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

• Published in: Nature communications Vol. 13; no. 1; p. 3749
• Main Authors: Guo, Xuanming, Asthana, Pallavi, Gurung, Susma, Zhang, Shuo, Wong, Sheung Kin Ken, Fallah, Samane, Chow, Chi Fung Willis, Che, Sijia, Zhai, Lixiang, Wang, Zening, Ge, Xin, Jiang, Zhixin, Wu, Jiayan, Zhang, Yijing, Wu, Xiaoyu, Xu, Keyang, Lin, Cheng Yuan, Kwan, Hiu Yee, Lyu, Aiping, Zhou, Zhongjun, Bian, Zhao-Xiang, Wong, Hoi Leong Xavier
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 29.06.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 13/95; 38; 38/79; 38/88; 42/109; 42/44; 631/80/86/2367; 64/110; 692/163/2743/137/773; 82/80; 96/106; Age; Age Factors; Aging; Aging (metallurgy); Animal models; Animals; Cleavage; Diabetes mellitus; Humanities and Social Sciences; Humans; Insulin; Insulin - metabolism; Insulin Resistance; Matrix metalloproteinase; Matrix Metalloproteinase 14 - metabolism; Matrix metalloproteinases; Membranes; Metabolism; Metalloproteinase; Mice; multidisciplinary; Receptor, Insulin - metabolism; Receptors; Science; Science (multidisciplinary); Sensitivity; Signal Transduction
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-31563-2

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.