The DOI matches its Crossref record; 59 of the 59 references it cites were found in a registry or an index.
Mechanisms of Insulin Resistance in Primary and Secondary Nonalcoholic Fatty Liver
Open accessAbstract
Nonalcoholic fatty liver disease is associated with hepatic insulin resistance and may result primarily from increased hepatic de novo lipogenesis (PRIM) or secondarily from adipose tissue lipolysis (SEC). We studied mice with hepatocyte- or adipocyte-specific SREBP-1c overexpression as models of PRIM and SEC. PRIM mice featured increased lipogenic gene expression in the liver and adipose tissue. Their selective, liver-specific insulin resistance was associated with increased C18:1-diacylglycerol content and protein kinase Cε translocation. SEC mice had decreased lipogenesis mediated by hepatic cholesterol responsive element–binding protein and featured portal/lobular inflammation along with total, whole-body insulin resistance. Hepatic mitochondrial respiration transiently increased and declined with aging along with higher muscle reactive oxygen species production. In conclusion, hepatic insulin resistance originates from lipotoxicity but not from lower mitochondrial capacity, which can even transiently adapt to increased peripheral lipolysis. Peripheral insulin resistance is prevented during increased hepatic lipogenesis only if adipose tissue lipid storage capacity is preserved.
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“Of note, IR in these two different models with MASLD can result not from impaired mitochondrial function but from increased accumulation of specific DAG [84].”
From Hepatic Insulin Resistance and Steatosis in Metabolic Dysfunction-Associated Steatotic Liver Disease: New Insights into Mechanisms and Clinical Implications (2025) · cites this paper as [84]
In the citing paper
“This is in line with the results from some studies in that hepatic esterification of FAs into TG, unlike DNL, depends on substrate delivery rather than insulin action [84-86].”
From Hepatic Insulin Resistance and Steatosis in Metabolic Dysfunction-Associated Steatotic Liver Disease: New Insights into Mechanisms and Clinical Implications (2025) · cites this paper as [84]
In the citing paper
“Actually, impaired mitochondrial function (i.e., decreased oxidative capacity and/or increased oxidative stress) did not precede IR.”
From Hepatic Insulin Resistance and Steatosis in Metabolic Dysfunction-Associated Steatotic Liver Disease: New Insights into Mechanisms and Clinical Implications (2025) · cites this paper as [84]
In the citing paper
“While this mechanism is important in the initial stages, the progression of MASLD ultimately depends on the development of total hepatic IR and systemic IR [84].”
From Hepatic Insulin Resistance and Steatosis in Metabolic Dysfunction-Associated Steatotic Liver Disease: New Insights into Mechanisms and Clinical Implications (2025) · cites this paper as [84]
In the citing paper
“However, augmented FA flux to the liver and/or peripheral IR may lead to so-called ‘secondary MASLD’ and total hepatic IR [84].”
From Hepatic Insulin Resistance and Steatosis in Metabolic Dysfunction-Associated Steatotic Liver Disease: New Insights into Mechanisms and Clinical Implications (2025) · cites this paper as [84]
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Citations
Cites
EASL–EASD–EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease
(2016) · Journal of Hepatology · doi:10.1016/j.jhep.2015.11.004 · Cited by 4,836
Donnelly, K. L., Smith, C. I., Schwarzenberg, S. J., Jessurun, J., Boldt, M. D., & Parks, E. J. (2005) · Journal of Clinical Investigation · doi:10.1172/jci23621 · Cited by 3,604
Assessing mitochondrial dysfunction in cells
Brand, M. D., & Nicholls, D. G. (2011) · Biochemical Journal · doi:10.1042/bj20110162 · Cited by 2,436
INFLUENCES OF GLUCOSE LOADING AND OF INJECTED INSULIN ON HEPATIC GLUCOSE OUTPUT*
Steele, R. D. (1959) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1959.tb44923.x · Cited by 1,680
The pathogenesis of insulin resistance: integrating signaling pathways and substrate flux
Samuel, V. T., & Shulman, G. I. (2016) · Journal of Clinical Investigation · doi:10.1172/jci77812 · Cited by 1,484
Self-citationMechanism of hepatic insulin resistance in non-alcoholic fatty liver disease
Samuel, V. T., Liu, Z.-X., Qu, X., Elder, B. D., Bilz, S., Befroy, D., Romanelli, A. J., & Shulman, G. I. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m313478200 · Cited by 1,322
Self-citationEctopic Fat in Insulin Resistance, Dyslipidemia, and Cardiometabolic Disease
Shulman, G. I. (2014) · New England Journal of Medicine · doi:10.1056/nejmra1011035 · Cited by 1,126
Self-citationLambert, J. E., Ramos–Roman, M. A., Browning, J. D., & Parks, E. J. (2014) · Gastroenterology · doi:10.1053/j.gastro.2013.11.049 · Cited by 1,069 · cited 1×
“Although a feature of human NAFL (6), hepatic DNL does not necessarily lead to IR (7).”
