TY - JOUR
T1 - Regulation of age-associated insulin resistance by MT1-MMP-mediated cleavage of insulin receptor
AU - Guo, Xuanming
AU - Asthana, Pallavi
AU - Gurung, Susma
AU - Zhang, Shuo
AU - Wong, Sheung Kin Ken
AU - Fallah, Samane
AU - Chow, Chi Fung Willis
AU - Che, Sijia
AU - Zhai, Lixiang
AU - Wang, Zening
AU - Ge, Xin
AU - Jiang, Zhixin
AU - Wu, Jiayan
AU - Zhang, Yijing
AU - Wu, Xiaoyu
AU - Xu, Keyang
AU - Lin, Cheng Yuan
AU - Kwan, Hiu Yee
AU - Lyu, Aiping
AU - Zhou, Zhongjun
AU - Bian, Zhao Xiang
AU - Wong, Hoi Leong Xavier
N1 - Funding Information:
The presented work was kindly supported by General Research Fund (12101019 and 12102020), Health and Medical Research Fund (06170056 and 08793626), National Natural Science Fund (81802838), and Guangdong Natural Science Foundation (2021A1515011128 and 2019A1515011851).
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/6/29
Y1 - 2022/6/29
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85133130803&partnerID=8YFLogxK
U2 - 10.1038/s41467-022-31563-2
DO - 10.1038/s41467-022-31563-2
M3 - Journal article
C2 - 35768470
SN - 2041-1723
VL - 13
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 3749
ER -