Pleiotropic and age-dependent effects of decreased protein modification by O-linked N-acetylglucosamine on pancreatic ß-cell function and vascularization.
J Biol Chem
; 286(29): 26118-26, 2011 Jul 22.
Article
em En
| MEDLINE
| ID: mdl-21622566
ABSTRACT
The hexosamine biosynthesis pathway (HBP) regulates the post-translational modification of nuclear and cytoplasmic protein by O-linked N-acetylglucosamine (O-GlcNAc). Numerous studies have demonstrated increased flux through this pathway contributes to the development of ß-cell dysfunction. The effect of decreased O-GlcNAc on the maintenance of normal ß-cell function, however, is not well understood. We studied transgenic mice that over express ß-N-acetylglucosaminidase (O-GlcNAcase), an enzyme that catalyzes the removal of O-GlcNAc from proteins, in the pancreatic ß-cell under control of the rat insulin promoter. 3-4-Month-old O-GlcNAcase transgenic mice have higher glucose excursions with a concomitant decrease in circulating insulin levels, insulin mRNA levels, and total islet insulin content. In older (8-9-month-old) O-GlcNAcase transgenic mice glucose tolerance is no longer impaired. This is associated with increased serum insulin, islet insulin content, and insulin mRNA in the O-GlcNAcase transgenic mice. These improvements in ß-cell function with aging are associated with increased angiogenesis and increased VEGF expression, with parallel increases in activation of Akt and expression of PGC1α. The biphasic effects as a function of age are consistent with published observations of mice with increased O-GlcNAc in islets and demonstrate that O-GlcNAc signaling exerts multiple effects on both insulin secretion and islet survival.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Oxigênio
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Acetilglucosamina
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Envelhecimento
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Processamento de Proteína Pós-Traducional
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Neovascularização Fisiológica
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Células Secretoras de Insulina
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Pleiotropia Genética
Limite:
Animals
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Female
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Humans
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Male
Idioma:
En
Ano de publicação:
2011
Tipo de documento:
Article