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The complex link between NAFLD and type 2 diabetes mellitus — mechanisms and treatments

Nature Reviews Gastroenterology & Hepatology volume 18, pages 599–612 (2021)Cite this article

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Abstract

Nonalcoholic fatty liver disease (NAFLD) has reached epidemic proportions worldwide. NAFLD and type 2 diabetes mellitus (T2DM) are known to frequently coexist and act synergistically to increase the risk of adverse (hepatic and extra-hepatic) clinical outcomes. T2DM is also one of the strongest risk factors for the faster progression of NAFLD to nonalcoholic steatohepatitis, advanced fibrosis or cirrhosis. However, the link between NAFLD and T2DM is more complex than previously believed. Strong evidence indicates that NAFLD is associated with an approximate twofold higher risk of developing T2DM, irrespective of obesity and other common metabolic risk factors. This risk parallels the severity of NAFLD, such that patients with more advanced stages of liver fibrosis are at increased risk of incident T2DM. In addition, the improvement or resolution of NAFLD (on ultrasonography) is associated with a reduction of T2DM risk, adding weight to causality and suggesting that liver-focused treatments might reduce the risk of developing T2DM. This Review describes the evidence of an association and causal link between NAFLD and T2DM, discusses the putative pathophysiological mechanisms linking NAFLD to T2DM and summarizes the current pharmacological treatments for NAFLD or T2DM that might benefit or adversely affect the risk of T2DM or NAFLD progression.

Key points

  • An updated meta-analysis of 33 observational studies showed that nonalcoholic fatty liver disease (NAFLD) is associated with an approximate doubled risk of type 2 diabetes mellitus (T2DM), irrespective of obesity and other metabolic risk factors.

  • Patients with more advanced stages of liver fibrosis are at increased risk of T2DM; some observational studies have shown that improvement or resolution of NAFLD on ultrasonography is closely associated with a reduction of diabetes risk.

  • NAFLD exacerbates hepatic and peripheral insulin resistance, predisposes to atherogenic dyslipidaemia and causes the systemic release of pro-inflammatory cytokines and hepatokines that can promote the development of T2DM.

  • Treatment of NAFLD and T2DM is based on lifestyle modifications aiming at substantial weight loss in individuals with overweight or obesity.

  • Although no pharmacotherapy is currently approved for NAFLD, some antihyperglycaemic drugs, such as pioglitazone, glucagon-like peptide 1 analogues and sodium–glucose cotransporter 2 inhibitors, have some efficacy.

  • Multiple investigational compounds for NAFLD treatment, including modulators of bile acid and lipid metabolism, are in phase II and phase III randomized controlled trials.

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Fig. 1: Potential hepatic mediators of diabetes risk in NAFLD: bile acid metabolism, FXR and TGR5 receptor activity and adipose function.
Fig. 2: Increased lipid availability, lipotoxic mediators and hepatic insulin resistance.

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Acknowledgements

The work of G.T. is supported in part by grants from the University School of Medicine of Verona, Verona, Italy. The work of C.D.B. is supported in part by grants from the Southampton National Institute for Health Research Biomedical Research Centre. The work of M.R. is supported by grants from the German Federal Ministry of Health (BMG) and the Ministry of Culture and Science of the state North Rhine-Westphalia (MKW NRW) to the German Diabetes Center (DDZ), the German Federal Ministry of Education and Research (BMBF) to DZD e. V., the European Funds for Regional Development (EFRE-0400191), EUREKA Eurostars-2 (E. 113230 DIA-PEP), the German Science Foundation (DFG; CRC/SFB 1116/2 B12) and the Schmutzler Stiftung.

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Authors and Affiliations

  1. Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy

    Giovanni Targher

  2. Liver Center, Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    Kathleen E. Corey

  3. Nutrition and Metabolism, Faculty of Medicine, University of Southampton, Southampton, UK

    Christopher D. Byrne

  4. Southampton National Institute for Health Research Biomedical Research Centre, University Hospital Southampton, Southampton General Hospital, Tremona Road, Southampton, UK

    Christopher D. Byrne

  5. Division of Endocrinology and Diabetology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany

    Michael Roden

  6. Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany

    Michael Roden

  7. German Center for Diabetes Research, München-Neuherberg, Germany

    Michael Roden

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  1. Giovanni Targher
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  4. Michael Roden
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All authors contributed to researching data for the article, made a substantial contribution to discussion of content, and wrote and reviewed/edited the manuscript before submission.

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Correspondence to Giovanni Targher.

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Competing interests

M.R. is on the scientific advisory boards of Allergan, Astra-Zeneca, Bristol-Myers Squibb, Eli Lilly, Gilead Sciences, Inventiva, Intercept Pharma, Novartis, NovoNordisk, Servier Laboratories, Target Pharmasolutions, and Terra Firma and receives investigator-initiated support from Boehringer Ingelheim, Nutricia/Danone and Sanofi–Aventis. K.C. is on the scientific advisory boards for Bristol-Myers Squibb and NovoNordisk and has received grant funding from Boehringer-Ingelheim, Bristol-Myers Squibb and Novartis. G.T. and C.D.B. declare no competing interests.

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Nature Reviews Gastroenterology & Hepatology thanks Geoff Farrell, Vincent Wong and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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Targher, G., Corey, K.E., Byrne, C.D. et al. The complex link between NAFLD and type 2 diabetes mellitus — mechanisms and treatments. Nat Rev Gastroenterol Hepatol 18, 599–612 (2021). https://doi.org/10.1038/s41575-021-00448-y

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