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A consensus of experts has recently proposed the novel definition of \u2018metabolic dysfunction\u2010associated fatty liver disease, MAFLD\u2019 instead of \u2018nonalcoholic fatty liver disease, NAFLD\u2019, emphasizing the central role of dysmetabolism in the disease pathogenesis. Conversely, a direct and independent contribution of FLD <jats:italic>per se<\/jats:italic> on risk of developing T2D is still a controversial topic. When dealing with FLD as a potential risk factor for T2D, it is straightforward to think of hepatic insulin resistance as the most relevant underlying mechanism. Emerging evidence supports genetic determinants of FLD (eg <jats:italic>PNPLA3, TM6SF2, MBOAT7, GCKR, HSD17B13<\/jats:italic>) as determinants of insulin resistance and T2D. However, recent studies highlighted that the key molecular mechanism of dysmetabolism is not fat accumulation <jats:italic>per se<\/jats:italic> but the degree of hepatic fibrosis (excess liver fat content\u2014lipotoxicity), leading to reduced insulin clearance, insulin resistance and T2D. A consequence of these findings is that drugs that will ameliorate liver fat accumulation and fibrosis in principle may also exert a beneficial effect on insulin resistance and risk of T2D in individuals with FLD. Finally, initial findings show that these genetic factors might be directly implicated in modulating pancreatic beta\u2010cell function, although future studies are needed to fully understand this relationship.<\/jats:p>","DOI":"10.1002\/edm2.179","type":"journal-article","created":{"date-parts":[[2020,9,4]],"date-time":"2020-09-04T17:02:37Z","timestamp":1599238957000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Human and molecular genetics shed lights on fatty liver disease and diabetes conundrum"],"prefix":"10.1002","volume":"3","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1720-4355","authenticated-orcid":false,"given":"Federica","family":"Tavaglione","sequence":"first","affiliation":[{"name":"Clinical Medicine and Hepatology Unit Department of Internal Medicine and Geriatrics Campus Bio\u2010Medico University  Rome Italy"},{"name":"Department of Molecular and Clinical Medicine Sahlgrenska Academy 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