, Mas MR, Erdem H, et al. Insulin resistance in non-alcoholic steatohepatitis. Dig Liver Dis. 2001;33(4):353-358.Cцmert B, Mas MR, Erdem H, et al. Insulin resistance in non-alcoholic steatohepatitis. Dig Liver Dis. 2001;33(4):353-358.Barrows BR, Parks EJ. Contributions of Different Fatty Acid Sources to Very Low-Density Lipoprotein-Triacylglycerol in the Fasted and Fed States. J Clin Endocrinol Metab. 2006;91(4):1446-1452. https://doi.org/10.1210/jc.2005-1709Barrows BR, Parks EJ. Contributions of Different Fatty Acid Sources to Very Low-Density Lipoprotein-Triacylglycerol in the Fasted and Fed States. J Clin Endocrinol Metab. 2006;91(4):1446-1452. https://doi.org/10.1210/jc.2005-1709Donnelly KL, Smith CI, Schwarzenberg SJ, et al. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J Clin Invest. 2005;115(5):1343-1351. https://doi.org/10.1172/JCI23621Donnelly KL, Smith CI, Schwarzenberg SJ, et al. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J Clin Invest. 2005;115(5):1343-1351. https://doi.org/10.1172/JCI23621Цветкова М.В., Хирманов В.Н., Зыбина Н.Н. Роль неэтерифицированных жирных кислот в патогенезе сердечнососудистых заболеваний // Артериальная гипертензия. — 2010. — Т. 16. — №1. — С. 93-103. https://doi.org/10.18705/1607-419X-2010-16-1-93-103Tsvetkova MV, Khirmanov VN, Zybina NN. The role of nonesterified fatty acids in pathogenesis of cardiovascular diseases. Arterial Hypertension. 2010;16(1):93-103. (In Russ.). https://doi.org/10.18705/1607-419X-2010-16-1-93-103Lomonaco R, Ortiz-Lopez C, Orsak B, et al. Effect of adipose tissue insulin resistance on metabolic parameters and liver histology in obese patients with nonalcoholic fatty liver disease. Hepatology. 2012;55(5):1389-1397. https://doi.org/10.1002/hep.25539Lomonaco R, Ortiz-Lopez C, Orsak B, et al. Effect of adipose tissue insulin resistance on metabolic parameters and liver histology in obese patients with nonalcoholic fatty liver disease. Hepatology. 2012;55(5):1389-1397. https://doi.org/10.1002/hep.25539Armstrong MJ, Hazlehurst JM, Hull D, et al. Abdominal subcutaneous adipose tissue insulin resistance and lipolysis in patients with nonalcoholic steatohepatitis. Diabetes Obes Metab. 2014;16(7):651-660. https://doi.org/10.1111/dom.12272Armstrong MJ, Hazlehurst JM, Hull D, et al. Abdominal subcutaneous adipose tissue insulin resistance and lipolysis in patients with nonalcoholic steatohepatitis. Diabetes Obes Metab. 2014;16(7):651-660. https://doi.org/10.1111/dom.12272Kempinska-Podhorodecka A, Wunsch E, Milkiewicz P, et al. The Association between SOCS1−1656G>A Polymorphism, Insulin Resistance and Obesity in Nonalcoholic Fatty Liver Disease (NAFLD) Patients. J Clin Med. 2019;8(11):1912. https://doi.org/10.3390/jcm8111912Kempinska-Podhorodecka A, Wunsch E, Milkiewicz P, et al. The Association between SOCS1−1656G>A Polymorphism, Insulin Resistance and Obesity in Nonalcoholic Fatty Liver Disease (NAFLD) Patients. J Clin Med. 2019;8(11):1912. https://doi.org/10.3390/jcm8111912Loomba R, Schork N, Chen C-H, et al. Heritability of Hepatic Fibrosis and Steatosis Based on a Prospective Twin Study. Gastroenterology. 2015;149(7):1784-1793. https://doi.org/10.1053/j.gastro.2015.08.011Loomba R, Schork N, Chen C-H, et al. Heritability of Hepatic Fibrosis and Steatosis Based on a Prospective Twin Study. Gastroenterology. 