After decades of popularity, the “star drug” has been caught out of its “old pit”

2022-06-09 0 By

The discovery of metformin by The Team of Lin Shengca provides the first molecular roadmap for the function of metformin, which is crucial for improving the safety and effectiveness of drug targets. It is important for the treatment of diabetes.Even the research and development and application of anti-tumor and anti-aging drugs provide a new idea.Metformin, the most commonly used drug in the treatment of diabetes, is no stranger to the public.In recent years, some clinical studies have found that metformin can relieve fatty liver, protect cardiovascular system, inhibit tumor growth and relieve symptoms of neurodegenerative diseases in addition to lowering blood glucose.Where do these effects come from?Metformin has been on the market for more than 60 years and has benefited countless patients. However, its mechanism of action is still unknown, which greatly limits the understanding and application of metformin in the medical community.The answer to this scientific mystery has been revealed.Member of Chinese Academy of Sciences, xiamen university, college of life science professor Lin sc team after 7 years researches, managed to find metformin targets directly, for the first time from the point of view of molecular outlined the metformin function roadmap, laid the foundation to further expand the scope of its application, the relevant research results published in the journal nature.Metformin was isolated from the goat bean plant in the 1920s and was subsequently modified and optimized for its hypoglycemic properties.Metformin has been on the market since 1957 and is widely used to treat diabetes.It is generally believed that metformin acts directly on liver, kidney and intestinal tract. After being transported into cells, metformin plays important biological functions such as reducing fat content and blood glucose mainly by activating the adenosine monophosphate activated protein kinase (AMPK) signaling pathway.AMPK is known as the master switch of human metabolism. It is activated by elevated adenosine phosphate (AMP) when cell energy level drops, and plays an important role in maintaining substance and energy homeostasis.So how exactly does metformin control this switch?Metformin has previously been shown to increase AMP levels and activate AMPK by inhibiting mitochondrial electron transport chain complex function.It is important to note, however, that these trials used very high, above-clinical concentrations of metformin, much higher than the clinical dose, so this effect is hardly a true reflection of physiological effects.It’s worth noting that scientists also discovered a strange phenomenon when studying how metformin activates AMPK.In contrast to metformin, other synthetic AMPK activators do not have all the effects of metformin, and clinical doses of metformin have no effect on AMP levels.Intuitively, when patients were treated with metformin, the level of AMP in their cells that activates AMPK did not rise, but the drug still worked.Lin’s team, who has been studying metabolic homeostasis and the pathogenesis of metabolic diseases for a long time, believes that there are indications that metformin may activate AMPK in a “different way,” possibly through a novel amP-independent pathway.In 2016, the team published preliminary findings that metformin might activate AMPK through a pathway they had previously found the body uses to sense hunger and a drop in blood sugar levels, called the lysosomal pathway, giving a rough indication of how metformin might work.”The research at the time was equivalent to tracking a thief into a building without knowing which room he was in.”Lin Shengcai image to explain.Based on the above research direction, the team explored for more than 5 years and found the molecular target of metformin — PEN2, confirming that the lysosomal pathway is the correct pathway for metformin to activate AMPK.In this work, Lin shengcai team first cooperated with Deng Xianming team of Xiamen University. The latter, through a series of explorations, broke through several chemical synthesis problems and synthesized metformin chemical probe.Put simply, the probe works like a fishing probe, with metformin as the molecule on the front end and a tag called biotin as the rod.Once the front-end metformin molecule meets the protein it binds to, the target, researchers can hook metformin up with its target by using the tag on the back end, and then analyze it to know exactly what target metformin binds to.Using this method, the team fished out more than 2,000 proteins from cells that might bind to metformin, and screened out 317 proteins that could be found on lysosomes for further validation.By examining metformin and these protein interactions one by one, the researchers again narrowed the field to 113 proteins that bind specifically to metformin.The team then silenced each of the 113 proteins in turn and found that metformin failed to activate AMPK when PEN2 expression was inhibited.These results suggest that PEN2 can mediate metformin’s activation of AMPK, which means that PEN2 is a key target of metformin to activate the lysosomal pathway and AMPK.The researchers then confirmed the identity of PEN2 in animal studies.When they knocked out PEN2 of caenorhabditis elegans in mice, metformin no longer activated AMPK, and metformin-induced reductions in glucose levels and liver fat disappeared.All the experimental results indicate that PEN2 is an indispensable signaling molecule in the mechanism of metformin.The researchers also note that this pathway is amP-independent and does not disturb intracellular AMP levels, which may explain why metformin does its job without damaging cells by lowering energy levels and causing significant side effects.It is widely believed that metformin’s mechanism of action may lead to the development of new and safer alternative drugs in the future.Metformin, for example, currently affects only a few tissues, such as the liver and intestines, and its efficacy remains limited.People should be especially cautious if they want to use metformin to lose fat and retain muscle mass, rather than all at once.After finding metformin molecular targets, it is highly possible to design metformin targeted drugs specifically targeting adipose tissue, which will undoubtedly bring benefits to the treatment of metabolic diseases such as malnutrition, which is increasingly serious at present.In addition, the role of PEN2 in tumor formation, aging and dementia has also been gradually revealed.A number of alzheimer’s patients have been found to have mutations in the PEN2 gene.Therefore, metformin targeting PEN2 may play a role in the prevention and treatment of alzheimer’s disease.Zhongshan hospital affiliated to fudan university endocrine metabolism xiao-ying li, director of the evaluation, “Lin sc team for the first time the discovery from the point of view of molecular outlined the metformin function roadmap, for improving the safety and efficacy of drug targets are vital, for the treatment of diabetes, and even the anti-tumor, anti-aging drug research and development and the application provides a new train of thought.”For now, the team says, the field of unravelling the interactions between small molecules like metformin and proteins is still very frontier, or immature.Finding a target for metformin is like finding a needle in a haystack. There are as many water-soluble protein molecules that bind to metformin as there are salt ions in water.In this case, there is no better way to screen, the only way is to take the time to screen one by one.In addition, whether PEN2 targets can fully explain the different effects of metformin and whether there are other targets requires more research in the future.(Science and Technology Daily)