diaendoСахарный диабетDiabetes mellitus2072-03512072-0378Endocrinology research centre10.14341/DM9372diaendo-9372Research ArticleВопросы патогенезаPathogenesisНеалкогольная жировая болезнь печени: причина или следствие инсулинорезистентности?Nonalcoholic fatty liver disease: cause or consequence of insulin resistance?https://orcid.org/0000-0002-5371-8708МишинаЕкатерина ЕвгеньевнаMishinaEkaterina E.

аспирант, научный сотрудник

MD, PhD student

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

д.м.н., заведующий отделом прогнозирования и инноваций диабета

MD, PhD

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

руководитель отдела гепатологии

MD, PhD

bpo73@list.ruhttps://orcid.org/0000-0002-1292-4409МациевичМария ВладиславовнаMatsievichMaria V.

старший научный сотрудник

MD, PhD

macievich@gmail.comhttps://orcid.org/0000-0003-4864-1483КокинаКсения ЮрьевнаKokinaKsenia Y.

научный сотрудник

MD

sucliks@gmail.comhttps://orcid.org/0000-0002-8664-6341БоголюбоваАполлинария ВасильевнаBogolyubovaApollinariya V.

младший научный сотрудник

junior staff scientist

apollinariya.bogolyubova@gmail.com<p>ФГБУ Национальный медицинский исследовательский центр эндокринологии Минздрава России</p>Россия<p>Endocrinology Research Centre</p>Russian Federation<p>ГБУЗ МО Московский областной научно-исследовательский клинический институт имени М.Ф. Владимирского</p>Россия<p>Moscow Area Moscows regional research clinical institute n.a. M.F. Vladimirskiy</p>Russian Federation<p>ФГБУН Институт молекулярной биологии им. В.А. Энгельгардта РАН</p>Россия<p>Engelhardt Institute of Molecular Biology of the Russian Academy of Sciences</p>Russian Federation201713122017205335343Copyright &#x00A9; Мишина Е.Е., Майоров А.Ю., Богомолов П.О., Мациевич М.В., Кокина К.Ю., Боголюбова А.В., 20172017Мишина Е.Е., Майоров А.Ю., Богомолов П.О., Мациевич М.В., Кокина К.Ю., Боголюбова А.В.Mishina E.E., Mayorov A.Y., Bogomolov P.O., Matsievich M.V., Kokina K.Y., Bogolyubova A.V.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/9372

Неалкогольная жировая болезнь печени (НАЖБП) и сахарный диабет 2 типа (СД2) – патологические состояния, ассоциированные друг с другом и достигающие размеров эпидемии. Одним из наиболее значимых факторов риска развития как СД2, так и НАЖБП является ожирение, которое усиливает имеющуюся инсулинорезистентность (ИР). Последняя является основным патогенетическим звеном СД2 и НАЖБП, связывая эти два патологических состояния. В настоящее время повышен интерес к поиску неинвазивных методик исследования; для оценки фиброза и определения показаний для биопсии печени неинвазивным методом используется Шкала оценки стадии фиброза при НАЖБП (NAFLD fibrosis score), расширенная панель фиброза печени (ELF) и транзиентная эластография. Однако золотым стандартом диагностики остается биопсия печени. Ввиду того, что у пациентов с СД чаще выявляется НАЖБП, чем в общей популяции, а также учитывая, что наличие СД является фактором риска прогрессии НАЖБП, данная когорта пациентов должна находиться под более тщательным контролем клиницистов. Данная обзорная работа посвящена поиску причинно-следственных связей таких коморбидных заболеваний, как НАЖБП и различные нарушения углеводного обмена, а также приоритетным направлениям диагностики НАЖБП.

Nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) are pathological conditions that are co-occurring, and have been reaching epidemic proportions. One of the most significant risk factors for the development of both T2DM and NAFLD is obesity, which increases existing insulin resistance (IR). IR thought to be one of the main pathogenic causes linking T2DM and NAFLD. In recent years, there has been increased interest in obtaining non-invasive methods for assessing fibrosis and determining indications for liver biopsy, such as the NAFLD fibrosis score, extended liver fibrosis panel, and transient elastography. However, liver biopsy remains the gold standard for diagnosing NAFLD. Given that patients with T2DM are at higher risk of NAFLD than the general population, and that the presence of diabetes is a risk factor for the progression of NAFLD, patients with T2DM should be more closely monitored by clinicians. The present review paper is devoted to the search for cause–effect relationships of concurrent diseases such as NAFLD and disorders of carbohydrate metabolism, and priority areas of diagnosis of NAFLD.