2015;149(7):1784-1793. https://doi.org/10.1053/j.gastro.2015.08.011Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2018;67(1):328-357. https://doi.org/10.1002/hep.29367Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2018;67(1):328-357. https://doi.org/10.1002/hep.29367IDF W. Definition and diagnosis of diabetes mellitus and intermediate hyperglycaemia Report of a WHO/IDF consultation. 2006. 50 р.IDF W. Definition and diagnosis of diabetes mellitus and intermediate hyperglycaemia Report of a WHO/IDF consultation. 2006. 50 р.Майоров А.Ю. Состояние инсулинорезистентности в эволюции сахарного диабета 2 типа: Дис. … докт. мед. наук. — Москва; 2009.Mayorov AYu. Sostoyanie insulinoresistentnosti v evolyucii saharnogo diabeta 2 tipa. [dissertation]. Moscow; 2009. (In Russ.).Matthews DR, Hosker JP, Rudenski AS, et al. Homeostasis model assessment: insulin resistance and в-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985;28(7):412-419. https://doi.org/10.1007/BF00280883Matthews DR, Hosker JP, Rudenski AS, et al. Homeostasis model assessment: insulin resistance and в-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985;28(7):412-419. https://doi.org/10.1007/BF00280883Gayoso-Diz P, Otero-Gonzбlez A, Rodriguez-Alvarez MX, et al. Insulin resistance (HOMA-IR) cut-off values and the metabolic syndrome in a general adult population: effect of gender and age: EPIRCE cross-sectional study. BMC Endocr Disord. 2013;13(1):47. https://doi.org/10.1186/1472-6823-13-47Gayoso-Diz P, Otero-Gonzбlez A, Rodriguez-Alvarez MX, et al. Insulin resistance (HOMA-IR) cut-off values and the metabolic syndrome in a general adult population: effect of gender and age: EPIRCE cross-sectional study. BMC Endocr Disord. 2013;13(1):47. https://doi.org/10.1186/1472-6823-13-47Ивашкин В.Т., Маевская М.В., Павлов Ч.С., и др. Клинические рекомендации по диагностике и лечению неалкогольной жировой болезни печени Российского общества по изучению печени и Российской гастроэнтерологической ассоциации // Российский журнал гастроэнтерологии, гепатологии, колопроктологии. — 2016. — Т. 26. — №2. — С. 4-42. https://doi.org/10.22416/1382-4376-2016-26-2-24-42Ivashkin VT, Mayevskaya MV,Pavlov ChS, et al. Diagnostics and treatment of non-alcoholic fatty liver disease: clinical guidelines of the Russian Scientifi Liver Society and the Russian gastroenterological association. Russian Journal of Gastroenterology, Hepatology, Coloproctology. 2016;26(2):4-42 (In Russ.). https://doi.org/10.22416/1382-4376-2016-26-2-24-42Bugianesi E, Gastaldelli A, Vanni E, et al. Insulin resistance in non-diabetic patients with non-alcoholic fatty liver disease: sites and mechanisms. Diabetologia. 2005;48(4):634-642. https://doi.org/10.1007/s00125-005-1682-xBugianesi E, Gastaldelli A, Vanni E, et al. Insulin resistance in non-diabetic patients with non-alcoholic fatty liver disease: sites and mechanisms. Diabetologia. 2005;48(4):634-642. https://doi.org/10.1007/s00125-005-1682-xGastaldelli A, Cusi K, Pettiti M, et al. Relationship Between Hepatic/ Visceral Fat and Hepatic Insulin Resistance in Nondiabetic and Type 2 Diabetic Subjects. Gastroenterology. 2007;133(2):496-506. https://doi.org/10.1053/j.gastro.2007.04.068Gastaldelli A, Cusi K, Pettiti M, et al. Relationship Between Hepatic/ Visceral Fat and Hepatic Insulin Resistance in Nondiabetic and Type 2 Diabetic Subjects. Gastroenterology. 