"Nature" heavy: Chinese scientists crack the mechanism of action of metformin

In 1957, when metformin was first marketed in France as an alternative to insulin for lowering blood sugar, no one could have imagined that this inconspicuous drug at the time has become a "star" drug more than half a century later

As a derivative of the natural product goatine, metformin is not only widely used in clinical treatment as a first-line drug for the treatment of type 2 diabetes, but also can reduce the body weight of diabetic patients, reduce liver fat content, and reduce the risk of diabetes-induced cancer

Countless people have benefited from this ancient drug, but for scientists, a key question has remained unanswered: What is the target of metformin? In other words, we know metformin works, but exactly how it works is not clear

Previous studies have proposed several candidate theories for the mechanism of action of metformin

Evidence suggests that metformin works by inhibiting a class of mitochondrial electron transport chain complexes that activate AMPK

Now, this "mystery of the century" has finally ushered in the answer

In the journal "Cell Metabolism" 6 years ago, a study led by Professor Lin Shengcai's team proposed that metformin may activate AMPK protein through the lysosomal pathway

To this end, the authors synthesized photosensitive metformin chemical probes—when metformin molecules bind to a protein molecule, they can be detected by tags on the probe

Subsequently, the research team sequentially inhibited the expression of these 113 proteins through gene silencing, and finally found a distinctive protein-only when the expression of presenilin enhancer 2 (PEN2, a subunit of γ-secretase) was inhibited , cells become insensitive to metformin treatment, and metformin cannot activate AMPK

▲Metformin binds to PEN2 to activate AMPK (Image source: Reference [1])

Next, the research team revealed the pathway by which metformin works based on this newly discovered target

▲ Molecular pathway of metformin’s effect (Image source: Reference [1])

In subsequent animal experiments, the research team further verified the above mechanism

Normally, metformin mediates a decrease in liver fat content

Through this series of experimental designs, this study is the first to clearly demonstrate the mechanism of action of metformin at the molecular level

References:

[1] Ma, T.

[2] Chen-Song Zhang et al.

[3] Breakthrough! Lin Shengcai and Deng Xianming's team collaborated to decipher metformin targets.