ArticleProceedings of the National Academy of Sciences of the United States of America1999
Prevention of glucose toxicity in HIT-T15 cells and Zucker diabetic fatty rats by antioxidants.
Article in Proceedings of the National Academy of Sciences of the United States of America, 1999. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 136 papers.
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Who cites it
136 citing papers in PubMed, 459 citations in OpenAlex.
- Human β-Cell Dedifferentiation and Diabetes.Journal of diabetes · 2026Review
- Antioxidant therapy, N-acetyl-L-cysteine, effects on pancreatic β cells: therapeutic promise or potential harm?Endocrinology · 2026Review
- Perspective: Beta Cell Glucose Toxicity in Type 2 Diabetes: Nrf2 and the Endogenous Antioxidant Response.Antioxidants (Basel, Switzerland) · 2026Article
- Experimental models in diabetes research.Laboratory animal research · 2026Review
- Lipid Metabolic Disorders: a Pivotal Driver in Type 2 Diabetes Mellitus Pathogenesis.Current obesity reports · 2026Review
- Ppid is necessary for overnutrition-induced β-cell loss.American journal of physiology. Endocrinology and metabolism · 2026Article
- Modulation of gene expression by traditional Asian antidiabetic nutraceuticals: A review of potential effects.Asia Pacific journal of clinical nutrition · 2025Review
- Distribution of glutathione peroxidase-1 immunoreactive cells in pancreatic islets from type 1 diabetic donors and non-diabetic donors with and without islet cell autoantibodies is variable and independent of disease.Cell and tissue research · 2025Article
- β-Cell Dedifferentiation in HOMA-βlow and HOMA-βhigh Subjects.The Journal of clinical endocrinology and metabolism · 2025Article
- Umbilical Cord Mesenchymal Stem Cell-Derived Extracellular Vesicles Attenuate Oxidative Damage via the miR-191-5p/DAPK1/AKT Axis in Type 2 Diabetes.Biomaterials research · 2025Article
- Exploring the key role of DNA methylation as an epigenetic modulator in oxidative stress related islet cell injury in patients with type 2 diabetes mellitus: a review.Journal of diabetes and metabolic disorders · 2024Review
- β-cell neogenesis: A rising star to rescue diabetes mellitus.Journal of advanced research · 2024Review
- Oxidative stress suppresses PHB2-mediated mitophagy in β-cells via the Nrf2/PHB2 pathway.Journal of diabetes investigation · 2024Article
- Antioxidants for Early Treatment of Type 2 Diabetes in Rodents and Humans: Lost in Translation?Diabetes · 2024Review
- Pancreatic β-Cell Identity Change through the Lens of Single-Cell Omics Research.International journal of molecular sciences · 2024Review
- Models in Pancreatic Neuroendocrine Neoplasms: Current Perspectives and Future Directions.Cancers · 2023Review
- Redox Balance in Type 2 Diabetes: Therapeutic Potential and the Challenge of Antioxidant-Based Therapy.Antioxidants (Basel, Switzerland) · 2023Review
- Nanofibrous Scaffolds for Diabetic Wound Healing.Pharmaceutics · 2023Review
- Nrf2 and Antioxidant Response in Animal Models of Type 2 Diabetes.International journal of molecular sciences · 2023Review
- Evolution of Nrf2 Gene Expression in HIT-T15 β-Cells During Chronic Oxidative Stress and Glucose Toxicity.Journal of the Endocrine Society · 2023Article
76 more citing papers are in PubMed but not listed here.
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
Chronic exposure of pancreatic islets to supraphysiologic concentrations of glucose causes adverse alterations in beta cell function, a phenomenon termed glucose toxicity and one that may play a secondary pathogenic role in type 2 diabetes. However, no mechanism of action has been definitively identified for glucose toxicity in beta cells. To ascertain whether chronic oxidative stress might play a role, we chronically cultured the beta cell line, HIT-T15, in medium containing 11.1 mM glucose with and without the antioxidants, N-acetyl-L-cysteine (NAC) or aminoguanidine (AG). Addition of NAC or AG to the culture medium at least partially prevented decreases in insulin mRNA, insulin gene promoter activity, DNA binding of two important insulin promoter transcription factors (PDX-1/STF-1 and RIPE-3b1 activator), insulin content, and glucose-induced insulin secretion. These findings suggested that one mechanism of glucose toxicity in the beta cell may be chronic exposure to reactive oxygen species, i.e., chronic oxidative stress. To ascertain the effects of these drugs on diabetes, NAC or AG was given to Zucker diabetic fatty rats, a laboratory model of type 2 diabetes, from 6 through 12 weeks of age. Both drugs prevented a rise in blood oxidative stress markers (8-hydroxy-2'-deoxyguanosine and malondialdehyde + 4-hydroxy-2-nonenal), and partially prevented hyperglycemia, glucose intolerance, defective insulin secretion as well as decrements in beta cell insulin content, insulin gene expression, and PDX-1 (STF-1) binding to the insulin gene promoter. We conclude that chronic oxidative stress may play a role in glucose toxicity, which in turn may worsen the severity of type 2 diabetes.
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