инсулинорезистентностьсахарный диабетнеалкогольная жировая болезнь печенинеалкогольный стеатогепатитожирениеinsulin resistancediabetes mellitusnonalcoholic fatty liver diseasenonalcoholic steatohepatitisobesityРоссийский научный фонд (грант №17-15-01475)ReferencesLudwig J, Viggiano TR, McGill DB, Oh BJ. Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin Proc. 1980;55(7):434-438.Ludwig J, Viggiano TR, McGill DB, Oh BJ. Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin Proc. 1980;55(7):434-438.Sanyal AJ. NASH: A global health problem. Hepatol Res. 2011;41(7):670-674. doi: 10.1111/j.1872-034X.2011.00824.xSanyal AJ. NASH: A global health problem. Hepatol Res. 2011;41(7):670-674. doi: 10.1111/j.1872-034X.2011.00824.xAhmed A, Wong RJ, Harrison SA. Nonalcoholic Fatty Liver Disease Review: Diagnosis, Treatment, and Outcomes. Clin Gastroenterol Hepatol. 2015;13(12):2062–2070. doi: 10.1016/j.cgh.2015.07.029Ahmed A, Wong RJ, Harrison SA. Nonalcoholic Fatty Liver Disease Review: Diagnosis, Treatment, and Outcomes. Clin Gastroenterol Hepatol. 2015;13(12):2062–2070. doi: 10.1016/j.cgh.2015.07.029Chalasani N, Younossi Y, Lavine JE, et al. The diagnosis and management of non-alcoholic fatty liver disease: Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology. 2012;55(6):2005-2023. doi: 10.1002/hep.25762Chalasani N, Younossi Y, Lavine JE, et al. The diagnosis and management of non-alcoholic fatty liver disease: Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology. 2012;55(6):2005-2023. doi: 10.1002/hep.25762Browning JD. Statins and hepatic steatosis: Perspectives from the Dallas heart study. Hepatology. 2006;44(2):466-471. doi: 10.1002/hep.21248Browning JD. Statins and hepatic steatosis: Perspectives from the Dallas heart study. Hepatology. 2006;44(2):466-471. doi: 10.1002/hep.21248Драпкина О.М., Ивашкин В.Т. Эпидемиологические особенности неалкогольной жировой болезни печени в России (результаты открытого многоцентрового проспективного исследования наблюдения DIREGL 01903) // Российский журнал гастроэнтерологии, гепатологии, колопроктологии. – 2014. – Т. 24. – №4. – С. 32–38. [Drapkina OM, Ivashkin VT. Epidemiologic features of non-alcoholic fatty liver disease in Russia. Results of open multicenter prospective observational study DIREG L 01903). Ross z gastroenterol gepatol koloproktol. 2014;34(4):32-38. (In Russ.)]Драпкина О.М., Ивашкин В.Т. Эпидемиологические особенности неалкогольной жировой болезни печени в России (результаты открытого многоцентрового проспективного исследования наблюдения DIREGL 01903) // Российский журнал гастроэнтерологии, гепатологии, колопроктологии. – 2014. – Т. 24. – №4. – С. 32–38. [Drapkina OM, Ivashkin VT. Epidemiologic features of non-alcoholic fatty liver disease in Russia. Results of open multicenter prospective observational study DIREG L 01903). Ross z gastroenterol gepatol koloproktol. 2014;34(4):32-38. (In Russ.)]Angulo P, Kleiner DE, Dam-Larsen S, et al. Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology. 2015;149(2):389-397. doi: 10.1053/j.gastro.2015.04.043Angulo P, Kleiner DE, Dam-Larsen S, et al. Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology. 