Metformin, the most prescribed antidiabetic medicine, has shown other benefits such as anti-ageing and anticancer effects. However, the direct molecular target of metformin remains unknown.
Recently, a research group led by Prof. LIN Shengcai and Prof. DENG Xianming from Xiamen University, in collaboration with Prof. PIAO Hailong’s group from the Dalian Institute of Chemical Physics (DICP) of the Chinese Academy of Sciences (CAS), identified PEN2, a subunit of γ-secretase, as a binding partner of metformin and revealed its mechanism.
Their findings were published in Nature on Feb. 23.
Schematic diagramme showing that the FBP-unoccupied aldolase-triggered glucose sensing and the PEN2-mediated metformin signalling axes converge at the v-ATPase complex to trigger AMPK activation. (Image by WANG Wen)
The researchers synthesized a photoactive metformin probe to identify PEN2. They revealed that metformin could bind PEN2 and initiate a route that intersected, through ATP6AP1, the lysosomal glucose-sensing pathway for AMP-activated protein kinase activation.
This study ensured that metformin exerts its therapeutic benefits in patients without substantial adverse effect.
This work was supported by the Natural Science Foundation of China. (Text by WANG Wen)