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over the years, academia has made repeated breakthroughs in the clinical cure of diabetes.

written by | ling jun

the 25-year-old female patient had a history of two liver transplants and 11 years of type 1 diabetes. in 2017, she underwent a pancreas transplant but the transplant had to be removed due to thrombosis. if she had not tried the most advanced stem cell regenerative therapy at tianjin first central hospital, the survival prospects of this 25-year-old female patient would not have been optimistic.

on september 25, the research groups of shen zhongyang and wang shusen from tianjin first central hospital and the team of deng hongkui from peking university/changping laboratory published a major article in the top journal cell. for the first time in the world, innovative stem cell islet transplantation was used to clinically functionally cure type 1 diabetes. patients no longer needed exogenous insulin treatment during the one-year follow-up period.

type 1 diabetes usually occurs in children and adolescents. if it is not effectively controlled, patients will develop serious complications and even endanger their lives. although islet transplantation has achieved good clinical efficacy in the treatment of diabetes for decades, its widespread application is severely limited by the shortage of human pancreas donors.

the transplantation of regenerative pancreatic islets derived from the body's own cells is expected to completely solve this problem.

experts and patients take photos

get rid of insulin and achieve functional cure!

relevant statistics show that there are millions of patients with type 1 diabetes in my country. they cannot be cured and can only rely on lifelong insulin injections and hypoglycemic drugs to control blood sugar and maintain life. however, accurate control of blood sugar is still a problem, and the risk of diabetic complications exists for a long time, including difficult-to-prevent microvascular, macrovascular and neuropathy.

for the patients enrolled in this trial, the situation was much more serious.

according to the researchers, the 25-year-old female patient had a history of cryptogenic cirrhosis and underwent two liver transplants in 2014 and 2016. at the same time, she was diagnosed with type 1 diabetes in 2012. due to poor long-term blood sugar control, doctors performed a whole pancreas transplant on her one year after the liver transplant in 2017.

pancreas transplantation and pancreatic islet transplantation are one of the means of treating type 1 diabetes, but they are not a perfect solution. due to a series of pain points such as the need for long-term use of immunosuppressants and the scarcity of donors, this treatment strategy is limited to the most serious cases.

in fact, one year after the patient completed the whole pancreas transplant, the doctor had to remove her pancreas transplant again due to severe thrombotic complications. before going to tianjin first central hospital, her plasma c-peptide level, which reflects the function of pancreatic islet cells, was below the detection limit, and her glycosylated hemoglobin was higher than the normal standard.

although she had received intensive glucose-lowering treatments many times, her blood sugar control was still not up to standard, her blood sugar fluctuated greatly, and she also showed serious hypoglycemia. in the past year, she had three severe hypoglycemic events.

initially, the patient could only undergo another islet transplant, but after evaluation, the doctor found that her related antigen test was positive, which meant that allogeneic transplantation would face a serious risk of rejection and a high failure rate. after a multidisciplinary discussion between the department of endocrinology and the transplantation center, and with the patient's informed consent, the doctor decided to perform a new autologous stem cell islet transplant on her.

the principle of this transplantation method is based on the unlimited proliferation of pluripotent stem cells (psc), which can differentiate into all functional cell types of an organism. the developer of this technology, professor deng hongkui, just won the future science award, known as the "chinese nobel prize", in august this year. his contribution is "the creation of 'chemically induced pluripotent stem cells' (cipsc) and outstanding achievements in changing the fate and state of cells."

on june 25, 2023, under the guidance of ultrasound, the research team injected the islets differentiated from cipsc into the patient. at the same time, in order to avoid the onset of autoimmune disease and attack on the new islets, the doctors also carried out induction therapy to prevent rejection in advance.

within two weeks after the transplant, the amount of insulin the patient needed to inject daily began to decrease. from the 18th day after the operation, the downward trend gradually stabilized, and by the 75th day, the patient was completely free of insulin, and the efficacy has been stable for more than a year. at the same time, her fasting blood sugar continued to decrease and remained at normal values ​​for a long time.

after the transplant, the patient's insulin dosage continued to decrease until it was no longer needed (above); fasting blood sugar levels remained stable at normal values ​​for a long time (below)

in the "glucose tolerance" test, the doctor observed her condition before and after the glucose injection. before the operation, the patient's blood sugar soared rapidly within 3 hours after the glucose injection, indicating that her pancreatic beta cell function had been completely destroyed. after the transplant, even with the glucose injection, the patient's blood sugar remained stable.

it is worth mentioning that this treatment also used a new islet transplantation strategy of "transplantation under the anterior rectus sheath". compared with the traditional transplantation through portal vein injection, this approach is less invasive and easier to operate, and the transplanted islet cells are more likely to survive and maintain function for a long time.

