Human and molecular genetics shed lights on fatty liver disease and diabetes conundrum
Abstract The causal role of abdominal overweight/obesity, insulin resistance and type 2 diabetes (T2D) on the risk of fatty liver disease (FLD) has robustly been proven. A consensus of experts has recently proposed the novel definition of ‘metabolic dysfunction‐associated fatty liver disease, MAFLD’...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2020-10-01
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| Series: | Endocrinology, Diabetes & Metabolism |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/edm2.179 |
| _version_ | 1819230126066368512 |
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| author | Federica Tavaglione Giovanni Targher Luca Valenti Stefano Romeo |
| author_facet | Federica Tavaglione Giovanni Targher Luca Valenti Stefano Romeo |
| author_sort | Federica Tavaglione |
| collection | DOAJ |
| description | Abstract The causal role of abdominal overweight/obesity, insulin resistance and type 2 diabetes (T2D) on the risk of fatty liver disease (FLD) has robustly been proven. A consensus of experts has recently proposed the novel definition of ‘metabolic dysfunction‐associated fatty liver disease, MAFLD’ instead of ‘nonalcoholic fatty liver disease, NAFLD’, emphasizing the central role of dysmetabolism in the disease pathogenesis. Conversely, a direct and independent contribution of FLD per se 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 PNPLA3, TM6SF2, MBOAT7, GCKR, HSD17B13) as determinants of insulin resistance and T2D. However, recent studies highlighted that the key molecular mechanism of dysmetabolism is not fat accumulation per se but the degree of hepatic fibrosis (excess liver fat content—lipotoxicity), 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‐cell function, although future studies are needed to fully understand this relationship. |
| first_indexed | 2024-12-23T11:24:06Z |
| format | Article |
| id | doaj.art-e32fca988a1543549630f4657e1beb90 |
| institution | Directory Open Access Journal |
| issn | 2398-9238 |
| language | English |
| last_indexed | 2024-12-23T11:24:06Z |
| publishDate | 2020-10-01 |
| publisher | Wiley |
| record_format | Article |
| series | Endocrinology, Diabetes & Metabolism |
| spelling | doaj.art-e32fca988a1543549630f4657e1beb902022-12-21T17:48:59ZengWileyEndocrinology, Diabetes & Metabolism2398-92382020-10-0134n/an/a10.1002/edm2.179Human and molecular genetics shed lights on fatty liver disease and diabetes conundrumFederica Tavaglione0Giovanni Targher1Luca Valenti2Stefano Romeo3Clinical Medicine and Hepatology Unit Department of Internal Medicine and Geriatrics Campus Bio‐Medico University Rome ItalySection of Endocrinology, Diabetes and Metabolism Department of Medicine University and Azienda Ospedaliera Universitaria Integrata of Verona Verona ItalyDepartment of Pathophysiology and Transplantation Università degli Studi di Milano Milano ItalyDepartment of Molecular and Clinical Medicine Sahlgrenska Academy University of Gothenburg Gothenburg SwedenAbstract The causal role of abdominal overweight/obesity, insulin resistance and type 2 diabetes (T2D) on the risk of fatty liver disease (FLD) has robustly been proven. A consensus of experts has recently proposed the novel definition of ‘metabolic dysfunction‐associated fatty liver disease, MAFLD’ instead of ‘nonalcoholic fatty liver disease, NAFLD’, emphasizing the central role of dysmetabolism in the disease pathogenesis. Conversely, a direct and independent contribution of FLD per se 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 PNPLA3, TM6SF2, MBOAT7, GCKR, HSD17B13) as determinants of insulin resistance and T2D. However, recent studies highlighted that the key molecular mechanism of dysmetabolism is not fat accumulation per se but the degree of hepatic fibrosis (excess liver fat content—lipotoxicity), 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‐cell function, although future studies are needed to fully understand this relationship.https://doi.org/10.1002/edm2.179diabetesfatty liver diseasehuman genetics |
| spellingShingle | Federica Tavaglione Giovanni Targher Luca Valenti Stefano Romeo Human and molecular genetics shed lights on fatty liver disease and diabetes conundrum Endocrinology, Diabetes & Metabolism diabetes fatty liver disease human genetics |
| title | Human and molecular genetics shed lights on fatty liver disease and diabetes conundrum |
| title_full | Human and molecular genetics shed lights on fatty liver disease and diabetes conundrum |
| title_fullStr | Human and molecular genetics shed lights on fatty liver disease and diabetes conundrum |
| title_full_unstemmed | Human and molecular genetics shed lights on fatty liver disease and diabetes conundrum |
| title_short | Human and molecular genetics shed lights on fatty liver disease and diabetes conundrum |
| title_sort | human and molecular genetics shed lights on fatty liver disease and diabetes conundrum |
| topic | diabetes fatty liver disease human genetics |
| url | https://doi.org/10.1002/edm2.179 |
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