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}
}
  • H. Kaneto, G. Xu, +4 authors G. Weir
  • Published 17 August 2001
  • Biology, Medicine
  • The Journal of Biological Chemistry
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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306 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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References

SHOWING 1-10 OF 43 REFERENCES
Glucose stimulates protein modification by O-linked GlcNAc in pancreatic β cells: Linkage of O-linked GlcNAc to β cell death
TLDR
A causal link between apoptosis in β cells and glucose metabolism through glucosamine to O-GlcNAc is provided, implicating this pathway of glucose metabolism with β cell glucose toxicity. Expand
Overexpression of glutamine:fructose-6-phosphate amidotransferase in transgenic mice leads to insulin resistance.
TLDR
The hypothesis that excessive flux through the hexosamine biosynthesis pathway mediates adverse regulatory and metabolic effects of hyperglycemia, specifically insulin resistance of glucose disposal, is supported. Expand
Glycation-dependent, reactive oxygen species-mediated suppression of the insulin gene promoter activity in HIT cells.
TLDR
It is suggested that protein glycation in pancreatic beta cells, which occurs in vivo under chronic hyperglycemia, suppresses insulin gene transcription and thus can explain part of the beta cell glucose toxicity. Expand
Activation of the hexosamine pathway by glucosamine in vivo induces insulin resistance of early postreceptor insulin signaling events in skeletal muscle.
TLDR
Activation of the hexosamine pathway may directly modulate early postreceptor insulin signal transduction, perhaps via posttranslation modification of IRS proteins, and thus contribute to the insulin resistance induced by chronic hyperglycemia. Expand
Prevention of glucose toxicity in HIT-T15 cells and Zucker diabetic fatty rats by antioxidants.
TLDR
It is concluded that chronic oxidative stress may play a role in glucose toxicity, which in turn may worsen the severity of type 2 diabetes. Expand
Hyperglycemia-induced mitochondrial superoxide overproduction activates the hexosamine pathway and induces plasminogen activator inhibitor-1 expression by increasing Sp1 glycosylation.
  • X. Du, D. Edelstein, +5 authors M. Brownlee
  • Biology, Medicine
  • Proceedings of the National Academy of Sciences of the United States of America
  • 2000
TLDR
Hyperglycemia-induced mitochondrial superoxide overproduction increases hexosamine synthesis and O-glycosylation of Sp1, which activates expression of genes that contribute to the pathogenesis of diabetic complications. Expand
Transgenic mice with increased hexosamine flux specifically targeted to beta-cells exhibit hyperinsulinemia and peripheral insulin resistance.
TLDR
It is concluded that hexosamine biosynthesis is involved in the regulation of insulin content in beta-cells by glucose, which results in hyperinsulinemia, insulin resistance, and (in males) mild type 2 diabetes. Expand
Role of the glucosamine pathway in fat-induced insulin resistance.
TLDR
The hypothesis that increased FFA availability induces skeletal muscle insulin resistance by increasing the flux of fructose-6-phosphate into the hexosamine pathway is supported. Expand
Increased O-GlcNAc transferase in pancreas of rats with streptozotocin-induced diabetes
TLDR
It is suggested that the increase in O-GlcNAc modification of the proteins correlates closely with diabetes and plays an important part in the modulation of O- GlcNAC concentrations in the pancreas. Expand
Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage
TLDR
This work shows that hyperglycaemia increases the production of reactive oxygen species inside cultured bovine aortic endothelial cells and is prevented by an inhibitor of electron transport chain complex II, by an uncoupler of oxidative phosphorylation, by uncoupling protein-1 and by manganese superoxide dismutase. Expand
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