Glucose toxicity in beta-cells： type 2 diabetes, good radicals gone bad, and the glutathione connection PY2003 IR95 教材

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2025-10-13
Glucose toxicity in beta-cells: type 2 diabetes, good radicals gone bad, and the glutathione connection

Glucose toxicity in beta-cells： type 2 diabetes, good radicals gone bad, and the glutathione connection PY2003 IR95 教材

Source or References (資訊來源或是參考的資訊):
https://pubmed.ncbi.nlm.nih.gov/12606496/
Info cited on 2025-10-13-WD1 (資訊引用於 中華民國114年西元2025年10月13日) by 湯偉晉 (WeiJin Tang)
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Review Diabetes
. 2003 Mar;52(3):581-7. doi: 10.2337/diabetes.52.3.581.
Glucose toxicity in beta-cells: type 2 diabetes, good radicals gone bad, and the glutathione connection
R Paul Robertson 1, Jamie Harmon, Phuong Oanh Tran, Yoshito Tanaka, Hiroki Takahashi
Affiliations collapse
Affiliation
1Pacific Northwest Research Institute, 720 Broadway, Seattle, WA 98122, USA.
PMID: 12606496 DOI: 10.2337/diabetes.52.3.581
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 beta-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 beta-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 beta-cell function.

glucose toxicity
葡萄糖毒性
glucose toxicity (葡萄糖毒性)
葡萄糖毒性 (glucose toxicity)

Abstract
摘要

Chronic exposure to hyperglycemia can lead to cellular dysfunction that may become irreversible over time, a process that is termed glucose toxicity.
長期暴露於高血糖環境可導致細胞功能障礙，且此損傷可能隨時間而不可逆，這一過程被稱為葡萄糖毒性（glucose toxicity）。

Our perspective about glucose toxicity as it pertains to the pancreatic beta-cell is that the characteristic decreases in insulin synthesis and secretion are caused by decreased insulin gene expression.
我們對於葡萄糖毒性在胰臟 β 細胞中的看法是，其特徵性胰島素合成與分泌下降，主要是由胰島素基因表現降低所導致。

The responsible metabolic lesion appears to involve a posttranscriptional defect in pancreas duodenum homeobox-1 (PDX-1) mRNA maturation.
造成此現象的代謝異常似乎涉及胰臟十二指腸同源盒基因-1（pancreas duodenum homeobox-1，PDX-1）mRNA 成熟過程中的轉錄後缺陷。

PDX-1 is a critically important transcription factor for the insulin promoter, is absent in glucotoxic islets, and, when transfected into glucotoxic beta-cells, improves insulin promoter activity.
PDX-1 是調控胰島素啟動子的關鍵轉錄因子，在受到葡萄糖毒性影響的胰島中缺乏；然而，當其被轉染入葡萄糖毒性的 β 細胞中時，可恢復胰島素啟動子活性。

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.
由於在超出生理濃度的葡萄糖條件下，反應性氧化物（ROS）可經由厭氧糖解過程中的氧化磷酸化、糖化反應中的席夫反應（Schiff reaction）、葡萄糖自動氧化，以及己糖胺代謝途徑產生，因此我們推測慢性氧化壓力是葡萄糖毒性的主要機制之一。

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.
此假說的支持來自以下觀察結果：高葡萄糖濃度會提升胰島內過氧化物水平；胰島內抗氧化酵素活性極低；而在體外以腺病毒過表達抗氧化酵素的胰島模型，或在動物體內以外源性抗氧化劑處理時，皆能保護胰島免受過量葡萄糖的毒性影響。

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 beta-cell function.
在臨床上，考慮將抗氧化劑作為第二型糖尿病的輔助治療具有合理性，因為許多研究報告指出此類患者普遍存在氧化壓力標誌物升高的現象，而該疾病特徵為血糖控制不完全、慢性高血糖，以及 β 細胞功能持續惡化。

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