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- Title
Regulation of age-associated insulin resistance by MT1-MMP-mediated cleavage of insulin receptor.
- 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
- 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. 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.
- Subjects
INSULIN regulation; INSULIN resistance; INSULIN sensitivity; INSULIN receptors; METABOLIC disorders; MATRIX metalloproteinases
- Publication
Nature Communications, 2022, Vol 13, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-022-31563-2