Advanced glycation end products are direct modulators of β-cell function.
Advanced glycation end products are direct modulators of β-cell function.
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作者：
Coughlan MT;Yap FY;Tong DC;Andrikopoulos S;Gasser A;Thallas-Bonke V;Webster DE;Miyazaki J;Kay TW;Slattery RM;Kaye DM;Drew BG;Kingwell BA;Fourlanos S;Groop PH;Harrison LC;Knip M;Forbes JM
晚期糖基化终产物（AGEs）的过量积累有助于衰老和慢性疾病。我们的目的是获得暴露于AGEs在1型糖尿病（T1D）发展中起作用的证据。在三种不同的啮齿动物模型中：注射age或高喂养age的Sprague-Dawley大鼠和非肥胖糖尿病（NODLt）小鼠，研究了AGEs对MIN6N8细胞和小鼠胰岛胰岛素分泌的影响。啮齿动物也用降龄剂alagebrium治疗。暴露于AGEs的β-细胞表现出急性葡萄糖刺激的胰岛素分泌缺陷，线粒体异常，包括过量的超氧化物生成，ATP含量下降，MnSOD活性丧失，钙通量降低，葡萄糖摄取增加，所有这些都通过alagbrium处理或MnSOD腺病毒过表达得到改善。暴露于AGEs的离体小鼠胰岛降低了葡萄糖刺激的胰岛素分泌，增加了线粒体超氧化物的产生，并消耗了ATP含量，而alagbrium或mntmap（一种SOD模拟物）改善了这一现象。在大鼠中，短暂或慢性暴露于AGEs会导致进行性胰岛素分泌缺陷、超氧化物产生和β细胞死亡，而这一现象在掺入agagium后得到改善。NODLt小鼠循环AGEs的增加与胰岛线粒体超氧化物生成的增加有关，而这一现象可由alagbrium预防，也可降低自身免疫性糖尿病的发病率。最后，进展为T1D的高危儿童的AGE浓度高于匹配的非进展者。这些发现表明，AGEs直接导致胰岛素分泌缺陷，最有可能是通过损害线粒体功能，这可能有助于T1D的发展。
Excess accumulation of advanced glycation end products (AGEs) contributes to aging and chronic diseases. We aimed to obtain evidence that exposure to AGEs plays a role in the development of type 1 diabetes (T1D). The effect of AGEs was examined on insulin secretion by MIN6N8 cells and mouse islets and in vivo in three separate rodent models: AGE-injected or high AGE–fed Sprague-Dawley rats and nonobese diabetic (NODLt) mice. Rodents were also treated with the AGE-lowering agent alagebrium. β-Cells exposed to AGEs displayed acute glucose-stimulated insulin secretory defects, mitochondrial abnormalities including excess superoxide generation, a decline in ATP content, loss of MnSOD activity, reduced calcium flux, and increased glucose uptake, all of which were improved with alagebrium treatment or with MnSOD adenoviral overexpression. Isolated mouse islets exposed to AGEs had decreased glucose-stimulated insulin secretion, increased mitochondrial superoxide production, and depletion of ATP content, which were improved with alagebrium or with MnTBAP, an SOD mimetic. In rats, transient or chronic exposure to AGEs caused progressive insulin secretory defects, superoxide generation, and β-cell death, ameliorated with alagebrium. NODLt mice had increased circulating AGEs in association with an increase in islet mitochondrial superoxide generation, which was prevented by alagebrium, which also reduced the incidence of autoimmune diabetes. Finally, at-risk children who progressed to T1D had higher AGE concentrations than matched nonprogressors. These findings demonstrate that AGEs directly cause insulin secretory defects, most likely by impairing mitochondrial function, which may contribute to the development of T1D.
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影响因子：
4.4
作者：
Chen, Yali;Akirav, Eitan M.;Chen, Wei;Henegariu, Octavian;Moser, Bernhard;Desai, Dharmesh;Shen, Jane M.;Webster, Jeffery C.;Andrews, Robert C.;Mjalli, Adnan M.;Rothlein, Robert;Schmidt, Ann Marie;Clynes, Raphael;Herold, Kevan C.
通讯作者：
Herold, Kevan C.
影响因子：
8.2
作者：
Forbes, J. M.;Soderlund, J.;Groop, P. -H.
通讯作者：
Groop, P. -H.
影响因子：
168.9
作者：
Harjutsalo, Valma;Sjoberg, Lena;Tuomilehto, Jaakko
通讯作者：
Tuomilehto, Jaakko
影响因子：
11
作者：
HEWER, RL;ROBINSON, N
通讯作者：
ROBINSON, N
影响因子：
4.8
作者：
Forbes, JM;Thallas, V;Cooper, ME
通讯作者：
Cooper, ME