Preview

Obesity and metabolism

Advanced search

Non-alcoholic fatty liver disease and type 2 diabetes mellitus: the problem of conjunction and phasing

https://doi.org/10.14341/omet12758

Abstract

The widespread prevalence of non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM), as well as their combination, determines the need for a targeted analysis of this pathology in order to optimize approaches to the diagnosis and treatment of patients with NAFLD and T2DM. As components of the metabolic syndrome, these two diseases have largely similar mechanisms of development and progression, simultaneously increasing the risk of adverse outcomes in comorbid patients. Despite the common pathophysiological mechanisms, the question of the development of NAFLD and T2DM remains significant.

Upon conducting literature analysis, two main theories have been identified: alimentary and metabolic. According to the alimentary theory, the primary link in the pathogenesis is obesity and the associated excessive accumulation of free fatty acids and triglycerides in the liver, which subsequently leads to insulin resistance and the development of T2DM. In contrast, the metabolic theory considers diabetes-related insulin resistance as the first hit, which, regardless of obesity, creates preconditions for liver damage. In addition, the review focuses on the consideration of the new concept of Metabolic associated fatty liver disease (MAFLD) as a hepatic manifestation of the metabolic syndrome and considers the clinical phenotypes identified within this pathology. In conclusion, pathogenically based treatment goals in patients with NAFLD and T2DM are overcoming insulin resistance, correcting atherogenic dyslipidemia, and restoring the structures and functions of liver cells.

About the Authors

E. V. Kiseleva
Pirogov Russian National Research Medical University (RNRMU)
Russian Federation

Elizaveta V. Kiseleva

1 Ostrovityanova street, 117997 Moscow, Russia



T. Y. Demidova
Pirogov Russian National Research Medical University (RNRMU)

Tatiana Yu. Demidova, MD, PhD, Professor

Moscow



References

1. В Who.int [Internet]. The top 10 causes of death [cited 2020 9 Dec]. Available from: https://www.who.int/news-room/fact-sheets/detail/the-top-10-causes-of-death

2. Rothberg GE, ed. Metabolic syndrome. Moscow: MED-M54 press-inform; 2007. (In Russ.).

3. Lang GF. Hypertonic disease. Leningrad: Medgiz; 1950. (In Russ.).

4. Reaven GM. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes. 1988;37(12):1595-1607. doi: https://doi.org/10.2337/diab.37.12.1595

5. D’Adamo E, Marcovecchio ML, Giannini C, et al. The possible role of liver steatosis in defining metabolic syndrome in prepubertal children. Metabolism. 2010;59:671-676. doi: https://doi.org/10.1016/j.metabol.2009.09.012

6. Belenkov YuN, Privalova EV, Kaplunova VY, et al. Metabolic Syndrome: Development of the Issue, Main Diagnostic Criteria. Rational Pharmacotherapy in Cardiology. 2018;14(5):757-764. (In Russ.). doi: https://doi.org/10.20996/1819-6446-2018-14-5-757-764

7. Lazebnik LB, Golovanova EV, Turkina SV, et al. Non-alcoholic fatty liver disease in adults: clinic, diagnostics, treatment. Guidelines for therapists, third version. Experimental and Clinical Gastroenterology. 2021;1(1):4-52. (In Russ.). doi: https://doi.org/10.31146/1682-8658-ecg-185-1-4-52

8. Younossi ZM, Koenig AB, Abdelatif D, et al. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016;64(1):73-84. doi: https://doi.org/10.1002/hep.28431

9. Younossi ZM, Blissett D, Blissett R, et al. The economic and clinical burden of nonalcoholic fatty liver disease in the United States and Europe. Hepatology. 2016;64(5):1577-1586. doi: https://doi.org/10.1002/hep.28785

10. de Alwis NM, Day CP. Non-alcoholic fatty liver disease: the mist gradually clears. J Hepatol. 2008;48 Suppl 1:S104-S112. doi: https://doi.org/10.1016/j.jhep.2008.01.009

11. Sanyal AJ; American Gastroenterological Association. AGA technical review on nonalcoholic fatty liver disease. Gastroenterology. 2002;123(5):1705-1725. doi: https://doi.org/10.1053/gast.2002.36572

12. Eslam M, Sanyal AJ, George J; International Consensus Panel. MAFLD: A Consensus-Driven Proposed Nomenclature for Metabolic Associated Fatty Liver Disease. Gastroenterology. 2020;158(7):1999-2014.e1. doi: https://doi.org/10.1053/j.gastro.2019.11.312

13. International Diabetes Federation. IDF Diabetes Atlas. 9th ed. Brussels: IDF; 2019; 176 p.

14. Idf.org [Internet]. One adult in ten will have diabetes by 2030. International Diabetes Federation [cited 2011 Nov 14]. Available from: http://www.idf.org/ media-events/press-releases/2011/diabetes-atlas-5th-edition

15. Younossi ZM, Golabi P, de Avila L, et al. The global epidemiology of NAFLD and NASH in patients with type 2 diabetes: A systematic review and meta-analysis. J Hepatol. 2019;71(4):793-801. doi: https://doi.org/10.1016/j.jhep.2019.06.021

16. Targher G, Bertolini L, Padovani R, et al. Prevalence of nonalcoholic fatty liver disease and its association with cardiovascular disease among type 2 diabetic patients. Diabetes Care. 2007;30(5):1212-1218. doi: https://doi.org/10.2337/dc06-2247

17. Targher G. Is it time for non-alcoholic fatty liver disease screening in patients with type 2 diabetes mellitus? Hepatobiliary Surg Nutr. 2020;9(2):239-241. doi: https://doi.org/10.21037/hbsn.2019.10.21

18. Younossi ZM, Gramlich T, Matteoni CA, et al. Nonalcoholic fatty liver disease in patients with type 2 diabetes [published correction appears in Clin Gastroenterol Hepatol. 2004 Jun;2(6):522]. Clin Gastroenterol Hepatol. 2004;2(3):262-265. doi: https://doi.org/10.1016/s1542-3565(04)00014-x

19. Hossain N, Afendy A, Stepanova M, et al. Independent predictors of fibrosis in patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2009;7(11):1224-1229.e12292. doi: https://doi.org/10.1016/j.cgh.2009.06.007

20. Stepanova M, Rafiq N, Makhlouf H, et al. Predictors of all-cause mortality and liver-related mortality in patients with non-alcoholic fatty liver disease (NAFLD). Dig Dis Sci. 2013;58(10):3017-3023. doi: https://doi.org/10.1007/s10620-013-2743-5

21. Fracanzani AL, Valenti L, Bugianesi E, et al. Risk of severe liver disease in nonalcoholic fatty liver disease with normal aminotransferase levels: a role for insulin resistance and diabetes. Hepatology. 2008;48(3):792-798. doi: https://doi.org/10.1002/hep.22429

22. Mofrad P, Contos MJ, Haque M, et al. Clinical and histologic spectrum of nonalcoholic fatty liver disease associated with normal ALT values. Hepatology. 2003;37(6):1286-1292. doi: https://doi.org/10.1053/jhep.2003.50229

23. Leitner DR, Frühbeck G, Yumuk V, et al. Obesity and Type 2 Diabetes: Two Diseases with a Need for Combined Treatment Strategies — EASO Can Lead the Way. Obes Facts. 2017;10(5):483-492. doi: https://doi.org/10.1159/000480525

24. Wang HH, Lee DK, Liu M, Portincasa P, Wang DQ. Novel Insights into the Pathogenesis and Management of the Metabolic Syndrome. Pediatr Gastroenterol Hepatol Nutr. 2020;23(3):189-230. doi: https://doi.org/10.5223/pghn.2020.23.3.189

25. Bae JC, Cho YK, Lee WY, et al. Impact of nonalcoholic fatty liver disease on insulin resistance in relation to HbA1c levels in nondiabetic subjects. Am J Gastroenterol. 2010;105(11):2389-2395. doi: https://doi.org/10.1038/ajg.2010.275

26. Dongiovanni P, Stender S, Pietrelli A, et al. Causal relationship of hepatic fat with liver damage and insulin resistance in nonalcoholic fatty liver. J Intern Med. 2018;283(4):356-370. doi: https://doi.org/10.1111/joim.12719

27. Manchanayake J, Chitturi S, Nolan C, Farrell GC. Postprandial hyperinsulinemia is universal in non-diabetic patients with nonalcoholic fatty liver disease. J Gastroenterol Hepatol. 2011;26(3):510-516. doi: https://doi.org/10.1111/j.1440-1746.2010.06528.x

28. Bakulin IG, Sandler YuG, Vinnitskaya EV. Diabetes mellitus and nonalcoholic fatty liver disease: The verges of contingency. Terapevticheskiy Archiv. 2017;89(2):59-65 (In Russ.). doi: https://doi.org/10.17116/terarkh201789259-65

29. De Bruyne RM, Fitzpatrick E, Dhawan A. Fatty liver disease in children: eat now pay later. Hepatol Int. 2010;4(1):375-385. Published 2010 Jan 29. doi: https://doi.org/10.1007/s12072-009-9160-z

30. Drapkina OM, Korneyeva ON, Ivashkin VT. Treatment of nonalcoholic steatohepatitis and metabolic syndrome: focus on essential phospholipids]. Lechashchii vrach [Therapist]. 2010;2: 43–45. (In Russ.).

31. European Association for the Study of the Liver (EASL); European Association for the Study of Diabetes (EASD); European Association for the Study of Obesity (EASO). EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J Hepatol. 2016;64(6):1388-1402. doi: https://doi.org/10.1016/j.jhep.2015.11.004

32. Lavrenova EA, Drapkina OM. Insulin resistance in obesity: pathogenesis and effects. Obesity and metabolism. 2020;17(1):48-55. (In Russ.). doi: https://doi.org/10.14341/omet9759

33. Babenko AYu, Laevskaya MYu. Non-alcoholic fatty liver disease — relationships with metabolic syndrome. Russkiy Meditsinskiy Zhurnal. 2018;1(I):34–40. (In Russ.).

34. Ding X, Saxena NK, Lin S, et al. Exendin-4, a glucagon-like protein-1 (GLP-1) receptor agonist, reverses hepatic steatosis in ob/ob mice. Hepatology. 2006;43(1):173-81.

35. 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. doi: https://doi.org/ 10.1016/s0002-9343(99)00271-5

36. Watt MJ, Miotto PM, De Nardo W, Montgomery MK. The Liver as an Endocrine Organ-Linking NAFLD and Insulin Resistance. Endocr Rev. 2019;40(5):1367-1393. doi: https://doi.org/10.1210/er.2019-00034

37. Stefan N, Fritsche A, Weikert C, et al. Plasma fetuin-A levels and the risk of type 2 diabetes. Diabetes. 2008;57(10):2762-7. doi: https://doi.org/10.2337/db08-0538

38. Hussey SE, Liang H, Costford SR, et al. TAK-242, a small-molecule inhibitor of Toll-like receptor 4 signalling, unveils similarities and differences in lipopolysaccharide- and lipid-induced inflammation and insulin resistance in muscle cells. Biosci Rep. 2012;33(1):37-47. doi: https://doi.org/10.1042/BSR20120098

39. Kytikova OYu, Novgorodtseva TР, Denisenko YuК, Antonyuk MV, Gvozdenko TA. Toll-like receptors in the pathophysiology of obesity. Obesity and metabolism. 2020;17(1):56-63. (In Russ.). doi: https://doi.org/10.14341/omet10336

40. Butrova SA. Metabolic syndrome: pathogenesis, clinical presentation, diagnosis, treatment approaches. Russkiy Meditsinskiy Zhurnal. 2001;2:56-8. (In Russ.).

41. Seppälä-Lindroos A, Vehkavaara S, Häkkinen AM, et al. Fat accumulation in the liver is associated with defects in insulin suppression of glucose production and serum free fatty acids independent of obesity in normal men. J Clin Endocrinol Metab. 2002;87(7):3023-3028. doi: https://doi.org/10.1210/jcem.87.7.8638

42. Valenti 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: https://doi.org/10.1111/liv.13185

43. Pavlenko OA. Obesity as a risk factor of nonalcoholic fatty liver disease. Almanac of Clinical Medicine. 2015;1(1):60-66. (In Russ.). doi: https://doi.org/10.18786/2072-0505-2015-1-60-66

44. Mishina EE, Mayorov AY, Bogomolov PO, et al. Nonalcoholic fatty liver disease: cause or consequence of insulin resistance? Diabetes mellitus. 2017;20(5):335-342 (In Russ.). doi: https://doi.org/10.14341/DM9372

45. Petersen KF, Dufour S, Savage DB, et al. The role of skeletal muscle insulin resistance in the pathogenesis of the metabolic syndrome. Proc Natl Acad Sci U S A. 2007;104(31):12587-12594. doi: https://doi.org/10.1073/pnas.0705408104

46. Younossi Z, Anstee QM, Marietti M, et al. Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol. 2018;15(1):11-20. doi: https://doi.org/10.1038/nrgastro.2017.109

47. Das K, Chowdhury A. Lean NASH: distinctiveness and clinical implication. Hepatol Int. 2013;7 Suppl 2:806-813. doi: https://doi.org/10.1007/s12072-013-9477-5

48. Eckel N, Li Y, Kuxhaus O, et al. Transition from metabolic healthy to unhealthy phenotypes and association with cardiovascular disease risk across BMI categories in 90 257 women (the Nurses’ Health Study): 30 year follow-up from a prospective cohort study. Lancet Diabetes Endocrinol. 2018;6(9):714-724. doi: https://doi.org/10.1016/S2213-8587(18)30137-2

49. Caleyachetty R, Thomas GN, Toulis KA, et al. Metabolically Healthy Obese and Incident Cardiovascular Disease Events Among 3.5 Million Men and Women. J Am Coll Cardiol. 2017;70(12):1429-1437. doi: https://doi.org/10.1016/j.jacc.2017.07.763

50. Lassale C, Tzoulaki I, Moons KGM, et al. Separate and combined associations of obesity and metabolic health with coronary heart disease: a pan-European case-cohort analysis. Eur Heart J. 2018;39(5):397-406. doi: https://doi.org/10.1093/eurheartj/ehx448

51. Drapkina OM. Nonalcoholic fatty liver disease and metabolic syndrome. Spravochnik poliklinicheskogo vracha. 2008;3:71-74 (In Russ.)

52. European Association for the Study of the Liver (EASL); European Association for the Study of Diabetes (EASD); European Association for the Study of Obesity (EASO). EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J Hepatol. 2016;64(6):1388-1402. doi: https://doi.org/10.1016/j.jhep.2015.11.004

53. Whitsett M, VanWagner LB. Physical activity as a treatment of non-alcoholic fatty liver disease: A systematic review. World J Hepatol. 2015;7(16):2041-2052. doi: https://doi.org/10.4254/wjh.v7.i16.2041

54. Borghouts LB, Keizer HA. Exercise and insulin sensitivity: a review. Int J Sports Med. 2000;21(1):1-12. doi: https://doi.org/10.1055/s-2000-8847

55. Golabi et al. Effectiveness of exercise in hepatic fat mobilization in nonalcoholic fatty liver disease: Systematic review. World J Gastroenterol. 2016;22(27):6318-632

56. Wang ST, Zheng J, Peng HW, et al. Physical activity intervention for non-diabetic patients with non-alcoholic fatty liver disease: a meta-analysis of randomized controlled trials. BMC Gastroenterol. 2020;20(1):66. Published 2020 Mar 12. doi: https://doi.org/ 10.1186/s12876-020-01204-3

57. Zhou J, Massey S, Story D, Li L. Metformin: An Old Drug with New Applications. Int J Mol Sci. 2018;19(10):2863. doi: https://doi.org/ 10.3390/ijms19102863


Review

For citations:


Kiseleva E.V., Demidova T.Y. Non-alcoholic fatty liver disease and type 2 diabetes mellitus: the problem of conjunction and phasing. Obesity and metabolism. 2021;18(3):313-319. (In Russ.) https://doi.org/10.14341/omet12758

Views: 34594


ISSN 2071-8713 (Print)
ISSN 2306-5524 (Online)