"the results show that further clinical research on cipsc-islet transplantation for the treatment of type 1 diabetes is warranted!" said the researcher. it is understood that a total of three patients have participated in this trial, and the other two have completed the treatment. the data is still being collated and analyzed.

stem cells, a new hope for diabetes treatment?

the research results were not achieved overnight. although the treatment plan adopted is the first of its kind in the world, through similar principles, the academic community has made considerable breakthroughs in the exploration of diabetes cures over the years.

pluripotent stem cells, including induced pluripotent stem cells (ipsc) and embryonic stem cells (nesc), are a source of reproducible human cells in the early developmental stage, with the potential to form any cell type in the adult body. as early as 2006, professor shinya yamanaka of kyoto university in japan discovered that adult cells could be "rejuvenated" and induced to return to a state similar to the early embryonic development, creating ipsc, and was awarded the 2012 "nobel prize in physiology or medicine".

professor deng hongkui has also been working in this field for more than 20 years. in 2013, he first published an article in science, proving that mouse somatic cells can be induced to reprogram into pluripotent stem cells using only chemical methods. professor deng hongkui remembers that once the research was published, the global regenerative medicine field was shocked - no one expected that reprogramming could be achieved in such a simple way.

in 2022, after numerous failures, professor deng hongkui's team finally succeeded in replicating the gene in humans, and the research was published in nature. compared with traditional induction methods, this new technology does not require genome manipulation, which is not only more convenient, but also avoids safety risks.

in addition to being used to treat type 1 diabetes, the differentiated new islets can also be used in patients with type 2 diabetes accompanied by pancreatic islet failure.

professor deng hongkui won the 2024 future science award "life science award"

professor cheng xin's team at the center for excellence in molecular cell science of the chinese academy of sciences is also a leader in this field. the new type of "endodermal stem cells (ensc)" they developed successfully achieved in vitro regeneration of pancreatic islet tissue. in april this year, the team and scholars from shanghai changzheng hospital jointly announced the results of the study in cell discovery. for the first time in the world, autologous regenerative pancreatic islet transplantation derived from ipscs was used to cure a patient with severe type 2 diabetes.

internationally, this field is also developing rapidly. in june this year, the us biotech giant vertex announced that its stem cell therapy vx-880 had made significant progress. seven out of 10 patients with type 1 diabetes no longer needed to use insulin, two had their medication dosage reduced by 70%, and all patients’ blood sugar levels were under control.

unlike the aforementioned domestic treatment strategies, vx-880 uses allogeneic stem cells, which are "someone else's". the advantage is that they can be prepared in advance and are expected to achieve "universality". however, compared with autologous stem cell transplantation, allogeneic transplantation may also have a stronger risk of immune rejection.

it is worth mentioning that in june last year, the us food and drug administration (fda) approved the first cell therapy for the treatment of type 1 diabetes, lantidra. although it is not a stem cell therapy, this therapy uses pancreatic islet cells from deceased donors. in clinical trials, 33% of patients no longer needed to use insulin for more than 5 years.

on the other hand, the use of mesenchymal stem cells (msc) to repair pancreatic islets also provides an opportunity for the treatment of early-onset type 1 diabetes, and many studies are underway.

however, due to the risk of immune rejection and carcinogenicity, these cutting-edge studies are currently only allowed to be carried out in a small number of patients with severe diseases. for example, in order to avoid rejection, the american company vertex has adopted strategies such as "encapsulating" transplanted islets and gene editing, but whether they are effective and whether additional operations will increase safety risks still require long-term verification.

as for the "autologous transplantation" carried out by tianjin first central hospital, since the patient's type 1 diabetes is an autoimmune disease, the immune system may still attack the new "autologous islets", and immunosuppression may still be required.

"but because this patient had previously undergone a liver transplant and was already using immunosuppressants, our understanding of the immune status after stem cell islet transplantation alone is still limited," the researchers pointed out.

"there is still a long way to go." professor ding guoshan, academic leader in organ transplantation science at shanghai changzheng hospital, also said in an interview that the current research results are still preliminary and require the accumulation of more cases, more in-depth clinical trials, and further analysis before the vast number of diabetic patients who have long relied on insulin injections can truly have a new cure.