Emerging Therapeutic Approaches for the Treatment of NAFLD and Type 2 Diabetes Mellitus

Overview

Journal Nat Rev Endocrinol

Specialty Endocrinology

Date 2021 Jun 16

PMID 34131333

Citations 156

Authors

Daniel Ferguson

Brian N Finck

Affiliations

Soon will be listed here.

Abstract

Non-alcoholic fatty liver disease (NAFLD) has emerged as the most prevalent liver disease in the world, yet there are still no approved pharmacological therapies to prevent or treat this condition. NAFLD encompasses a spectrum of severity, ranging from simple steatosis to non-alcoholic steatohepatitis (NASH). Although NASH is linked to an increased risk of hepatocellular carcinoma and cirrhosis and has now become the leading cause of liver failure-related transplantation, the majority of patients with NASH will ultimately die as a result of complications of type 2 diabetes mellitus (T2DM) and cardiometabolic diseases. Importantly, NAFLD is closely linked to obesity and tightly interrelated with insulin resistance and T2DM. Thus, targeting these interconnected conditions and taking a holistic attitude to the treatment of metabolic disease could prove to be a very beneficial approach. This Review will explore the latest relevant literature and discuss the ongoing therapeutic options for NAFLD focused on targeting intermediary metabolism, insulin resistance and T2DM to remedy the global health burden of these diseases.

Citing Articles

RNA Modification in Metabolism.

Liu Y, Sun Z, Gui D, Zhao Y, Xu Y MedComm (2020). 2025; 6(3):e70135.

PMID: 40066222 PMC: 11892166. DOI: 10.1002/mco2.70135.

Natural Bioactive Compounds in the Management of Type 2 Diabetes and Metabolic (Dysfunction)-Associated Steatotic Liver Disease.

Ciobarca D, Catoi A, Gavrilas L, Banc R, Miere D, Filip L Pharmaceuticals (Basel). 2025; 18(2).

PMID: 40006091 PMC: 11859434. DOI: 10.3390/ph18020279.

Advances in the Development of Mitochondrial Pyruvate Carrier Inhibitors for Therapeutic Applications.

Politte H, Maram L, Elgendy B Biomolecules. 2025; 15(2).

PMID: 40001526 PMC: 11852594. DOI: 10.3390/biom15020223.

M6A methyltransferase METTL3 promotes glucose metabolism hub gene expression and induces metabolic dysfunction-associated steatotic liver disease (MASLD).

Wang S, Xu Z, Wang Z, Yi X, Wu J BMC Genomics. 2025; 26(1):188.

PMID: 39994526 PMC: 11853331. DOI: 10.1186/s12864-025-11377-4.

Pre-diabetes and cardiovascular risk factors in NAFLD patients: a retrospective comparative analysis.

Teimouri A, Ebrahimpour Z, Feizi A, Iraj B, Saffari E, Akbari M Front Endocrinol (Lausanne). 2025; 16:1416407.

PMID: 39991738 PMC: 11842249. DOI: 10.3389/fendo.2025.1416407.

References

Younossi Z, Koenig A, Abdelatif D, Fazel Y, Henry L, Wymer M . Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2015; 64(1):73-84. DOI: 10.1002/hep.28431. View

Younossi Z, Blissett D, Blissett R, Henry L, Stepanova M, Younossi Y . The economic and clinical burden of nonalcoholic fatty liver disease in the United States and Europe. Hepatology. 2016; 64(5):1577-1586. DOI: 10.1002/hep.28785. View

Vilar-Gomez E, Martinez-Perez Y, Calzadilla-Bertot L, Torres-Gonzalez A, Gra-Oramas B, Gonzalez-Fabian L . Weight Loss Through Lifestyle Modification Significantly Reduces Features of Nonalcoholic Steatohepatitis. Gastroenterology. 2015; 149(2):367-78.e5. DOI: 10.1053/j.gastro.2015.04.005. View

Chalasani N, Younossi Z, Lavine J, Charlton M, Cusi K, Rinella M . The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2017; 67(1):328-357. DOI: 10.1002/hep.29367. View

Younossi Z, Stepanova M, Younossi Y, Golabi P, Mishra A, Rafiq N . Epidemiology of chronic liver diseases in the USA in the past three decades. Gut. 2019; 69(3):564-568. DOI: 10.1136/gutjnl-2019-318813. View

