Details

Autor(en) / Beteiligte

• 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

Titel

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

Ist Teil von

• Nature communications, 2022-06, Vol.13 (1), p.3749-3749, Article 3749

Ort / Verlag

England: Nature Publishing Group

Erscheinungsjahr

2022

Link zum Volltext

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• 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.