Pathway to diabetes through attenuation of pancreatic beta cell glycosylation and glucose transport.
Pathway to diabetes through attenuation of pancreatic beta cell glycosylation and glucose transport.
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作者：
饮食、肥胖和糖尿病之间的联系存在于多个物种中，是人类健康问题不断升级的基础。负责的因素引起胰岛素抵抗和胰腺β细胞功能障碍，但仍有待充分确定。我们报告了人类和小鼠胰腺β细胞中的分子事件的组合，由游离脂肪酸水平升高或通过施用高脂肪饮食与相关肥胖诱导，其包括糖尿病的致病途径。游离脂肪酸浓度升高导致β细胞核排斥和转录因子FOXA 2和HNF 1A表达减少。这导致β细胞中GnT-4a糖基转移酶表达不足，产生代谢疾病的体征，包括高血糖症、葡萄糖耐量受损、高胰岛素血症、肝脂肪变性以及肌肉和脂肪组织中胰岛素作用减弱。通过强化β细胞特异性GnT-4a蛋白糖基化来提供对疾病的保护，并涉及葡萄糖转运蛋白表达的维持和葡萄糖转运的保存。我们观察到，这种致病过程在从2型糖尿病供体获得的人类胰岛细胞中是活跃的;因此，阐明了与2型糖尿病的饮食和肥胖相关成分有关的疾病途径。
A connection between diet, obesity and diabetes exists in multiple species and is the basis of an escalating human health problem. The factors responsible provoke both insulin resistance and pancreatic beta cell dysfunction but remain to be fully identified. We report a combination of molecular events in human and mouse pancreatic beta cells, induced by elevated levels of free fatty acids or by administration of a high-fat diet with associated obesity, that comprise a pathogenic pathway to diabetes. Elevated concentrations of free fatty acids caused nuclear exclusion and reduced expression of the transcription factors FOXA2 and HNF1A in beta cells. This resulted in a deficit of GnT-4a glycosyltransferase expression in beta cells that produced signs of metabolic disease, including hyperglycemia, impaired glucose tolerance, hyperinsulinemia, hepatic steatosis and diminished insulin action in muscle and adipose tissues. Protection from disease was conferred by enforced beta cell–specific GnT-4a protein glycosylation and involved the maintenance of glucose transporter expression and the preservation of glucose transport. We observed that this pathogenic process was active in human islet cells obtained from donors with type 2 diabetes; thus, illuminating a pathway to disease implicated in the diet- and obesity-associated component of type 2 diabetes mellitus.
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DOI：
10.1111/j.1463-1326.2009.01114.x
发表时间：
2009-11
期刊：
Diabetes, obesity & metabolism
影响因子：
--
作者：
Kebede MA;Alquier T;Latour MG;Poitout V
通讯作者：
Poitout V
影响因子：
5.9
作者：
Korner, Judith;Woods, Stephen C.;Woodworth, Kristina A.
通讯作者：
Woodworth, Kristina A.
影响因子：
4.8
作者：
Minowa, MT;Oguri, S;Takeuchi, M
通讯作者：
Takeuchi, M
影响因子：
4.8
作者：
Gremlich, S;Roduit, R;Thorens, B
通讯作者：
Thorens, B
影响因子：
7.7
作者：
Chen, Ya Wen;Huang, Chun Fa;Liu, Shing Hwa
通讯作者：
Liu, Shing Hwa