2015;149(2):389-397. doi: 10.1053/j.gastro.2015.04.043Pagadala MR, McCullough AJ. The relevance of liver histology to predicting clinically meaningful outcomes in nonalcoholic steatohepatitis. Clin Liver Dis. 2012;16(3):487-504. doi: 10.1016/j.cld.2012.05.006Pagadala MR, McCullough AJ. The relevance of liver histology to predicting clinically meaningful outcomes in nonalcoholic steatohepatitis. Clin Liver Dis. 2012;16(3):487-504. doi: 10.1016/j.cld.2012.05.006Ekstedt M, Franzén LE, Holmqvist M. Alcohol consumption is associated with progression of hepatic fibrosis in non-alcoholic fatty liver disease. Scand J Gastroenterol. 2009;44(3):366-374. doi: 10.1080/00365520802555991Ekstedt M, Franzén LE, Holmqvist M. Alcohol consumption is associated with progression of hepatic fibrosis in non-alcoholic fatty liver disease. Scand J Gastroenterol. 2009;44(3):366-374. doi: 10.1080/00365520802555991Portillo-Sanchez P, Bril F, Maximos M, et al. High Prevalence of Nonalcoholic Fatty Liver Disease in Patients With Type 2 Diabetes Mellitus and Normal Plasma Aminotransferase Levels. J Clin Endocrinol Metab. 2015;100:2231–2238. doi: 10.1210/jc.2015-1966Portillo-Sanchez P, Bril F, Maximos M, et al. High Prevalence of Nonalcoholic Fatty Liver Disease in Patients With Type 2 Diabetes Mellitus and Normal Plasma Aminotransferase Levels. J Clin Endocrinol Metab. 2015;100:2231–2238. doi: 10.1210/jc.2015-1966Doycheva I, Cui J, Nquyen P, et al. Non-invasive screening of diabetics in primary care for NAFLD and advanced fibrosis by MRI and MRE. Aliment Pharmacol Ther. 2016;43(1):83-95. doi: 10.1111/apt.13405Doycheva I, Cui J, Nquyen P, et al. Non-invasive screening of diabetics in primary care for NAFLD and advanced fibrosis by MRI and MRE. Aliment Pharmacol Ther. 2016;43(1):83-95. doi: 10.1111/apt.13405Диагностика и лечение неалкогольной жировой болезни печени. / Под ред. Ивашкина В.Т. – М.: Российское общество по изучению печени; 2015. [Diagnostika i lechenie nealkogol’noj zhirovoj bolezni pecheni. Ed by Ivashkin VT. Moscow: Rossijskoe obshhestvo po izucheniju pecheni; 2015. (In Russ.)]Диагностика и лечение неалкогольной жировой болезни печени. / Под ред. Ивашкина В.Т. – М.: Российское общество по изучению печени; 2015. [Diagnostika i lechenie nealkogol’noj zhirovoj bolezni pecheni. Ed by Ivashkin VT. Moscow: Rossijskoe obshhestvo po izucheniju pecheni; 2015. (In Russ.)]Yki-Järvinen H. Diagnosis of non-alcoholic fatty liver disease (NAFLD). Diabetologia. 2016;59(6):1104-1111. doi: 10.1007/s00125-016-3944-1Yki-Järvinen H. Diagnosis of non-alcoholic fatty liver disease (NAFLD). Diabetologia. 2016;59(6):1104-1111. doi: 10.1007/s00125-016-3944-1Rinella ME. Nonalcoholic Fatty Liver Disease. JAMA. 2015;313(22):2263-2273. doi: 10.1001/jama.2015.5370Rinella ME. Nonalcoholic Fatty Liver Disease. JAMA. 2015;313(22):2263-2273. doi: 10.1001/jama.2015.5370Lonardo A, Ballestri S, Marchesini G, et al. Nonalcoholic fatty liver disease: A precursor of the metabolic syndrome. Dig Liver Dis. 2015;47(3):181-190. doi: 10.1016/j.dld.2014.09.020Lonardo A, Ballestri S, Marchesini G, et al. Nonalcoholic fatty liver disease: A precursor of the metabolic syndrome. Dig Liver Dis. 2015;47(3):181-190. doi: 10.1016/j.dld.2014.09.020Targher G, Marchesini G, Byrne CD. Risk of type 2 diabetes in patients with non-alcoholic fatty liver disease: Causal association or epiphenomenon? Diabetes Metab. 