Glucose and fatty acids synergize to promote B-cell apoptosis through activation of glycogen synthase kinase 3β independent of JNK activation.
Glucose and fatty acids synergize to promote B-cell apoptosis through activation of glycogen synthase kinase 3β independent of JNK activation.
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DOI：
10.1371/journal.pone.0018146
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发表时间：
2011-04-26
期刊：
影响因子：
3.7
通讯作者：
Permutt MA
中科院分区：
文献类型：
--
作者：
Tanabe K;Liu Y;Hasan SD;Martinez SC;Cras-Méneur C;Welling CM;Bernal-Mizrachi E;Tanizawa Y;Rhodes CJ;Zmuda E;Hai T;Abumrad NA;Permutt MA
糖尿病中普遍存在的葡萄糖和游离脂肪酸 (FFA) 升高的组合被认为是导致胰腺 β 细胞死亡的主要原因。本研究探讨了葡萄糖和 FFA 对 β 细胞凋亡的协同作用及其分子机制。在增加葡萄糖的情况下用棕榈酸酯处理小鼠胰岛素瘤细胞和原代胰岛，并检查对细胞凋亡、内质网（ER）应激和胰岛素受体底物（IRS）信号传导的影响。增加葡萄糖 (5–25 mM) 与棕榈酸酯 (400 µM) 对细胞凋亡具有协同作用。 Jun NH2 末端激酶 (JNK) 激活在最低葡萄糖浓度时达到峰值，与 IRS2 蛋白逐渐减少和胰岛素受体底物信号传导受损相反。观察到 ER 应激标记物激活以及 SREBP1 向细胞核募集的协同效应。这些发现在初级胰岛中得到了证实。上述效应与糖原合酶激酶 3β (Gsk3β) 活性的增加相关，并随着表达激酶死亡 Gsk3β 的腺病毒的细胞凋亡而逆转。 FFA 存在下的葡萄糖会对 ER 应激、胰岛素受体底物信号传导受损和 Gsk3β 激活产生协同作用。这些数据支持了控制高血糖和高脂血症在 2 型糖尿病治疗中的重要性，并将胰岛 β 细胞 Gsk3β 确定为潜在的治疗靶点。
The combination of elevated glucose and free-fatty acids (FFA), prevalent in diabetes, has been suggested to be a major contributor to pancreatic β-cell death. This study examines the synergistic effects of glucose and FFA on β-cell apoptosis and the molecular mechanisms involved. Mouse insulinoma cells and primary islets were treated with palmitate at increasing glucose and effects on apoptosis, endoplasmic reticulum (ER) stress and insulin receptor substrate (IRS) signaling were examined. Increasing glucose (5–25 mM) with palmitate (400 µM) had synergistic effects on apoptosis. Jun NH2-terminal kinase (JNK) activation peaked at the lowest glucose concentration, in contrast to a progressive reduction in IRS2 protein and impairment of insulin receptor substrate signaling. A synergistic effect was observed on activation of ER stress markers, along with recruitment of SREBP1 to the nucleus. These findings were confirmed in primary islets. The above effects associated with an increase in glycogen synthase kinase 3β (Gsk3β) activity and were reversed along with apoptosis by an adenovirus expressing a kinase dead Gsk3β. Glucose in the presence of FFA results in synergistic effects on ER stress, impaired insulin receptor substrate signaling and Gsk3β activation. The data support the importance of controlling both hyperglycemia and hyperlipidemia in the management of Type 2 diabetes, and identify pancreatic islet β-cell Gsk3β as a potential therapeutic target.
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影响因子：
4.8
作者：
Cnop, Miriam;Ladriere, Laurence;Eizirik, Decio L.
通讯作者：
Eizirik, Decio L.
影响因子：
8.2
作者：
Donath, MY;Halban, PA
通讯作者：
Halban, PA
影响因子：
15.9
作者：
Bernal-Mizrachi, E;Fatrai, S;Permutt, MA
通讯作者：
Permutt, MA
DOI：
10.1073/pnas.97.15.8536
发表时间：
2000-07-18
影响因子：
11.1
作者：
Kakuma, T;Lee, Y;Unger, RH
通讯作者：
Unger, RH
影响因子：
7.7
作者：
Butler, AE;Janson, J;Butler, PC
通讯作者：
Butler, PC