2007;133(2):496-506. https://doi.org/10.1053/j.gastro.2007.04.068Goodpaster BH, Leland Thaete F, Simoneau J-A, Kelley DE. Subcutaneous Abdominal Fat and Thigh Muscle Composition Predict Insulin Sensitivity Independently of Visceral Fat. Diabetes. 1997;46(10):1579-1585. https://doi.org/10.2337/diacare.46.10.1579Goodpaster BH, Leland Thaete F, Simoneau J-A, Kelley DE. Subcutaneous Abdominal Fat and Thigh Muscle Composition Predict Insulin Sensitivity Independently of Visceral Fat. Diabetes. 1997;46(10):1579-1585. https://doi.org/10.2337/diacare.46.10.1579Gastaldelli A, Cusi K. From NASH to diabetes and from diabetes to NASH: Mechanisms and treatment options. JHEP Reports. 2019;1(4):312-328. https://doi.org/10.1016/j.jhepr.2019.07.002Gastaldelli A, Cusi K. From NASH to diabetes and from diabetes to NASH: Mechanisms and treatment options. JHEP Reports. 2019;1(4):312-328. https://doi.org/10.1016/j.jhepr.2019.07.002Cersosimo E, Gastaldelli A, Cervera A, et al. Effect of Exenatide on Splanchnic and Peripheral Glucose Metabolism in Type 2 Diabetic Subjects. J Clin Endocrinol Metab. 2011;96(6):1763-1770. https://doi.org/10.1210/jc.2010-2146Cersosimo E, Gastaldelli A, Cervera A, et al. Effect of Exenatide on Splanchnic and Peripheral Glucose Metabolism in Type 2 Diabetic Subjects. J Clin Endocrinol Metab. 2011;96(6):1763-1770. https://doi.org/10.1210/jc.2010-2146Armstrong MJ, Hull D, Guo K, et al. Glucagon-like peptide 1 decreases lipotoxicity in non-alcoholic steatohepatitis. J Hepatol. 2016;64(2):399-408. https://doi.org/10.1016/j.jhep.2015.08.038Armstrong MJ, Hull D, Guo K, et al. Glucagon-like peptide 1 decreases lipotoxicity in non-alcoholic steatohepatitis. J Hepatol. 2016;64(2):399-408. https://doi.org/10.1016/j.jhep.2015.08.038Armstrong MJ, Gaunt P, Aithal GP, et al. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebocontrolled phase 2 study. Lancet. 2016;387(10019):679-690. https://doi.org/10.1016/S0140-6736(15)00803-XArmstrong MJ, Gaunt P, Aithal GP, et al. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebocontrolled phase 2 study. Lancet. 2016;387(10019):679-690. https://doi.org/10.1016/S0140-6736(15)00803-XMacauley M, Hollingsworth KG, Smith FE, et al. Effect of Vildagliptin on Hepatic Steatosis. J Clin Endocrinol Metab. 2015;100(4):1578-1585. https://doi.org/10.1210/jc.2014-3794Macauley M, Hollingsworth KG, Smith FE, et al. Effect of Vildagliptin on Hepatic Steatosis. J Clin Endocrinol Metab. 2015;100(4):1578-1585. https://doi.org/10.1210/jc.2014-3794Joy TR, McKenzie CA, Tirona RG, et al. Sitagliptin in patients with non-alcoholic steatohepatitis: A randomized, placebocontrolled trial. World J Gastroenterol. 2017;23(1):141. https://doi.org/10.3748/wjg.v23.i1.141Joy TR, McKenzie CA, Tirona RG, et al. Sitagliptin in patients with non-alcoholic steatohepatitis: A randomized, placebocontrolled trial. World J Gastroenterol. 