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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >lnterleukin-6 regulates pancreatic α-cell mass expansion
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lnterleukin-6 regulates pancreatic α-cell mass expansion

机译：白细胞介素6调节胰腺α细胞质量扩张

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摘要

lnterleukin-6 (IL-6) is systemically elevated in obesity and is a predictive factor to develop type 2 diabetes. Pancreatic islet pathology in type 2 diabetes is characterized by reduced β-cell function and mass, an increased proportion of α-cells relative to β-cells, and α-cell dysfunction. Here we show that the α cell is a primary target of IL-6 actions. Beginning with investigating the tissue-specific expression pattern of the IL-6 receptor (IL-6R) in both mice and rats, we find the highest expression of the IL-6R in the endocrine pancreas, with highest expression on the α-cell. The islet IL-6R is functional, and IL-6 acutely regulates both pro-glucagon mRNA and glucagon secretion in mouse and human islets, with no acute effect on insulin secretion. Furthermore, IL-6 stimulates α-cell proliferation, prevents apoptosis due to metabolic stress, and regulates α-cell mass in vivo. Using IL-6 KO mice fed a high-fat diet, we find that IL-6 is necessary for high-fat diet-induced increased a-cell mass, an effect that occurs early in response to diet change. Further, after high-fat diet feeding, IL-6 KO mice without expansion of α-cell mass display decreased fasting glucagon levels. However, despite these α-cell effects, high-fat feeding of IL-6 KO mice results in increased fed glycemia due to impaired insulin secretion, with unchanged insulin sensitivity and similar body weights. Thus, we conclude that IL-6 is necessary for the expansion of pancreatic α-cell mass in response to high-fat diet feeding, and we suggest that this expansion may be needed for functional β-cell compensation to increased metabolic demand.
机译：白细胞介素-6（IL-6）肥胖症全身性升高，是发展2型糖尿病的预测因素。 2型糖尿病的胰岛病理学特征是β细胞功能和质量降低，α细胞相对于β细胞的比例增加以及α细胞功能障碍。在这里，我们显示α细胞是IL-6行为的主要靶标。从研究小鼠和大鼠中IL-6受体（IL-6R）的组织特异性表达模式开始，我们发现内分泌胰腺中IL-6R的表达最高，而在α细胞上表达最高。胰岛IL-6R起作用，并且IL-6急性调节小鼠和人类胰岛中的胰高血糖素原和胰高血糖素分泌，而对胰岛素分泌没有急性影响。此外，IL-6刺激α细胞增殖，防止由于代谢应激引起的细胞凋亡，并在体内调节α细胞的质量。使用高脂饮食喂养的IL-6 KO小鼠，我们发现IL-6对于高脂饮食诱导的a细胞质量增加是必需的，这种作用是对饮食变化的早期反应。此外，高脂饮食喂养后，没有α-细胞质量膨胀的IL-6 KO小鼠的空腹胰高血糖素水平降低。但是，尽管有这些α细胞效应，但由于胰岛素分泌受损，高脂喂养的IL-6 KO小鼠会导致喂养的血糖升高，同时胰岛素敏感性不变且体重相似。因此，我们得出结论，IL-6对于响应高脂饮食喂养的胰腺α细胞团的扩张是必需的，并且我们建议这种扩张对于功能性β细胞补偿以增加代谢需求可能是必需的。

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