2016;42(3):142-156. doi: 10.1016/j.diabet.2016.04.002Targher G, Marchesini G, Byrne CD. Risk of type 2 diabetes in patients with non-alcoholic fatty liver disease: Causal association or epiphenomenon? Diabetes Metab. 2016;42(3):142-156. doi: 10.1016/j.diabet.2016.04.002Shah RV, Allison MA, Lima JA, et al. Liver fat, statin use, and incident diabetes: The Multi-Ethnic Study of Atherosclerosis. Atherosclerosis. 2015;242(1):211-217. doi: 10.1016/j.atherosclerosis.2015.07.018Shah RV, Allison MA, Lima JA, et al. Liver fat, statin use, and incident diabetes: The Multi-Ethnic Study of Atherosclerosis. Atherosclerosis. 2015;242(1):211-217. doi: 10.1016/j.atherosclerosis.2015.07.018Day CP, James OF. Steatohepatitis: a tale of two «hits»? Gastroenterology. 1998;114(4):842-845. doi: 10.1016/S0016-5085(98)70599-2Day CP, James OF. Steatohepatitis: a tale of two «hits»? Gastroenterology. 1998;114(4):842-845. doi: 10.1016/S0016-5085(98)70599-2Jung U, Choi MS. Obesity and Its Metabolic Complications: The Role of Adipokines and the Relationship between Obesity, Inflammation, Insulin Resistance, Dyslipidemia and Nonalcoholic Fatty Liver Disease. Int J Mol Sci. 2014;15(4):6184–6223 doi: 10.3390/ijms15046184Jung U, Choi MS. Obesity and Its Metabolic Complications: The Role of Adipokines and the Relationship between Obesity, Inflammation, Insulin Resistance, Dyslipidemia and Nonalcoholic Fatty Liver Disease. Int J Mol Sci. 2014;15(4):6184–6223 doi: 10.3390/ijms15046184Valenti L, Bugianesi E, Pajvani U, Targher G. Nonalcoholic fatty liver disease: Cause or consequence of type 2 diabetes? Liver Int. 2016;36(11):1563-1579. doi: 10.1111/liv.13185Valenti L, Bugianesi E, Pajvani U, Targher G. Nonalcoholic fatty liver disease: Cause or consequence of type 2 diabetes? Liver Int. 2016;36(11):1563-1579. doi: 10.1111/liv.13185Ткачук В.А., Воротников А.В. Молекулярные механизмы развития резистентности к инсулину // Сахарный диабет. – 2014. – Т. 17. – №2. – C. 29-40. [Tkachuk VA, Vorotnikov AV. Molecular Mechanisms of Insulin Resistance Development. Diabetes mellitus. 2014;17(2):29-40. (In Russ.)] doi: 10.14341/DM2014229-40Ткачук В.А., Воротников А.В. Молекулярные механизмы развития резистентности к инсулину // Сахарный диабет. – 2014. – Т. 17. – №2. – C. 29-40. [Tkachuk VA, Vorotnikov AV. Molecular Mechanisms of Insulin Resistance Development. Diabetes mellitus. 2014;17(2):29-40. (In Russ.)] doi: 10.14341/DM2014229-40Samuel VT, Shulman GI. The pathogenesis of insulin resistance: Integrating signaling pathways and substrate flux. J Clin Invest. 2016;126(1);12–22. doi: 10.1172/JCI77812Samuel VT, Shulman GI. The pathogenesis of insulin resistance: Integrating signaling pathways and substrate flux. J Clin Invest. 2016;126(1);12–22. doi: 10.1172/JCI77812Donnelly 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. doi: 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. doi: 10.1172/JCI23621Fabbrini E, Magkos F, Mohammed BS, et al. Intrahepatic fat, not visceral fat, is linked with metabolic complications of obesity. Proc Natl Acad Sci. 2009;106(36):15430–15435. doi: 10.1073/pnas.0904944106Fabbrini E, Magkos F, Mohammed BS, et al. Intrahepatic fat, not visceral fat, is linked with metabolic complications of obesity. Proc Natl Acad Sci. 2009;106(36):15430–15435. doi: 10.1073/pnas.0904944106Gaggini M, Morelli M, Buzzigoli E, et al. Non-Alcoholic Fatty Liver Disease (NAFLD) and Its Connection with Insulin Resistance, Dyslipidemia, Atherosclerosis and Coronary Heart Disease. Nutrients. 