Korean Diabetes J.  2008 Jun;32(3):175-181. 10.4093/kdj.2008.32.3.175.

Glucose Toxicity and Pancreatic Beta Cell Dysfunction in Type 2 Diabetes

• Won KC
• Yoon JS

• KMID: 2298087
• DOI: http://doi.org/10.4093/kdj.2008.32.3.175

Abstract

The adverse effects of prolonged exposure of pancreatic islets to supraphysiologic glucose concentrations (i.e. glucose toxicity) is mediated at least in part by glucose oxidation and the subsequent generation of reactive oxygen species (ROS) that can impair insulin gene expression and beta cell function. Multiple biochemical pathways and mechanisms of action for glucose toxicity have been suggested. These include glucose autoxidation, protein kinase C activation, methylglyoxal formation and glycation, hexosamine metabolism, sorbitol formation, and oxidative phosphorylation. There are many potential mechanisms whereby excess glucose metabolites traveling along these pathways might cause beta cell damage. However, all these pathways have in common the formation of reactive oxygen species that, in excess and over time, cause chronic oxidative stress, which in turn causes defective insulin gene expression and insulin secretion as well as increased apoptosis. The intracellular peroxide levels of the pancreatic islets (INS-1 cells, rat islets) by flow cytometry were increased in the high glucose media compared to 5.6 mM glucose media. The insulin, MafA, PDX-1 mRNA levels and glucose stimulated insulin secretion (GSIS) were decreased in high glucose media compared to 5.6 mM glucose media. The HO-1 seems to mediate the protective response of pancreatic islets against the oxidative stress that is due to high glucose conditions. Also, we observed decreased glutathione level, gamma-GCS expression and increased oxidized LDL, malondialdehyde level at leukocytes and mesothelial cells from patients with Korean Type 2 Diabetes (esp, poorly controlled patients). In conclusion, this pathophysiologic sequence sets the scene for considering antioxidant therapy as an adjunct in the management of diabetes, especially type 2 Diabetes.

Keyword

Beta cell dysfunction; Glucose toxicity; Type 2 Diabetes

MeSH Terms

Animals
Apoptosis
Flow Cytometry
Gene Expression
Glucose
Glutathione
Humans
Insulin
Insulin-Secreting Cells
Islets of Langerhans
Leukocytes
Lipoproteins, LDL
Malondialdehyde
Oxidative Phosphorylation
Oxidative Stress
Protein Kinase C
Pyruvaldehyde
Rats
Reactive Oxygen Species
RNA, Messenger
Sorbitol
Glucose
Glutathione
Insulin
Lipoproteins, LDL
Malondialdehyde
Protein Kinase C
Pyruvaldehyde
RNA, Messenger
Reactive Oxygen Species
Sorbitol

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