The DOI matches its Crossref record; 99 of the 102 references it cites were found in a registry or an index.
Resolving the Paradox of Hepatic Insulin Resistance
Open accessAbstract
Insulin resistance is associated with numerous metabolic disorders, such as obesity and type II diabetes, that currently plague our society. Although insulin normally promotes anabolic metabolism in the liver by increasing glucose consumption and lipid synthesis, insulin-resistant individuals fail to inhibit hepatic glucose production and paradoxically have increased liver lipid synthesis, leading to hyperglycemia and hypertriglyceridemia. Here, we detail the intrahepatic and extrahepatic pathways mediating insulin's control of glucose and lipid metabolism. We propose that the interplay between both of these pathways controls insulin signaling and that mis-regulation between the 2 results in the paradoxic effects seen in the insulin-resistant liver instead of the commonly proposed deficiencies in particular branches of only the direct hepatic pathway.
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“Reduced phosphorylation of the PI3K/Akt pathway is a hallmark of IR in PCOS patients10–12.”
From Efficacy and safety of GLP-1 receptor agonists on weight management and metabolic parameters in PCOS women: a meta-analysis of randomized controlled trials (2025) · cites this paper as [11]
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“hepatic insulin resistance, among other effects, has proved to result in increased gluconeogenesis, lipogenesis, and synthesis of very-low-density lipoproteins (VLDL) [22]”
From The Role of Exercise in the Interplay between Myokines, Hepatokines, Osteokines, Adipokines, and Modulation of Inflammation for Energy Substrate Redistribution and Fat Mass Loss: A Review (2020) · cites this paper as [22]
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1 retracted
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Cited by
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Mechanisms of Fibrosis Development in Nonalcoholic Steatohepatitis
Schwabe, R. F., Tabas, I., & Pajvani, U. B. (2020) · Gastroenterology · doi:10.1053/j.gastro.2019.11.311 · Cited by 671
Role of Insulin in Health and Disease: An Update
Rahman, M. S., Hossain, K. S., Das, S., Kundu, S., Adegoke, E. O., Rahman, M. A., Hannan, M. A., Uddin, M. J., & Pang, M. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22126403 · Cited by 574
The Role of Estrogen in Insulin Resistance
Paoli, M. D., Zakharia, A., & Werstuck, G. H. (2021) · American Journal Of Pathology · doi:10.1016/j.ajpath.2021.05.011 · Cited by 322
“However, insulin-resistant individuals do not respond to this signaling process, and paradoxically show an increase in both hepatic glucose production and insulin secretion, which can induce or aggravate hyperglycemia.(15) The factors that promote the emergence of insulin resistance include altered insulin signaling,…”
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Wang, Y., Yu, W., Li, S., Guo, D., He, J., & Wang, Y. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.836058 · Cited by 238
“In mammals, the accumulation of lipid in tissues, such as muscle and liver, is closely related to insulin resistance that associates with a myriad of metabolic disorders (84, 85).”
Background
Metadata
- Authors
- Santoleri, D., & Titchenell, P. M.
- Affiliations
- University of Pennsylvania (US)
- Corresponding author
- Titchenell, Paul M.
- Venue
- Cellular and Molecular Gastroenterology and Hepatology
- Publisher
- Elsevier BV
- Published
- 2019
- Volume
- 7
- Issue
- 2
- Pages
- 447-456
- ISSN
- 2352-345X (ISSN-L)
- PMC
- PMC6369222
- OpenAlex
- W2899043265
- Cited by
- 336
- References
- 102
- Citations by year
- 2026: 35 · 2025: 57 · 2024: 61 · 2023: 63 · 2022: 51 · 2021: 40 · 2020: 24 · 2019: 5
- FWCI
- 2.57
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cellular and Molecular Gastroenterology and Hepatology (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institutes of Health (K01 DK111715, P30 DK19525)
- Topics
- Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Keywords
- hepatic insulin resistance, insulin signaling, hepatic glucose production, hepatic lipid synthesis, hypertriglyceridemia, hyperglycemia, type 2 diabetes, obesity, glucose metabolism, lipid metabolism
- MeSH terms
- Animals, Humans, Insulin, Insulin Resistance, Liver, Models, Biological, Signal Transduction, Lipid Metabolism
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