ArticleScientific reports2016
Long-term exposure to abnormal glucose levels alters drug metabolism pathways and insulin sensitivity in primary human hepatocytes.
Article in Scientific reports, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 44 papers.
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Who cites it
44 citing papers in PubMed, 121 citations in OpenAlex.
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- Liver portal fibroblasts induce the functions of primary human hepatocytes in vitro.Communications biology · 2025Article
- Radiation induced dermatitis by increasing triglyceride levels to induce autophagy and inhibit the PI3K/Akt/mTOR signaling pathway.Lipids in health and disease · 2025Article
- Normoglycemia and physiological cortisone level maintain glucose homeostasis in a pancreas-liver microphysiological system.Communications biology · 2024Article
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- Characterization of diseased primary human hepatocytes in an all-human cell-based triculture system.Scientific reports · 2024Article
- Sex-biased gene expression and gene-regulatory networks of sex-biased adverse event drug targets and drug metabolism genes.BMC pharmacology & toxicology · 2024Article
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- Sex-biased gene expression and gene-regulatory networks of sex-biased adverse event drug targets and drug metabolism genes.bioRxiv : the preprint server for biology · 2023Article
- Modeling and therapeutic targeting of inflammation-induced hepatic insulin resistance using human iPSC-derived hepatocytes and macrophages.Nature communications · 2023Article
- Decellularized Liver Nanofibers Enhance and Stabilize the Long-Term Functions of Primary Human Hepatocytes In Vitro.Advanced healthcare materials · 2023Article
- The evolving role of investigative toxicology in the pharmaceutical industry.Nature reviews. Drug discovery · 2023Review
- Integrated experimental-computational analysis of a HepaRG liver-islet microphysiological system for human-centric diabetes research.PLoS computational biology · 2022Article
- Treatment of hyperglycemia not associated with NAFLD improvement in children with type 2 diabetes mellitus.International journal of pediatrics & adolescent medicine · 2022Article
- Improving human mesenchymal stem cell-derived hepatic cell energy metabolism by manipulating glucose homeostasis and glucocorticoid signaling.Frontiers in endocrinology · 2022Article
- Engineering Modular 3D Liver Culture MicroenvironmentsAdvanced nanobiomed research · 2022Article
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Hyperglycemia in type 2 diabetes mellitus has been linked to non-alcoholic fatty liver disease, which can progress to inflammation, fibrosis/cirrhosis, and hepatocellular carcinoma. Understanding how chronic hyperglycemia affects primary human hepatocytes (PHHs) can facilitate the development of therapeutics for these diseases. Conversely, elucidating the effects of hypoglycemia on PHHs may provide insights into how the liver adapts to fasting, adverse diabetes drug reactions, and cancer. In contrast to declining PHH monocultures, micropatterned co-cultures (MPCCs) of PHHs and 3T3-J2 murine embryonic fibroblasts maintain insulin-sensitive glucose metabolism for several weeks. Here, we exposed MPCCs to hypo-, normo- and hyperglycemic culture media for ~3 weeks. While albumin and urea secretion were not affected by glucose level, hypoglycemic MPCCs upregulated CYP3A4 enzyme activity as compared to other glycemic states. In contrast, hyperglycemic MPCCs displayed significant hepatic lipid accumulation in the presence of insulin, while also showing decreased sensitivity to insulin-mediated inhibition of glucose output relative to a normoglycemic control. In conclusion, we show for the first time that PHHs exposed to hypo- and hyperglycemia can remain highly functional, but display increased CYP3A4 activity and selective insulin resistance, respectively. In the future, MPCCs under glycemic states can aid in novel drug discovery and mechanistic investigations.
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