ADAMTS9 Regulates Skeletal Muscle Insulin Sensitivity Through Extracellular Matrix Alterations
ADAMTS9 Regulates Skeletal Muscle Insulin Sensitivity Through Extracellular Matrix Alterations
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DOI：
10.2337/db18-0418
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发表时间：
2019-03-01
期刊：
影响因子：
7.7
通讯作者：
Holst, Birgitte
中科院分区：
文献类型：
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作者：
Graae, Anne-Sofie;Grarup, Niels;Holst, Birgitte
ADAMTS9 rs4607103 C等位基因是为数不多的通过胰岛素敏感性受损而增加2型糖尿病风险的基因变异之一。我们发现，该变异与人类骨骼肌中分泌的ADAMTS9表达增加和胰岛素敏感性和信号转导降低有关。与此相一致的是，骨骼肌中选择性缺乏Adamts9的小鼠改善了胰岛素敏感性。在ADAMTS9在骨骼肌中过表达的模型中，进一步表征了ADAMTS9和胰岛素信号之间的分子联系。这种选择性的过度表达导致胰岛素信号的减少，可能是通过改变整合素131信号通路和破坏细胞内的细胞骨架组织来实现的。此外，这还会导致线粒体受损！小鼠肌肉的功能-这一观察发现具有翻译特征，因为携带ADAMTS9风险等位基因的人减少了线粒体标记的表达。最后，我们发现ADAMTS9过表达与胰岛素信号转导受损之间的联系可能是由于有害的脂质中间体的积累。我们的发现有助于理解胰岛素抵抗和2型糖尿病的分子机制，并指出抑制ADAMTS9可能成为治疗胰岛素抵抗的一种新模式。
The ADAMTS9 rs4607103 C allele is one of the few gene variants proposed to increase the risk of type 2 diabetes through an impairment of insulin sensitivity. We show that the variant is associated with increased expression of the secreted ADAMTS9 and decreased insulin sensitivity and signaling in human skeletal muscle. In line with this, mice lacking Adamts9 selectively in skeletal muscle have improved insulin sensitivity. The molecular link between ADAMTS9 and insulin signaling was characterized further in a model where ADAMTS9 was overexpressed in skeletal muscle. This selective over expression resulted in decreased insulin signaling presumably mediated through alterations of the integrin 131 signaling pathway and disruption of the intracellular cytoskeletal organization. Furthermore, this led to impaired mitochondria! function in mouse muscle-an observation found to be of translational character because humans carrying the ADAMTS9 risk allele have decreased expression of mitochondrial markers. Finally, we found that the link between ADAMTS9 overexpression and impaired insulin signaling could be due to accumulation of harmful lipid intermediates. Our findings contribute to the understanding of the molecular mechanisms underlying insulin resistance and type 2 diabetes and point to inhibition of ADAMTS9 as a potential novel mode of treating insulin resistance.