Activation of the Hexosamine Pathway Leads to Deterioration of Pancreatic β-Cell Function through the Induction of Oxidative Stress*

@article{Kaneto2001ActivationOT,
  title={Activation of the Hexosamine Pathway Leads to Deterioration of Pancreatic $\beta$-Cell Function through the Induction of Oxidative Stress*},
  author={Hideaki Kaneto and G. Xu and Kyung-Hee Song and Kiyoshi Suzuma and Susan Bonner-Weir and A. J. Sharma and Gordon C. Weir},
  journal={The Journal of Biological Chemistry},
  year={2001},
  volume={276},
  pages={31099 - 31104}
}
It is known well that activation of the hexosamine pathway causes insulin resistance, but how this activation influences pancreatic β-cell function remains unclear. In this study, we found that in isolated rat islets adenovirus-mediated overexpression of glutamine:fructose-6-phosphate amidotransferase (GFAT), the first and rate-limiting enzyme of the hexosamine pathway, leads to deterioration of β-cell function, which is similar to that found in diabetes. Overexpression of GFAT or treatment… Expand
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305 Citations

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Oxidative Stress and Pancreatic β-Cell Dysfunction
TLDR
The suppression of oxidative stress by a potent antioxidant, N-acetyl-l-cysteine or probucol, led to the recovery of insulin biosynthesis and PDX-1 expression in nuclei and improved glucose tolerance in animal models for type 2 diabetes. Expand
Molecular convergence of hexosamine biosynthetic pathway and ER stress leading to insulin resistance in L6 skeletal muscle cells
TLDR
A molecular convergence of O-glycosylation processes and ER stress signals at the cross-road of insulin resistance in skeletal muscle is demonstrated for the first time. Expand
Hexosamines stimulate apoptosis by altering SIRT1 action and levels in rodent pancreatic β-cells.
TLDR
It is indicated that reduction of SIRT1 levels by hexosamines contributes to β-cell apoptosis, and methods to increase Sirt1 levels or activity could thus prevent the decrease in β- cell mass, notably that observed in type 2 diabetes. Expand
The hexosamine biosynthesis pathway regulates insulin secretion via protein glycosylation in mouse islets.
TLDR
It is shown that inhibition of the hexosamine biosynthesis pathway decreases insulin secretion from mouse islets in response to a number of secretagogues, including glucose, which may have implications for the development of type 2 diabetes. Expand
The molecular mechanisms of pancreatic β-cell glucotoxicity: Recent findings and future research directions
TLDR
Deciphering these molecular mechanisms of β- cell glucotoxicity is a mandatory first step toward the development of therapeutic strategies to protect β-cells and improve the functional β-cell mass in type 2 diabetes. Expand
Activation of the hexosamine pathway leads to phosphorylation of insulin receptor substrate-1 on Ser307 and Ser612 and impairs the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin insulin biosynthetic pathway in RIN pancreatic beta-cells.
TLDR
Results suggest that activation of the HBP accounts, in part, for glucose-induced phosphorylation at Ser(307) and Ser(612) of IRS-1 mediated by JNK and ERK1/2, respectively. Expand
The Hexosamine Biosynthesis Pathway
Prolonged hyperglycemia is the critical etiological factor in the development of the microvascular complications of diabetes including diabetic nephropathy (1, 2). The tissues subject to these… Expand
Role of Pancreatic Transcription Factors in Maintenance of Mature β-Cell Function
TLDR
Down-regulation of insulin gene transcription factors and incretin receptors explains, at least in part, the molecular mechanism for β-cell glucose toxicity found in type 2 diabetes. Expand
Protective Role of Glucagon-like Peptide-1 Against Glucosamine-induced Cytotoxicity in Pancreatic Beta Cells
TLDR
It is demonstrated that glucosamine may inhibit beta-cell survival by diminishing cellular glucose uptake independent of glycosylation, which can be blocked by GLP-1, which leads to recovery of the glucose uptake through a PKA-independent, cAMP-dependent mechanism. Expand
Disruption of O-linked N-Acetylglucosamine Signaling Induces ER Stress and β Cell Failure.
TLDR
Findings identify OGT as a regulator of β cell mass and function and provide a direct link between O-GlcNAcylation and β cell survival by regulation of ER stress responses and modulation of Akt1/2 signaling. Expand
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