2013;5(5):1544–1560. doi: 10.3390/nu5051544Gaggini M, Morelli M, Buzzigoli E, et al. Non-Alcoholic Fatty Liver Disease (NAFLD) and Its Connection with Insulin Resistance, Dyslipidemia, Atherosclerosis and Coronary Heart Disease. Nutrients. 2013;5(5):1544–1560. doi: 10.3390/nu5051544Frayn KN. Visceral fat and insulin resistance--causative or correlative? Br J Nutr. 2000;83(1):71-77. doi: 10.1017/S0007114500000982Frayn KN. Visceral fat and insulin resistance--causative or correlative? Br J Nutr. 2000;83(1):71-77. doi: 10.1017/S0007114500000982Lipina C, Hundal HS. Sphingolipids: Agents provocateurs in the pathogenesis of insulin resistance. Diabetologia. 2011;54(7):1596–1607. doi: 10.1007/s00125-011-2127-3Lipina C, Hundal HS. Sphingolipids: Agents provocateurs in the pathogenesis of insulin resistance. Diabetologia. 2011;54(7):1596–1607. doi: 10.1007/s00125-011-2127-3Okamoto M, Takeda Y, Yoda Y, et al. Fatty Liver and Diabetes Risk. Journal of Epidemiology. 2002;(1):15–21.Okamoto M, Takeda Y, Yoda Y, et al. Fatty Liver and Diabetes Risk. Journal of Epidemiology. 2002;(1):15–21.Bäckhed F, Dinq H, Wang T, et al. The gut microbiota as an environmental factor that regulates fat storage. Proc Natl Acad Sci U S A. 2004;101(44):15718–15723. doi: 10.1073/pnas.0407076101Bäckhed F, Dinq H, Wang T, et al. The gut microbiota as an environmental factor that regulates fat storage. Proc Natl Acad Sci U S A. 2004;101(44):15718–15723. doi: 10.1073/pnas.0407076101Byrne CD. Ectopic fat, insulin resistance and non-alcoholic fatty liver disease. Proc Nutr Soc. 2013;72(4):412–419. doi: 10.1017/S0029665113001249Byrne CD. Ectopic fat, insulin resistance and non-alcoholic fatty liver disease. Proc Nutr Soc. 2013;72(4):412–419. doi: 10.1017/S0029665113001249Meex RCR, Watt MJ. Hepatokines: linking nonalcoholic fatty liver disease and insulin resistance. Nat Rev Endocrinol. 2017;13(9):509–520. doi: 10.1038/nrendo.2017.56Meex RCR, Watt MJ. Hepatokines: linking nonalcoholic fatty liver disease and insulin resistance. Nat Rev Endocrinol. 2017;13(9):509–520. doi: 10.1038/nrendo.2017.56Meex RC, Hoy AJ, Morris A, et al. Fetuin B Is a Secreted Hepatocyte Factor Linking Steatosis to Impaired Glucose Metabolism. Cell Metab. 2015;22(6):1078–1089. doi: 10.1016/j.cmet.2015.09.023Meex RC, Hoy AJ, Morris A, et al. Fetuin B Is a Secreted Hepatocyte Factor Linking Steatosis to Impaired Glucose Metabolism. Cell Metab. 2015;22(6):1078–1089. doi: 10.1016/j.cmet.2015.09.023Yu XX, Murray SF, Pandey SK, et al. Antisense oligonucleotide reduction of DGAT2 expression improves hepatic steatosis and hyperlipidemia in obese mice. Hepatology. 2005;42(2):362–371. doi: 10.1002/hep.20783Yu XX, Murray SF, Pandey SK, et al. Antisense oligonucleotide reduction of DGAT2 expression improves hepatic steatosis and hyperlipidemia in obese mice. Hepatology. 2005;42(2):362–371. doi: 10.1002/hep.20783

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