Regulation of age-associated insulin resistance by MT1-MMP-mediated cleavage of insulin receptor.
Regulation of age-associated insulin resistance by MT1-MMP-mediated cleavage of insulin receptor.
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DOI：
10.1038/s41467-022-31563-2
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发表时间：
2022-06-29
影响因子：
16.6
通讯作者：
中科院分区：
文献类型：
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胰岛素敏感性随着年龄的增长而逐渐下降。目前，与年龄相关的胰岛素抵抗的机制仍不清楚。在这里，我们确定膜结合基质金属蛋白酶14（MT1-MMP/MMP 14）作为一个中央调节胰岛素敏感性在老化过程中。衰老促进MMP14在胰岛素敏感组织中的活化，其切割胰岛素受体以抑制胰岛素信号传导。MT1-MMP抑制恢复胰岛素受体表达，改善老年小鼠的胰岛素敏感性。MT1-MMP对胰岛素受体的切割也有助于肥胖诱导的胰岛素抵抗，并且MT1-MMP活性的抑制使糖尿病小鼠模型中的代谢功能障碍正常化。相反，肝脏中MT1-MMP的过表达降低了胰岛素受体的水平，损害了幼龄小鼠的肝脏胰岛素敏感性。在老年人和非人灵长类动物的血浆中，可溶性胰岛素受体和循环MT1-MMP呈正相关。我们的研究结果为生理衰老过程中胰岛素敏感性的调节提供了机制性见解，并强调MT1-MMP是一种有前途的糖尿病治疗途径的靶点。胰岛素敏感性随着年龄的增长而下降，机制尚不清楚。在这里，作者表明，膜1型基质金属蛋白酶（MT1-MMP）的活性随着年龄的增长而增加，导致胰岛素受体的裂解，并表明小鼠中的MT1-MMP抑制可以挽救代谢效应。
Insulin sensitivity progressively declines with age. Currently, the mechanism underlying age-associated insulin resistance remains unknown. Here, we identify membrane-bound matrix metalloproteinase 14 (MT1-MMP/MMP14) as a central regulator of insulin sensitivity during ageing. Ageing promotes MMP14 activation in insulin-sensitive tissues, which cleaves Insulin Receptor to suppress insulin signaling. MT1-MMP inhibition restores Insulin Receptor expression, improving insulin sensitivity in aged mice. The cleavage of Insulin Receptor by MT1-MMP also contributes to obesity-induced insulin resistance and inhibition of MT1-MMP activities normalizes metabolic dysfunctions in diabetic mouse models. Conversely, overexpression of MT1-MMP in the liver reduces the level of Insulin Receptor, impairing hepatic insulin sensitivity in young mice. The soluble Insulin Receptor and circulating MT1-MMP are positively correlated in plasma from aged human subjects and non-human primates. Our findings provide mechanistic insights into regulation of insulin sensitivity during physiological ageing and highlight MT1-MMP as a promising target for therapeutic avenue against diabetes. Insulin sensitivity declines with age via unclear mechanisms. Here, the authors show that the activity of membrane type 1 matrix metalloproteinase (MT1-MMP) is increased with ageing, leading to cleavage of the insulin receptor, and show that metabolic effects can be rescued by MT1-MMP inhibition in mice.
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影响因子：
--
作者：
Remacle AG;Cieplak P;Nam DH;Shiryaev SA;Ge X;Strongin AY
通讯作者：
Strongin AY
DOI：
10.1186/1476-9255-9-35
发表时间：
2012-10-01
期刊：
Journal of inflammation (London, England)
影响因子：
--
作者：
Frankwich K;Tibble C;Torres-Gonzalez M;Bonner M;Lefkowitz R;Tyndall M;Schmid-Schönbein GW;Villarreal F;Heller M;Herbst K
通讯作者：
Herbst K
通过 MT1-MMP 介导的 GFRAL 裂解调节体重
影响因子：
20.8
作者：
Chow, Chi Fung Willis;Guo, Xuanming;Wong, Hoi Leong Xavier
通讯作者：
Wong, Hoi Leong Xavier
影响因子：
11.4
作者：
Gutierrez-Fernandez, Ana;Soria-Valles, Clara;Lopez-Otin, Carlos
通讯作者：
Lopez-Otin, Carlos
影响因子：
7.7
作者：
Chun TH;Inoue M;Morisaki H;Yamanaka I;Miyamoto Y;Okamura T;Sato-Kusubata K;Weiss SJ
通讯作者：
Weiss SJ