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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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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