INTRACELLULAR O GLCNAC AND GLUCOTOXICITY

细胞内 O GLNAC 和葡萄糖毒性

• 批准号: 6177393
• 负责人: Jeffrey E Kudlow
• 金额: $ 23.22万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-30 至 2001-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6177393
• 关键词: N acetylglucosamine; acyltransferase; alloxan; animal tissue; cytotoxicity; gene expression; genetically modified animals; glucosamine; glucose metabolism; glycosylation; histopathology; hyperglycemia; immunocytochemistry; in situ hybridization; laboratory mouse; laboratory rat; noninsulin dependent diabetes mellitus; northern blottings; pancreatic islet function; pancreatic islets; posttranslational modifications

Clinical studies and studies on isolated islets or Beta cell lines have indicated that chronic exposure of the Beta cell to supraphysiological levels of glucose results in impaired Beta cell function, an important component in the pathogenesis of type 2 diabetes. How glucose exerts this toxicity upon the Beta cell remains unclear. We propose that the glucose metabolite, glucosamine plays a role in Beta cell function and this glucose toxicity. We came to this hypothesis as a result of our observations on the mechanism of toxicity of the Beta cell- specific toxin, streptozotocin (STZ). STZ is chemically analogous to N- acetylglucosamine (GlcNAc). Furthermore, we found that the Beta cell contains approximately 100-fold more of the mRNA encoding the enzyme o- GlcNAc transferase (OGT). This enzyme modifies nuclear and cytoskeletal proteins by linking the monosaccharide GlcNAc to serine or threonine residues in the protein. The resulting O-GlcNAc modification appears to modify the activity of transcription factors. We found that STZ blocks the activity of an enzyme that removes o-GlcNAc from proteins. Treatment of rats with STZ results in the accumulation of the O-GlcNAc modification specifically in the pancreatic Beta cells, hours before Beta cell death. Because the Beta cells are so richly endowed with OGT, these cells may be the most susceptible to an accumulation of O-GlcNAc on intracellular proteins. We have also shown in other cell types, that nuclear O-GlcNAc is sensitive to ambient glucose concentrations. If this is also true in the Beta cell, then hyperglycemia and STZ may both increase Beta cell O-GlcNAc content, thereby leading to a common mechanism of Beta cell toxicity. The experiments proposed in this grant are designed to determine if hyperglycemia indeed result in increased Beta cell O-GlcNAc. We will also create transgenic mouse models in which glucosamine synthesis from glucose is either augmented or decreased. We will determine the effect of these alterations in glucosamine metabolism on Beta cell function. We have also found that cAMP-dependent protein kinase inhibits the enzyme responsible for glucosamine synthesis. We propose to study the mechanism by which glucosamine synthesis is inhibited. Together, these studies will establish the role of glucosamine in glucose toxicity on the Beta cell and a means of controlling glucose metabolism to glucosamine.

临床研究和对孤立的胰岛或β细胞系的研究

项目成果

Responsiveness of the state of O-linked N-acetylglucosamine modification of nuclear pore protein p62 to the extracellular glucose concentration.

核孔蛋白 p62 的 O-连接 N-乙酰氨基葡萄糖修饰状态对细胞外葡萄糖浓度的响应性。

• 发表时间: 2000
• 期刊: The Biochemical journal
• 作者: Han,I;Oh,ES;Kudlow,JE
• 通讯作者: Kudlow,JE

Streptozotocin, an O-GlcNAcase inhibitor, blunts insulin and growth hormone secretion.

链脲佐菌素是一种 O-GlcNAcase 抑制剂，可抑制胰岛素和生长激素的分泌。

• DOI: 10.1016/s0303-7207(02)00155-7
• 发表时间: 2002
• 期刊: Molecular and cellular endocrinology
• 影响因子: 4.1
• 作者: Liu,Kan;Paterson,AndrewJ;Konrad,RobertJ;Parlow,AF;Jimi,Shiro;Roh,Meejeon;ChinJr,Edward;Kudlow,JeffreyE
• 通讯作者: Kudlow,JeffreyE