Lonardo A, Nascimbeni F, Ballestri S, Fairweather D, Win S, Than T . Sex Differences in Nonalcoholic Fatty Liver Disease: State of the Art and Identification of Research Gaps. Hepatology. 2019; 70(4):1457-1469. PMC: 6766425. DOI: 10.1002/hep.30626. View

Yang J, Abdelmalek M, Pang H, Guy C, Smith A, Diehl A . Gender and menopause impact severity of fibrosis among patients with nonalcoholic steatohepatitis. Hepatology. 2013; 59(4):1406-14. PMC: 3966932. DOI: 10.1002/hep.26761. View

DiStefano J . NAFLD and NASH in Postmenopausal Women: Implications for Diagnosis and Treatment. Endocrinology. 2020; 161(10). PMC: 7473510. DOI: 10.1210/endocr/bqaa134. View

Sanyal A, Harrison S, Ratziu V, Abdelmalek M, Diehl A, Caldwell S . The Natural History of Advanced Fibrosis Due to Nonalcoholic Steatohepatitis: Data From the Simtuzumab Trials. Hepatology. 2019; 70(6):1913-1927. DOI: 10.1002/hep.30664. View

10.

Sheka A, Adeyi O, Thompson J, Hameed B, Crawford P, Ikramuddin S . Nonalcoholic Steatohepatitis: A Review. JAMA. 2020; 323(12):1175-1183. DOI: 10.1001/jama.2020.2298. View

11.

Younossi Z, Anstee Q, Marietti M, Hardy T, Henry L, Eslam M . Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol. 2017; 15(1):11-20. DOI: 10.1038/nrgastro.2017.109. View

12.

Ivanics T, Abreu P, De Martin E, Sapisochin G . Changing Trends in Liver Transplantation: Challenges and Solutions. Transplantation. 2020; 105(4):743-756. DOI: 10.1097/TP.0000000000003454. View

13.

Donnelly K, Smith C, Schwarzenberg S, Jessurun J, Boldt M, Parks E . Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J Clin Invest. 2005; 115(5):1343-51. PMC: 1087172. DOI: 10.1172/JCI23621. View

14.

Fabbrini E, Mohammed B, Magkos F, Korenblat K, Patterson B, Klein S . Alterations in adipose tissue and hepatic lipid kinetics in obese men and women with nonalcoholic fatty liver disease. Gastroenterology. 2008; 134(2):424-31. PMC: 2705923. DOI: 10.1053/j.gastro.2007.11.038. View

15.

Korenblat K, Fabbrini E, Mohammed B, Klein S . Liver, muscle, and adipose tissue insulin action is directly related to intrahepatic triglyceride content in obese subjects. Gastroenterology. 2008; 134(5):1369-75. PMC: 2629391. DOI: 10.1053/j.gastro.2008.01.075. View

16.

Smith G, Shankaran M, Yoshino M, Schweitzer G, Chondronikola M, Beals J . Insulin resistance drives hepatic de novo lipogenesis in nonalcoholic fatty liver disease. J Clin Invest. 2019; 130(3):1453-1460. PMC: 7269561. DOI: 10.1172/JCI134165. View

17.

Lambert J, Ramos-Roman M, Browning J, Parks E . Increased de novo lipogenesis is a distinct characteristic of individuals with nonalcoholic fatty liver disease. Gastroenterology. 2013; 146(3):726-35. PMC: 6276362. DOI: 10.1053/j.gastro.2013.11.049. View

18.

Samuel V, Shulman G . Nonalcoholic Fatty Liver Disease as a Nexus of Metabolic and Hepatic Diseases. Cell Metab. 2017; 27(1):22-41. PMC: 5762395. DOI: 10.1016/j.cmet.2017.08.002. View

19.

Koliaki C, Szendroedi J, Kaul K, Jelenik T, Nowotny P, Jankowiak F . Adaptation of hepatic mitochondrial function in humans with non-alcoholic fatty liver is lost in steatohepatitis. Cell Metab. 2015; 21(5):739-46. DOI: 10.1016/j.cmet.2015.04.004. View

20.

Cable E, Finn P, Stebbins J, Hou J, Ito B, van Poelje P . Reduction of hepatic steatosis in rats and mice after treatment with a liver-targeted thyroid hormone receptor agonist. Hepatology. 2008; 49(2):407-17. DOI: 10.1002/hep.22572. View