The Bidirectional Relationship Between Type 2 Diabetes and NAFLD/MASH: Pathophysiology, Screening Strategies, and Therapeutic Opportunities
Main Article Content
Type 2 diabetes mellitus (T2DM) and nonalcoholic fatty liver disease (NAFLD), including its progressive forms—metabolic dysfunction–associated steatotic liver disease (MASLD) and steatohepatitis (MASH)—are closely linked manifestations of metabolic syndrome, bidirectionally influencing each other. Insulin resistance, adipose tissue dysfunction, inflammation, oxidative stress, and genetic–epigenetic factors contribute to their simultaneous development and progression to fibrosis. This review aims to explore the pathophysiological mechanisms connecting T2DM and NAFLD/MASH, evaluate bidirectional screening strategies, and summarize pharmacological and lifestyle treatments for patients with both conditions. The review is based on a narrative analysis of clinical evidence, screening guidelines, and therapeutic approaches from relevant documents, excluding external sources. T2DM and NAFLD/MASH are interconnected through insulin resistance, lipotoxicity, adipose dysfunction, inflammatory pathways, and genetic–epigenetic factors. T2DM increases NAFLD progression to MASH and fibrosis, while NAFLD raises the risk of prediabetes and T2DM. A layered screening strategy involving biomarkers, fibrosis scores, and imaging is recommended for high-risk populations. Lifestyle interventions—including weight loss, diet, and exercise—are fundamental, supported by modern antidiabetic agents and liver-targeted therapies. T2DM and NAFLD/MASH are intertwined, requiring integrated screening and management strategies that address both metabolic and liver disease progression. Lifestyle changes remain essential, with emerging pharmacological treatments offering additional benefits. Further research is needed to refine screening methods and optimize treatment approaches for patients with these interconnected metabolic conditions.
Keywords:
Type 2 diabetes mellitus, NAFLD, MASLD, MASH, insulin resistance, screening
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Gancheva, S., Roden, M., & Castera, L. (2024). Diabetes as a risk factor for MASH progression. Diabetes Research and Clinical Practice, 217, 111846.
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Kongmalai, T., Srinonprasert, V., Anothaisintawee, T., Kongmalai, P., McKay, G., Attia, J., & Thakkinstian, A. (2023). New anti-diabetic agents for the treatment of non-alcoholic fatty liver disease: a systematic review and network meta-analysis of randomized controlled trials. Frontiers in Endocrinology, 14. https://doi.org/10.3389/fendo.2023.1182037
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Lee, W. H., Kipp, Z. A., Bates, E. A., Pauss, S. N., Martinez, G. J., & Hinds, T. D. (2025). The physiology of MASLD: molecular pathways between liver and adipose tissues. Clinical Science (London, England?: 1979), 139(18). https://doi.org/10.1042/CS20257571
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Liu, Z., Chen, X., Yuan, H., Jin, L., Zhang, T., & Chen, X. (2025). Dissecting the shared genetic architecture between nonalcoholic fatty liver disease and type 2 diabetes. Human Molecular Genetics, 34(4), 338–346. https://doi.org/10.1093/hmg/ddae184
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Maruši?, M., Pai?, M., Knobloch, M., & Liberati Pršo, A. M. (2021). NAFLD, Insulin Resistance, and Diabetes Mellitus Type 2. Canadian Journal of Gastroenterology and Hepatology, 2021. https://doi.org/10.1155/2021/6613827
Nawrot, M., Peschard, S., Lestavel, S., & Staels, B. (2021). Intestine-liver crosstalk in Type 2 Diabetes and non-alcoholic fatty liver disease. Metabolism: Clinical and Experimental, 123. https://doi.org/10.1016/j.metabol.2021.154844
Ni, W., Lu, Y., & Wang, W. (2024). Exploring the interconnected between type 2 diabetes mellitus and nonalcoholic fatty liver disease: Genetic correlation and Mendelian randomization analysis. Medicine (United States), 103(19), E38008. https://doi.org/10.1097/MD.0000000000038008
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Parry, S. A., & Hodson, L. (2020). Managing NAFLD in Type 2 Diabetes: The Effect of Lifestyle Interventions, a Narrative Review. Advances in Therapy, 37(4), 1381–1406. https://doi.org/10.1007/s12325-020-01281-6
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