BackgroundLeptin reverses insulin resistance and diabetes mellitus in mice with congenital lipodystrophy
Shimomura, I., Hammer, R. E., Ikemoto, S., Brown, M. S., & Goldstein, J. L. (1999) · Nature · doi:10.1038/43448 · Cited by 1,038
Koliaki, C., Szendroedi, J., Kaul, K., Jelenik, T., Nowotny, P., Jankowiak, F., Herder, C., Carstensen, M., Krausch, M., Knoefel, W. T., et al. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2015.04.004 · Cited by 1,032
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Mechanisms of Insulin Action and Insulin Resistance
Petersen, M. C., & Shulman, G. I. (2018) · Physiological Reviews · doi:10.1152/physrev.00063.2017 · Cited by 3,028
Self-citationThe complex link between NAFLD and type 2 diabetes mellitus - mechanisms and treatments
Targher, G., Corey, K. E., Byrne, C. D., & Roden, M. (2021) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-021-00448-y · Cited by 850
Self-citationMitochondrial alterations in fatty liver diseases
Fromenty, B., & Roden, M. (2022) · Journal of Hepatology · doi:10.1016/j.jhep.2022.09.020 · Cited by 448
Self-citationKumar, S., Duan, Q., Wu, R., Harris, E. N., & Su, Q. (2021) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2021.113869 · Cited by 382
Nonalcoholic fatty liver disease (NAFLD) from pathogenesis to treatment concepts in humans
Pafili, K., & Roden, M. (2021) · Molecular Metabolism · doi:10.1016/j.molmet.2020.101122 · Cited by 330
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Metadata
- Authors
- Jelenik, T., Kaul, K., Séquaris, G., Flögel, U., Phielix, E., Kotzka, J., Knebel, B., Fahlbusch, P., Hörbelt, T., Lehr, S., Reinbeck, A. L., Müller-Wieland, D., Esposito, I., Shulman, G. I., Szendroedi, J., & Roden, M.
- Affiliations
- Institute for Clinical Diabetology, German Diabetes Center, Düsseldorf, Germany
- Deutsches Diabetes-Zentrum e.V. (DE)
- Heinrich Heine University Düsseldorf (DE)
- Department of Internal Medicine I, University Hospital Aachen, Aachen, Germany
- Institute of Pathology, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany
- Howard Hughes Medical Institute (US)
- Corresponding author
- Roden, Michael
- ORCID
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2017-05-10
- Volume
- 66
- Issue
- 8
- Pages
- 2241-2253
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- PMC
- PMC5521856
- OpenAlex
- W2612023289
- Cited by
- 154
- References
- 58
- Citations by year
- 2026: 8 · 2025: 9 · 2024: 11 · 2023: 18 · 2022: 15 · 2021: 16 · 2020: 28 · 2019: 25 · 2018: 19 · 2017: 5
- FWCI
- 16.50
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Diabetes (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- RWTH Publications (RWTH Aachen) (submittedVersion)
- Funders
- Ministry of Science and Research of the State of North Rhine-Westphalia
- German Federal Ministry of Health
- Federal Ministry for Research
- German Center for Diabetes Research
- Helmholtz Alliance to Universities
- German Research Foundation (SFB 1116)
- German Diabetes Association
- Schmutzler-Stiftung
- National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases (R01-DK-40936, U24-DK-059635, P30-DK-45735)
- Topics
- Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diet, Metabolism, and Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Keywords
- insulin resistance, non-alcoholic fatty liver disease, hepatic de novo lipogenesis, adipose tissue lipolysis, SREBP-1c, lipotoxicity, mitochondrial respiration, reactive oxygen species, liver inflammation, aging
- MeSH terms
- Animals, Diglycerides, Female, Insulin Resistance, Lipolysis, Liver, Mice, Transgenic, Reactive Oxygen Species, Adipocytes, Protein Transport, Hepatocytes, Lipogenesis, Mice, Protein Kinase C-epsilon, Sterol Regulatory Element Binding Protein 1, Non-alcoholic Fatty Liver Disease
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