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Emerging therapeutic approaches for the treatment of NAFLD and type 2 diabetes mellitus

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.

Key points

  • Non-alcoholic fatty liver disease (NAFLD) has become the most common liver disease globally, yet there are currently no approved therapies.

  • While NAFLD progression to non-alcoholic steatohepatitis is becoming the leading cause of end-stage liver failure, the leading causes of death in patients with NAFLD are complications of cardiometabolic disease.

  • A tight relationship exists between NAFLD, insulin resistance and type 2 diabetes mellitus.

  • It is likely that developing therapeutics that target both NAFLD and cardiometabolic risk factors might be extremely beneficial.

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Fig. 1: The pathological spectrum of NAFLD.
Fig. 2: Role of insulin resistance in NAFLD.
Fig. 3: Targeting of intermediary metabolism for NAFLD therapy.

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Acknowledgements

Work in the authors’ lab is supported by grants from the National Institutes of Health (R01 DK104735 and R01 DK117657). D.F. is supported by an NIH training grant, T32 DK007120.

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Correspondence to Brian N. Finck.

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B.N.F. is a stockholder and member of the scientific advisory board of Cirius Therapeutics Inc., which is developing MSDC-0602 for the treatment of NASH. D.F. declares no competing interests.

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Ferguson, D., Finck, B.N. Emerging therapeutic approaches for the treatment of NAFLD and type 2 diabetes mellitus. Nat Rev Endocrinol 17, 484–495 (2021). https://doi.org/10.1038/s41574-021-00507-z

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