Increased serum CXCL1 and CXCL5 are linked to obesity, hyperglycemia, and impaired islet function.
Increased serum CXCL1 and CXCL5 are linked to obesity, hyperglycemia, and impaired islet function.
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DOI：
10.1530/joe-14-0126
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发表时间：
2014-08
期刊：
影响因子：
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通讯作者：
Sharma PR
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文献类型：
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作者：
Nunemaker CS;Chung HG;Verrilli GM;Corbin KL;Upadhye A;Sharma PR
促炎细胞因子被认为在2型糖尿病（T2 D）的发病机制中起重要作用，并且甚至在疾病发作之前在循环中升高。然而，参与T2 D发展的细胞因子的完整补体尚不清楚。在这项研究中，在5周（非糖尿病/非肥胖）、6-7周（过渡性糖尿病）或11周（高血糖/肥胖）时，从易患糖尿病的BKS.Cg-m+/+Leprdb/J（db/db）小鼠和年龄匹配的杂合子对照小鼠中测量了32种血清细胞因子，然后将其与体重、血糖和脂肪含量相关联。在这32种细胞因子中，与非高血糖（193+/-13 mg/dl，n=8）相比，高血糖（血糖：519+/-23 mg/dl，n=6）db/db小鼠之间的CXCL 1显示出血清水平的最大增加（+78%）。类似地，增加的CXCL 1（+68%）和CXCL 5（+40%）与db/db小鼠的肥胖增加有关;注意这些影响不能完全与年龄分开。我们接下来检查了胰岛是否可以是这些趋化因子的来源。48-暴露于模拟低度系统性炎症的细胞因子（10 pg/ml IL-1 β + 20 pg/ml IL-6）10小时，胰岛CXCL 1表达上调53+/-3倍，CXCL 5上调83+/-10倍（n=4，p<0.001）。最后，用血清水平的CXCL 1和CXCL 5的组合过夜处理足以产生对葡萄糖刺激的峰值钙响应的显著降低，表明胰岛功能降低。我们的研究结果表明，CXCL 1和CXCL 5 1）随着T2 D的发作在循环中增加，2）由应激下的胰岛产生，3）协同影响胰岛功能，表明这些趋化因子参与T2 D的发病机制。
Proinflammatory cytokines are thought to play a significant role in the pathogenesis of type 2 diabetes (T2D) and are elevated in the circulation even before the onset of the disease. However, the full complement of cytokines involved in the development of T2D is not known. In this study, 32 serum cytokines were measured from diabetes-prone BKS.Cg-m+/+Leprdb/J (db/db) mice and heterozygous aged-matched control mice at 5-weeks (non-diabetic/non-obese), 6-7-weeks (transitional-to-diabetes), or 11-weeks (hyperglycemic/obese) and then correlated with body weight, blood glucose, and fat content. Among these 32 cytokines, CXCL1 showed the greatest increase (+78%) in serum levels between db/db mice that were hyperglycemic (blood glucose: 519+/-23 mg/dl, n=6) compared to non-hyperglycemic (193+/-13 mg/dl, n=8). Similarly, increased CXCL1 (+68%) and CXCL5 (+40%) were associated with increased obesity in db/db mice; note that these effects could not be entirely separated from age. We next examined whether islets could be a source of these chemokines. 48-hour exposure to cytokines mimicking low-grade systemic inflammation (10 pg/ml IL-1beta + 20 pg/ml IL-6) upregulated islet CXCL1 expression by 53+/-3-fold and CXCL5 by 83+/-10-fold (n=4, p<0.001). Finally, overnight treatment with the combination of CXCL1 and CXCL5 at serum levels was sufficient to produce a significant decrease in the peak calcium response to glucose stimulation, suggesting reduced islet function. Our findings show that CXCL1 and CXCL5 1) are increased in the circulation with the onset of T2D, 2) are produced by islets under stress, and 3) synergistically impact islet function, suggesting these chemokines participate in the pathogenesis of T2D.