Hope for a cure for diabetes?

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On February 12, 2020, a study published in Science Translational Medicine showed that under laboratory conditions, the combined use of GLP-1RA and DYRK1A inhibitors can induce rapid proliferation of human beta cells (5% -6%) And optimize the specificity of the drug β cell specificity, and has been validated in a squirrel model transplanted with human islet cells.Dr. Andrew F. Stewart, the principal of the study, said: “The synergistic effect of β-cell proliferation rate is much higher than the previous effect of using DYRK1A inhibitor alone, and it is possible to recover type 1 diabetes (T1DM) and T1DM to a certain extent.Normal β-cell function in patients with type 2 diabetes (T2DM). Previously, researchers believed that ‘β-cell proliferation’ was impossible to achieve, and it became ‘possible, but not fast enough’ by 2015, and now it has ‘yes’Probably fast enough ‘”.Method exploration: radical treatment of diabetes. Diabetes affects 422 million people worldwide, and the prevalence is still increasing year by year. All or part of the disease is caused by insufficient numbers of beta cells in the islets. For example, beta cells in T2DM patients have decreased.From 40% to 60%, beta cells in T1DM patients are reduced by 70% to 97%.Enabling islet β-cell proliferation is a key strategy in the treatment of diabetes. Researchers have tried a variety of alternative therapies to radically improve diabetes (such as islets, islet cell transplantation, stem cell therapy, etc.), but currently only pancreas transplantation is available clinically,Considering the risks of surgery and the large number of patients, the percentage of patients who can really benefit from them is very small, and patients undergoing transplantation also have to use immunosuppressants for life.Drug promotion of β-cell proliferation is a new research direction.If the drug can increase the number of beta cells, it may improve insulin secretion levels.But under natural conditions, mature beta cells can hardly increase their number through self-replication and proliferation.In 2015, an article published in the journal Nature Medicine stated that oral DYRK1A inhibitors can increase human β-cell proliferation by 2%.Later, as more research results came out, the DYRK1A inhibitor family received more and more attention.Why choose GLP-1RA in combination with DYRK1A inhibitor?In recent years, DYRK1A inhibitors (harmine, INDY, leucettine, GNF4877, 5-iodotubericidin, CC-401) have been shown to induce human β-cell proliferation, but at a slower rate.In addition, because related receptors and signal molecules are ubiquitous in humans, the specificity of drugs to human β cells is not strong. Therefore, it is urgent to find a method that can accelerate the proliferation of β cells and increase the specificity of drug β cells.GLP-1RA is widely used worldwide as a new type of hypoglycemic drug. Although GLP-1RA cannot induce human β-cell proliferation, its receptor, GLP-1R, has a limited distribution in humans, but is highly expressed in β-cells.Therefore, such drugs have significant β-cell specificity.Considering the superior β-cell specificity of GLP-1RA, and its safety has been affirmed in long-term clinical applications, researchers have selected GLP-1RA and DYRK1A inhibitors as a combination to explore.The synergistic effect of the drug combination is encouraging. The researchers obtained human islet cells from 111 non-diabetic corpse donors and 11 T2DM corpse donors.Beta cell proliferation in a cell culture environment.Finally, dose-dependent β-cell proliferation effects were observed, and the drug combination also increased the β-cell specificity of the drug.”Surprisingly and happily, we found that human islet beta cells have a high replication rate of 5% to 8% per day, some even as high as 20%,” said Dr. Andrew F. Stewart.Synergistic effect was confirmed in a mouse model of diabetes. The combined application of GLP-1RA and DYRK1A inhibitors not only enhanced human islet β-cell proliferation in cell culture, but also against diabetes induced by streptozotocin and transplanted human islet cells.In the study of the mouse model, it was observed that the combination therapy can induce the proliferation of human islet β cells, as well as the improvement of insulin secretion and glycemic control.The class-effect researchers found that each of the DYRK1A inhibitors tested in combination with GLP-1RA showed similar synergistic abilities to promote β-cell proliferation, as did GLP-1RA.This indicates that both DYRK1A inhibitors and GLP-1RA have a drug effect, that is, any member of the GLP-1RA family (exenatide, liraglutide, lixisenatide, somaglutide) and DYRK1AAny combination of members of the inhibitor family can show similar synergistic effects.What’s next?In tissue culture, human islet β cells can only survive for about a week, but if transplanted into mice that have lost immune function, human islet β cells can survive for one year or longer.”The next step is to conduct a long-term study to assess how long the drug combination can have a proliferative effect on beta cells. If this proliferation is terminated after discontinuation of the drug, it will have adverse effects on other organs.Observe the function of human pancreatic islet beta cells in mice. “Later, researchers will demonstrate the preclinical safety of the drug combination in animal models to determine that this medication will not affect the liver, muscle, spleen or other organs.Cause damage and determine the optimal dosage.Summary of this article.
Enabling islet β-cell proliferation is a key strategy in the treatment of diabetes. This study shows that GLP-1RA and DYRK1A inhibitors have a synergistic effect, on the one hand, it can stimulate the rapid proliferation of human islet β cells, and on the other hand, it improves the drug’s β cellsSpecificity, this synergistic effect was confirmed in a mouse model of diabetes.Moreover, it was also found that there is a class effect of the drug, that is, any member of GLP-1RA combined with any member of the DYRK1A inhibitor can show similar effects.The researchers said: “For patients with diabetes who need to inject insulin for life, the proliferation of beta cells was once thought impossible, but now we see greater hope. Although there is still a long way to go in the future,We are full of confidence in the future. “The above content is only authorized for exclusive use by, and please do not reprint it without the authorization of the copyright party.


The author ouyangshaoxia