Cited by 898Pancreatic function and diabetesEndoplasmic Reticulum Stress and DiseaseDiabetes Treatment and Management

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Glucose Toxicity in β-Cells: Type 2 Diabetes, Good Radicals Gone Bad, and the Glutathione Connection

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Robertson, R. Paul, Harmon, Jamie, Tran, Phuong Oanh, Tanaka, Yoshito, Takahashi, Hiroki·2003·Diabetes

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Abstract

Chronic exposure to hyperglycemia can lead to cellular dysfunction that may become irreversible over time, a process that is termed glucose toxicity. Our perspective about glucose toxicity as it pertains to the pancreatic β-cell is that the characteristic decreases in insulin synthesis and secretion are caused by decreased insulin gene expression. The responsible metabolic lesion appears to involve a posttranscriptional defect in pancreas duodenum homeobox-1 (PDX-1) mRNA maturation. PDX-1 is a critically important transcription factor for the insulin promoter, is absent in glucotoxic islets, and, when transfected into glucotoxic β-cells, improves insulin promoter activity. Because reactive oxygen species are produced via oxidative phosphorylation during anaerobic glycolysis, via the Schiff reaction during glycation, via glucose autoxidation, and via hexosamine metabolism under supraphysiological glucose concentrations, we hypothesize that chronic oxidative stress is an important mechanism for glucose toxicity. Support for this hypothesis is found in the observations that high glucose concentrations increase intraislet peroxide levels, that islets contain very low levels of antioxidant enzyme activities, and that adenoviral overexpression of antioxidant enzymes in vitro in islets, as well as exogenous treatment with antioxidants in vivo in animals, protect the islet from the toxic effects of excessive glucose levels. Clinically, consideration of antioxidants as adjunct therapy in type 2 diabetes is warranted because of the many reports of elevated markers of oxidative stress in patients with this disease, which is characterized by imperfect management of glycemia, consequent chronic hyperglycemia, and relentless deterioration of β-cell function.

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Robertson RP, HJ, Tanaka Y, Sacchi G, Tran POT, Gleason C, Poitout V: Glucose toxicity of the β-cell: cellular and molecular mechanisms. In Diabetes Mellitus. LeRoith D, Olefsky JM, Taylor S, Eds. New York, Lippincott Williams & Wilkins,2000, p.125–132

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Authors: Robertson, R. P., Harmon, J., Tran, P. O., Tanaka, Y., & Takahashi, H.
Affiliations: Pacific Northwest Research Institute (US)
From the Pacific Northwest Research Institute, Seattle, Washington
ORCID: Robertson, R. Paul
Takahashi, Hiroki
Venue: Diabetes
Publisher: American Diabetes Association
Published: 2003-03-01
Volume: 52
Issue: 3
Pages: 581-587
ISSN: 0012-1797 (ISSN-L)
1939-327X
DOI: 10.2337/diabetes.52.3.581
OpenAlex: W2097784879
Cited by: 897
References: 57
Citations by year: 2026: 14 · 2025: 13 · 2024: 22 · 2023: 27 · 2022: 43 · 2021: 40 · 2020: 29 · 2019: 35 · 2018: 45 · 2017: 44 · 2016: 54 · 2015: 36 · 2014: 43 · 2013: 50 · 2012: 44
FWCI: 8.49
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Diabetes (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health
National Institute of Diabetes and Digestive and Kidney Diseases (R-01-DK-38325, R01DK038325)
Topics: Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pancreatic function and diabetes
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
Keywords: glucotoxicity, pancreatic beta cells, type 2 diabetes, hyperglycemia, PDX1, insulin gene expression, mRNA splicing, oxidative stress, reactive oxygen species, glutathione, antioxidants, islets, insulin secretion, hexosamine metabolism, glycation
MeSH terms: Animals, Antioxidants, Diabetes Mellitus, Type 2, Glucose, Glutathione, Humans, Hyperglycemia, Insulin, Islets of Langerhans, RNA, Messenger, Trans-Activators, Oxidative Stress, Homeodomain Proteins

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Glucose Toxicity in β-Cells: Type 2 Diabetes, Good Radicals Gone Bad, and the Glutathione Connection

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