Regulation of Age-Associated Insulin Resistance by MT1-Mmp-Mediated Cleavage of Insulin Receptor

Authors

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
Hoi Leong Xavier Wong

Publication Date

6-29-2022

Journal

Nature Communications

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.

Keywords

Age Factors, Animals, Humans, Insulin, Insulin Resistance, Matrix Metalloproteinase 14, Mice, Receptor, Insulin, Signal Transduction

DOI

10.1038/s41467-022-31563-2

PMID

35768470

PMCID

PMC9242991

PubMedCentral® Posted Date

6-29-2022

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes