Circulating Levels of IL-1B+IL-6 Cause ER Stress and Dysfunction in Islets From Prediabetic Male Mice
Circulating Levels of IL-1B+IL-6 Cause ER Stress and Dysfunction in Islets From Prediabetic Male Mice
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DOI：
10.1210/en.2012-2138
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发表时间：
2013-09-01
期刊：
影响因子：
4.8
通讯作者：
Nunemaker, Craig S.
中科院分区：
文献类型：
--
作者：
O'Neill, Christina M.;Lu, Christine;Nunemaker, Craig S.
循环促炎细胞因子水平升高与肥胖和2型糖尿病风险增加有关，但其机制尚不清楚。我们测试了促炎症细胞因子IL-1B+IL-6在每毫升低皮克浓度(与血清水平一致)是否会直接引发胰岛功能障碍。从正常小鼠和人类分离的胰岛过夜暴露于IL-1B+IL-6扰乱了葡萄糖刺激的细胞内钙反应；细胞因子诱导的影响在糖尿病前期db/db小鼠中更为严重，否则没有表现出功能障碍的迹象。IL-1B+IL-6暴露仅在糖尿病前期db/db小鼠的胰岛中减少内质网(ER)钙储存，激活ER应激反应(NOS2，Bip，ATF4和Ddit3[CHOP])，削弱葡萄糖刺激的胰岛素分泌，并增加细胞死亡。此外，我们发现易患糖尿病的小鼠在表现出高血糖之前的年龄，血清IL-1B和IL-6水平升高，这表明低度全身炎症在疾病过程的早期发展。此外，我们在正常近交系和近交系小鼠体内植入了含有IL-1B+IL-6的皮下渗透微泵，以模拟糖尿病前期db/db小鼠的血清升高。细胞因子泵小鼠血清中IL-1B和IL-6均升高，但葡萄糖耐量和血糖水平与对照组无差异。然而，与对照组相比，从细胞因子泵小鼠分离的胰岛在钙处理和胰岛素分泌方面存在缺陷，这与体外观察到的暴露于细胞因子的胰岛相似。这些发现提供了原理证据，即低度全身炎症存在于2型糖尿病发展的早期，并可触发内质网应激介导的胰岛功能障碍，从而导致胰岛功能衰竭。
Elevated levels of circulating proinflammatory cytokines are associated with obesity and increased risk of type 2 diabetes, but the mechanism is unknown. We tested whether proinflammatory cytokines IL-1B+IL-6 at low picogram per milliliter concentrations (consistent with serum levels) could directly trigger pancreatic islet dysfunction. Overnight exposure to IL-1B+IL-6 in islets isolated from normal mice and humans disrupted glucose-stimulated intracellular calcium responses; cytokine-induced effects were more severe among islets from prediabetic db/db mice that otherwise showed no signs of dysfunction. IL-1B+IL-6 exposure reduced endoplasmic reticulum (ER) calcium storage, activated ER stress responses (Nos2, Bip, Atf4, and Ddit3 [CHOP]), impaired glucose-stimulated insulin secretion, and increased cell death only in islets from prediabetic db/db mice. Furthermore, we found increased serum levels of IL-1B and IL-6 in diabetes-prone mice at an age before hyperglycemia was exhibited, suggesting that low-grade systemic inflammation develops early in the disease process. In addition, we implanted normal outbred and inbred mice with subcutaneous osmotic mini-pumps containing IL-1B+IL-6 to mimic the serum increases found in prediabetic db/db mice. Both IL-1B and IL-6 were elevated in serum from cytokine-pump mice, but glucose tolerance and blood glucose levels did not differ from controls. However, when compared with controls, isolated islets from cytokine-pump mice showed deficiencies in calcium handling and insulin secretion that were similar to observations with islets exposed to cytokines in vitro. These findings provide proof of principle that low-grade systemic inflammation is present early in the development of type 2 diabetes and can trigger ER stress-mediated islet dysfunction that can lead to islet failure.