2017;23(1):141. https://doi.org/10.3748/wjg.v23.i1.141Alam S, Ghosh J, Mustafa G, et al. Effect of sitagliptin on histological activity and fibrosis of non-alcoholic steatohepatitis: A 1-year randomized control trial. Hepat Med. 2018;(10):23-31. https://doi.org/10.2147/HMER.S158053Alam S, Ghosh J, Mustafa G, et al. Effect of sitagliptin on histological activity and fibrosis of non-alcoholic steatohepatitis: A 1-year randomized control trial. Hepat Med. 2018;(10):23-31. https://doi.org/10.2147/HMER.S158053Kuchay MS, Krishan S, Mishra SK, et al. Effect of Empagliflozin on Liver Fat in Patients With Type 2 Diabetes and Nonalcoholic Fatty Liver Disease: A Randomized Controlled Trial (E-LIFT Trial). Diabetes Care. 2018;41(8):1801-1808. https://doi.org/10.2337/dc18-0165Kuchay MS, Krishan S, Mishra SK, et al. Effect of Empagliflozin on Liver Fat in Patients With Type 2 Diabetes and Nonalcoholic Fatty Liver Disease: A Randomized Controlled Trial (E-LIFT Trial). Diabetes Care. 2018;41(8):1801-1808. https://doi.org/10.2337/dc18-0165Bajaj HS, Brown RE, Bhullar L, et al. SGLT2 inhibitors and incretin agents: Associations with alanine aminotransferase activity in type 2 diabetes. Diabetes Metab. 2018;44(6):493-499. https://doi.org/10.1016/j.diabet.2018.08.001Bajaj HS, Brown RE, Bhullar L, et al. SGLT2 inhibitors and incretin agents: Associations with alanine aminotransferase activity in type 2 diabetes. Diabetes Metab. 2018;44(6):493-499. https://doi.org/10.1016/j.diabet.2018.08.001Seko Y, Sumida Y, Sasaki K, et al. Effects of canagliflozin, an SGLT2 inhibitor, on hepatic function in Japanese patients with type 2 diabetes mellitus: pooled and subgroup analyses of clinical trials. J Gastroenterol. 2018;53(1):140-151. https://doi.org/10.1007/s00535-017-1364-8Seko Y, Sumida Y, Sasaki K, et al. Effects of canagliflozin, an SGLT2 inhibitor, on hepatic function in Japanese patients with type 2 diabetes mellitus: pooled and subgroup analyses of clinical trials. J Gastroenterol. 2018;53(1):140-151. https://doi.org/10.1007/s00535-017-1364-8Seko Y, Nishikawa T, Umemura A, et al. Efficacy and safety of canagliflozin in type 2 diabetes mellitus patients with biopsy-proven nonalcoholic steatohepatitis classified as stage 1–3 fibrosis. Diabetes Metab Syndr Obes. 2018;11:835-843. https://doi.org/10.2147/DMSO.S184767.Seko Y, Nishikawa T, Umemura A, et al. Efficacy and safety of canagliflozin in type 2 diabetes mellitus patients with biopsy-proven nonalcoholic steatohepatitis classified as stage 1–3 fibrosis. Diabetes Metab Syndr Obes. 2018;11:835-843. https://doi.org/10.2147/DMSO.S184767.Lai L-L, Vethakkan SR, Nik Mustapha NR, , et al. Empagliflozin for the Treatment of Nonalcoholic Steatohepatitis in Patients with Type 2 Diabetes Mellitus. Dig Dis Sci. 2020;65(2):623-631. https://doi.org/10.1007/s10620-019-5477-1Lai L-L, Vethakkan SR, Nik Mustapha NR, , et al. Empagliflozin for the Treatment of Nonalcoholic Steatohepatitis in Patients with Type 2 Diabetes Mellitus. Dig Dis Sci. 2020;65(2):623-631. https://doi.org/10.1007/s10620-019-5477-1Belfort R, Harrison SA, Brown K, et al. A Placebo-Controlled Trial of Pioglitazone in Subjects with Nonalcoholic Steatohepatitis. N Engl J Med. 2006;355(22):2297-2307. https://doi.org/10.1056/NEJMoa060326Belfort R, Harrison SA, Brown K, et al. A Placebo-Controlled Trial of Pioglitazone in Subjects with Nonalcoholic Steatohepatitis. N Engl J Med. 2006;355(22):2297-2307. https://doi.org/10.1056/NEJMoa060326Aithal GP, Thomas JA, Kaye P V., et al. Randomized, Placebo-Controlled Trial of Pioglitazone in Nondiabetic Subjects With Nonalcoholic Steatohepatitis. Gastroenterology. 