Metformin has been hailed as a miracle drug clinically. It was first isolated and synthesized from goat beans. It is a galegine (prenylguanidine) derivative. It has been on the market since 1957. After more than 60 years of development, it is not only used as a first-line hypoglycemic drug, but also a real diabetes treatment drug. It can be used in all stages from diabetes prevention to pre-diabetes to diabetes.
In the horizontal comparison, the best effective dose of metformin treatment has better hypoglycemic effect than other oral hypoglycemic drugs. At the same time, metformin has no contraindications. It is the first choice drug and combination for the treatment of type 2 diabetes. Essential drugs in the treatment regimen. In addition, more and more magical effects have been discovered, including tumor prevention, aging prevention, and more.
However, its specific target has not been clear. In recent years, studies have shown that metformin has a target in mitochondria – mitochondrial glycerophosphate dehydrogenase (mGPD). Metformin inhibits the activity of mGPD, blocks the process of α-glycerol phosphate shuttling, makes NADH accumulate in the cytoplasm, and inhibits the process of gluconeogenesis using lactate and glycerol as substrates. In addition, it is also believed 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 vagal afferent fibers distributed in the intestine, and then innervates the liver through vagal efferent fibers, ultimately inhibiting the liver’s glucose output. In short, there are many opinions.
Although metformin has such a dazzling effect, it also has some side effects. If the target of action is clear, it may be possible to synthesize new alternative drugs in the future, which not only retains its effect but also reduces side effects. Novel compounds, which are really the requirements of scientific progress.
Recently, the team of Professor Lin Shengcai of Xiamen University, after 7 years of scientific research, solved the mystery of the direct target of metformin by “fishing” with the specific molecular probe method. The work can be regarded as a landmark work, known as the “Lin Pathway,” and the study was published in the journal Nature.
Since 2014, Shengcai Lin’s team has been studying 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 human autophagy signaling pathway. However, how AMPK is activated is not clear. At the same time, metformin has no obvious effect on AMPK, the natural activator of AMPK in human body. Therefore, metformin may affect AMPK through other pathways.
Their team reported in Cell Metabolism in 2016 that metformin may activate AMPK through the “lysosomal pathway” pathway.
On the basis of the above, they finally found the molecular target of metformin – Presenilin enhancer 2 (PEN2), which is a γ-secretase component subunit (γ-secretase component subunit (γ-secretase). -Secretases include PS1, nicastrin, APH1a, PEN2), which further clarifies the specific way it leads to the lysosomal pathway and activates AMPK.
Figure: PEN2 binds to metformin and is required for low-dose metformin-induced AMPK activation
Key to this work was their team’s synthesis of a chemical probe for metformin.
Fig. 3: ATP6AP1 tethers PEN2 to v-ATPase for AMPK activation.
After confirming how metformin can target PEN2, which leads to further changes in downstream signaling, the researchers next investigated how metformin binding causes PEN2 to intersect and inhibit v-ATPase.
PEN2 immunoprecipitated after incubation with protein extracts of lysosomes was analyzed by mass spectrometry. A total of 1881 proteins were detected in PEN2 prey, of which 889 were altered after metformin treatment. Of these 889 proteins, 123 were lysosomal resident proteins. Among these 123 candidates, we were particularly interested in the cofactor of v-ATPase8, ATP6AP1 (also known as Ac45), because its metformin-dependent interaction with PEN2 could be verified by cellular and in vitro co-immunoprecipitation assays. Domain mapping experiments determined that amino acid residues 420 to 440, which constitute the transmembrane domain of ATP6AP1, are responsible for PEN2 binding. showed that ATP6AP1 links PEN2 to v-ATPase to activate AMPK.
Further research on animal models found that if PEN2 or ATP6AP1 is knocked out, metformin not only cannot activate AMPK, but also reduces fatty liver, relieves hyperglycemia, and prolongs life expectancy.
These results fully demonstrate that metformin does activate AMPK through PEN2 and has various effects, that is, PEN2 is the target of metformin.
In conclusion, we found that PEN2, a molecular target of metformin, intersects the glucose sensing pathway to activate AMPK, eliciting benefits similar to those induced by glucose starvation or calorie restriction. The PEN2-ATP6AP1 axis provides a potential target for screening alternatives to metformin, which could be used in a wider range of tissues, such as muscle, leading to better outcomes in the treatment of diabetes and other metabolic diseases.
Mayes Medicine believes that this research may have many implications in the future. PS/γ secretase is responsible for the cleavage of Alzheimer’s disease-related protein beta amyloid precursor protein (APP), signal transduction receptor Notch and other type I transmembrane proteins, and its constituent units are at least four: presenilins (PS , including PS1 and PS2), nicastrin (NCT), APH-1 and PEN-2. Metformin targets PEN-2 and may have an effect on Alzheimer’s disease. In fact, many Alzheimer’s patients have mutations in the PEN-2 gene. In addition, a large retrospective study previously found that “the price of using the magic drug is a 50% increase in the risk of Alzheimer’s disease? Metformin will suffer from Waterloo again!” If it is explained from the perspective of the PEN-2 gene, it seems possible to find suitable answer.
Although, PEN2 has been gradually revealed in tumor, aging, dementia, hypoglycemic and other effects. However, whether the PEN-2 target can fully explain the effects of metformin requires further study. After all, as a small molecule drug, its target specificity is not particularly strong. More research may be needed in the future to explain the different effects of metformin.
References:
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