Regulation of age-associated insulin resistance by MT1-MMP-mediated cleavage of insulin receptor

Xuanming Guo, Pallavi Asthana, Susma Gurung, Shuo Zhang, Sheung Kin Ken Wong, Samane Fallah, Chi Fung Willis Chow, Sijia Che, Lixiang Zhai, Zening Wang, Xin Ge, Zhixin Jiang, Jiayan Wu, Yijing Zhang, Xiaoyu Wu, Keyang Xu, Cheng Yuan Lin, Hiu Yee Kwan, Aiping Lyu, Zhongjun Zhou, Zhao-Xiang Bian () and Hoi Leong Xavier Wong ()
Additional contact information
Xuanming Guo: Hong Kong Baptist University
Pallavi Asthana: Hong Kong Baptist University
Susma Gurung: Hong Kong Baptist University
Shuo Zhang: The University of Hong Kong
Sheung Kin Ken Wong: The University of Hong Kong
Samane Fallah: Hong Kong Baptist University
Chi Fung Willis Chow: Hong Kong Baptist University
Sijia Che: Hong Kong Baptist University
Lixiang Zhai: Hong Kong Baptist University
Zening Wang: University of Texas Health Science Center at Houston
Xin Ge: University of Texas Health Science Center at Houston
Zhixin Jiang: The University of Hong Kong
Jiayan Wu: Hong Kong Baptist University
Yijing Zhang: Hong Kong Baptist University
Xiaoyu Wu: Jinhua Guangfu hospital
Keyang Xu: Hong Kong Baptist University
Cheng Yuan Lin: Hong Kong Baptist University
Hiu Yee Kwan: Hong Kong Baptist University
Aiping Lyu: Hong Kong Baptist University
Zhongjun Zhou: The University of Hong Kong
Zhao-Xiang Bian: Hong Kong Baptist University
Hoi Leong Xavier Wong: Hong Kong Baptist University

Nature Communications, 2022, vol. 13, issue 1, 1-10

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-31563-2

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