2008;135(4):1176-1184. https://doi.org/10.1053/j.gastro.2008.06.047Aithal GP, Thomas JA, Kaye P V., et al. Randomized, Placebo-Controlled Trial of Pioglitazone in Nondiabetic Subjects With Nonalcoholic Steatohepatitis. Gastroenterology. 2008;135(4):1176-1184. https://doi.org/10.1053/j.gastro.2008.06.047Sanyal AJ, Chalasani N, Kowdley K V, et al. Pioglitazone, Vitamin E, or Placebo for Nonalcoholic Steatohepatitis. N Engl J Med. 2010;362(18):1675-1685. https://doi.org/10.1056/NEJMoa0907929Sanyal AJ, Chalasani N, Kowdley K V, et al. Pioglitazone, Vitamin E, or Placebo for Nonalcoholic Steatohepatitis. N Engl J Med. 2010;362(18):1675-1685. https://doi.org/10.1056/NEJMoa0907929Cusi K, Orsak B, Bril F, et al. Long-Term Pioglitazone Treatment for Patients With Nonalcoholic Steatohepatitis and Prediabetes or Type 2 Diabetes Mellitus. Ann Intern Med. 2016;165(5):305. https://doi.org/10.7326/M15-1774Cusi K, Orsak B, Bril F, et al. Long-Term Pioglitazone Treatment for Patients With Nonalcoholic Steatohepatitis and Prediabetes or Type 2 Diabetes Mellitus. Ann Intern Med. 2016;165(5):305. https://doi.org/10.7326/M15-1774Bril F, Kalavalapalli S, Clark VC, et al. Response to Pioglitazone in Patients With Nonalcoholic Steatohepatitis With vs Without Type 2 Diabetes. Clin Gastroenterol Hepatol. 2018;16(4):558-566.e2. https://doi.org/10.1016/j.cgh.2017.12.001Bril F, Kalavalapalli S, Clark VC, et al. Response to Pioglitazone in Patients With Nonalcoholic Steatohepatitis With vs Without Type 2 Diabetes. Clin Gastroenterol Hepatol. 2018;16(4):558-566.e2. https://doi.org/10.1016/j.cgh.2017.12.001Musso G, Cassader M, Paschetta E, Gambino R. Thiazolidinediones and Advanced Liver Fibrosis in Nonalcoholic Steatohepatitis. JAMA Intern Med. 2017;177(5):633. https://doi.org/10.1001/jamainternmed.2016.9607Musso G, Cassader M, Paschetta E, Gambino R. Thiazolidinediones and Advanced Liver Fibrosis in Nonalcoholic Steatohepatitis. JAMA Intern Med. 2017;177(5):633. https://doi.org/10.1001/jamainternmed.2016.9607Bril F, Lomonaco R, Orsak B, et al. Relationship between disease severity, hyperinsulinemia, and impaired insulin clearance in patients with nonalcoholic steatohepatitis. Hepatology. 2014;59(6):2178-2187. https://doi.org/10.1002/hep.26988Bril F, Lomonaco R, Orsak B, et al. Relationship between disease severity, hyperinsulinemia, and impaired insulin clearance in patients with nonalcoholic steatohepatitis. Hepatology. 2014;59(6):2178-2187. https://doi.org/10.1002/hep.26988Weston SR, Leyden W, Murphy R, et al. Racial and ethnic distribution of nonalcoholic fatty liver in persons with newly diagnosed chronic liver disease. Hepatology. 2005;41(2):372-379. https://doi.org/10.1002/hep.20554Weston SR, Leyden W, Murphy R, et al. Racial and ethnic distribution of nonalcoholic fatty liver in persons with newly diagnosed chronic liver disease. Hepatology. 2005;41(2):372-379. https://doi.org/10.1002/hep.20554Sreekumar R. Hepatic gene expression in histologically progressive nonalcoholic steatohepatitis. Hepatology. 2003;38(1):244-251 https://doi.org/10.1053/jhep.2003.50290Sreekumar R. Hepatic gene expression in histologically progressive nonalcoholic steatohepatitis. Hepatology. 2003;38(1):244-251 ttps://doi.org/10.1053/jhep.2003.50290

The authors declare that there are no conflicts of interest present.