Metformin has been known clinically as a miracle drug, the earliest isolated and synthesized from goat beans, is a goat beanine (galegine, isopreneguanide) derivative, since 1957 after the listing, after more than 60 years of development, so far not only as a first-line hypoglycemic drug in use, but also the real diabetes treatment drug, from diabetes prevention to pre-diabetes to diabetes at all stages can be used.
In the horizontal comparison, the hypoglycemic efficacy of the optimal effective dose metformin treatment is stronger than other oral hypoglycemic drugs, and metformin has no contraindications, which is the preferred drug for the treatment of type 2 diabetes mellitus and the basic drug in the combination therapy regimen. In addition, more and more miraculous effects are found, including preventing tumors, preventing aging, etc.
However, its specific target has not been clear. In recent years, studies have shown that metformin has a target in the mitochondria - mitochondrial glycerophosphate dehydrogenase (mGPD). Metformin inhibits the activity of mGPD, blocks the process of α-phosphoglycerol shuttle, allows NADH to accumulate in cytoplasm, and inhibits the gluconeogenesis process with lactic acid and glycerol as substrates. In addition, it is thought that the first target of metformin's hypoglycemic effect may be in the intestine. Metformin rapidly activates intestinal AMPK and its downstream signaling pathways in the intestine, and then transmits local signals to the center through the afferent fibers of the vagus nerve distributed in the intestine, and then innervates the liver through the vagus nerve efferent fibers, and finally inhibits the glucose output of the liver. In short, there are many opinions.
Although metformin has such a dazzling effect, but there are also some side effects, if its target is clear, it is possible to synthesize new alternative drugs in the future, both to retain its effect, but also to reduce the side effects of new compounds, which is really the requirement of scientific progress.
Recently, Professor Lin Shengcai's team of Xiamen University has experienced 7 years of scientific research, using the specific molecular probe method to "fish" to crack the mystery of the direct action target of metformin, and the work of Lin Shengcai's team is called a milestone work, known as "Lin Tonglu", this study was published in nature magazine.
Since 2014, Lin Shengcai's team has begun to study the mechanism of metformin. In the early years, many scholars found that metformin can activate the AMPK protein, which is a key protein in the body's autophagy signaling pathway. However, how to activate AMPK is not clear. At the same time, metformin has no significant effect on amplification of AMPK's natural activator in the human body, so metformin may affect AMPK through other pathways.
Their team reported in Cell Metabolism in 2016 that metformin may activate AMPK through pathways through the "lysosomal pathway."
On the basis of the above, they eventually found the molecular target of metformin, the progerin enhancer 2 (PEN2), which is a subunit of γ-secretase components (γ-secretases including PS1, nicastrin, APH1a, PEN2), further clarifying the specific way it directs the lysosomal pathway and activates AMPK.
图：PEN2 binds to metformin and is required for low-dose metformin-induced AMPK activation
The key to this work was that their team synthesized a chemical probe for metformin.
Fig. 3: ATP6AP1 tethers PEN2 to v-ATPase for AMPK activation.
After confirming how metformin can target PEN2 and further lead to changes in downstream signals, the researchers next investigated how metformin binding leads to PEN2 intersecting and inhibition with v-ATPase.
PEN2 immunoprecipitated after incubation with protein extracts from lysosomals was analyzed by mass spectrometry. A total of 1881 proteins were detected in PEN2 prey, of which 889 changed after metformin treatment. Of these 889 proteins, 123 are lysosomal-resident proteins. Of these 123 candidates, we are of particular interest to the cofactor ATP6AP1 (also known as Ac45) for v-ATPase8 because its metformin-dependent interaction with PEN2 can be verified by cellular and in vitro co-immunoprecipitation assays. Domain mapping experiments determine that the 420 to 440 amino acid residues that make up the ATP6AP1 transmembrane domain are responsible for PEN2 binding. Indicates that ATP6AP1 connects PEN2 to v-ATPase to activate ampK.
Further animal model studies have found that if PEN2 or ATP6AP1 is knocked out, metformin not only cannot activate AMPK, but also reduce fatty liver, alleviate hyperglycemia, prolong life and many other effects will disappear.
These results fully show that metformin does activate AMPK through PEN2 and play a variety of functions, that is, PEN2 is the target of metformin.
In summary, we found that PEN2 is a molecular target for metformin, which intersects the glucose sensing pathway to activate AMPK, triggering benefits similar to those induced by glucose starvation or calorie restriction. The PEN2-ATP6AP1 axis provides a potential target for screening metformin substitutes, which can be used in a wider range of tissues, such as muscle, resulting in better outcomes in the treatment of diabetes and other metabolic diseases.
Metz Medicine believes that this research may have many more implications in the future. PS/γ secretory enzymes are responsible for the shearing of Alzheimer's-related proteins β amyloid precursor proteins (APP), signal transduction receptor Notch, and other type I transmembrane proteins, which are composed of at least four components: presenilins (PS, including PS1 and PS2), nicastrin (NCT), APH-1, and PEN-2. Metformin targets PEN-2 and may have an effect on senile dementia. In fact, in many patients with senile dementia, there is a mutation in the PEN-2 gene. In addition, a large retrospective study found that "the price of using miracle drugs is a 50% increase in the risk of Alzheimer's disease?" Metformin is waterloo again! ", if interpreted from the perspective of the PEN-2 gene, it seems possible to find a suitable answer."
Although, PEN2 has been gradually revealed in tumors, aging, dementia, hypoglycemic and other effects. However, whether the PEN-2 target can fully explain the role of metformin needs further research. After all, as a small molecule drug, the specificity of its target is not particularly strong. More research may be needed in the future to explain the different effects of metformin.
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