Text/Zhuang Shili and Phoenix.com, Special Expert of CC Intelligence Bureau
Key Takeaways:
1. In 2021, a 59-year-old man with a 25-year history of type 2 diabetes who had undergone a kidney transplant was treated with autologous regenerative islet transplantation, and the patient has been completely weaned off insulin for 33 months. This is the first case report in the world that the use of stem cell-derived autologous regenerative islet transplantation has successfully cured diabetes with severely impaired islet function.
2. In this study, pancreatic islet tissue was differentiated from stem cells and treated with percutaneous hepatic portal vein transplantation. The patient was followed up for up to 116 weeks after transplantation, and tumor formation was not detected by his imaging tests (MRI of the upper abdomen) and blood tumor markers. This study demonstrated that non-tumorigenic human endodermal stem cell-derived islet tissue has the potential to restore islet function in patients with severe type 2 diabetes without serious adverse effects.
3. Experts said that from the preliminary research results, this research result has great scientific research significance and potential clinical application value for the treatment of severe diabetes. However, the research results are still preliminary, and more cases need to be accumulated and more in-depth clinical trials need to be conducted, especially focusing on survival rates and long-term safety of stem cell products. The islets of pancreatic cells, which are generated by the patient's own body, may still be recognized by the patient's immune system as a foreign object and attacked, so it is necessary to guard against immune rejection for a long time.
Why can stem cell-derived autologous regenerative islet transplantation cure patients with a 25-year history of diabetes? How does it work?
A 59-year-old man in Shanghai who has undergone a kidney transplant and has a 25-year history of type 2 diabetes mellitus underwent autologous regenerative islet transplantation at Shanghai Changzheng Hospital on July 19, 2021. Currently, the patient has been completely weaned off insulin for 33 months.
This is the first case report in the world that the use of stem cell-derived autologous regenerative islet transplantation has successfully cured diabetes with severely impaired islet function. The study was recently published online in Nature's Cell Discovery.
China is the largest country in the country with diabetes, with as many as 140 million patients, of which about 40 million need to rely on insulin injections for life.
Does the advent of this treatment mean that diabetes can be cured? Can diabetic patients use stem cell-derived autologous regenerative islet transplantation? Zhuang Shilihe, a special expert of Phoenix.com's "CC Intelligence Bureau", interpreted this.
Before interpreting this study, let's briefly introduce some basic knowledge about pancreatic islets.
Let's first distinguish the relationship between the pancreas, the pancreas and the islets. The pancreas, also known as the pancreas, is a long-shaped organ located at the back and bottom of the stomach that has both internal and external secretory functions, and the digestive enzymes secreted by the pancreas play an important role in the digestion of food.
The pancreatic islets are actually scattered cell clusters in the pancreas, each cell cluster has about three or four thousand cells, accounting for only 1%~2% of the volume of the entire pancreas. These clusters of cells resemble islands in the ocean, hence the name pancreatic islets. The islets also contain four different cells, of which the islet β cells secrete insulin, which is the only hormone in the body that lowers blood sugar.
Note that there are many hormones in the body that can raise blood sugar, but only this one can lower blood sugar.
When it comes to insulin, people naturally think of its relationship with diabetes. There are two types of diabetes, in simple terms, type 1 is an absolute deficiency of insulin secretion, and type 2 is mainly insulin resistance, which accounts for more than 90% of all diabetes cases.
However, with the development of type 2 diabetes, the function of pancreatic islets will gradually be lost, and more than 30% of patients with type 2 diabetes will eventually require exogenous insulin therapy.
All of this knowledge is not complicated, but they determine the basic strategies for the development and treatment of diabetes.
The study by Shanghai Changzheng Hospital, which uses stem cells to differentiate pancreatic islet tissue to treat diabetes, has been a hot topic in the field of diabetes treatment in the past two decades, because it can effectively solve the problem of insufficient islet transplant donors.
The patient in this study, a 59-year-old man who had had type 2 diabetes for 25 years, had a kidney transplant in June 2017 due to the microvascular complications of diabetes, which also progressively failed his kidneys.
However, since November 2019, his blood sugar has become difficult to control, fluctuating greatly and sometimes high and low, and the blood sugar level changes between 3.66~14.60 mmol/L, and blood sugar that is too high or too low is very harmful to health.
Concerned about low blood sugar and poor glycemic control of the transplanted kidney for long-term survival, the patient agreed to an E-islet transplant.
首先解释一下什么是“E-胰岛移植”，这个的全称是自体EnSC分化的胰岛组织移植。 EnSC是非致瘤性人内胚层干细胞（non-tumorigenic human endoderm stem cells）的意思。
You may have heard another term, which is called human pluripotent stem cells (hPSCs). In animal experiments, pancreatic progenitor cells or islet tissues produced from human pluripotent stem cells have been shown to survive, onset, and reverse hyperglycemia in diabetic animals.
However, the risk of hPSCs lies in the complexity of differentiation and the risk of teratoma formation in vivo from residual undifferentiated cells, so subsequent research has focused on the use of other types of stem cells, such as the EnSC mentioned above, which may be more suitable for large-scale production of pancreatic islet cells.
The transplant was a percutaneous hepatic portal vein transplant, in which 1.2 million E-islets were transplanted into his body, and after the surgery, his endocrine function and diabetes were monitored through a mixed diet tolerance test (MMTT).
During the 116-week (2 years and 3 months) post-transplant follow-up of this 59-year-old diabetic patient, no tumor formation was detected by imaging tests (MRI of the upper abdomen) or hematologic tumor markers (which was the focus of the investigators' monitoring and the most worrying adverse reactions), and the main adverse reactions in this patient were:
- Temporary bloating and loss of appetite within 4~8 weeks after transplantation;
- Restorable weight loss (<5%, from 80 kg to 76 kg).
On top of that, the effect of blood sugar control after transplantation is very significant.
In the second week after surgery, the patient's blood glucose fluctuations were significantly reduced, the level of glycemic control increased from 56.7% to 77.8%, the severe hyperglycemia and severe hypoglycemic events completely disappeared (until the end of follow-up), and the glycosylated hemoglobin A1c level decreased from the initial 6.6% to 5.5% at week 85 and 4.6% at week 113.
The average fasting level of C-peptide (an indicator of pancreatic islet function) increased by 3 times compared with that before surgery, and the secretion level of C-peptide and insulin was significantly increased.
In addition, the patient's need for exogenous insulin gradually decreases after surgery, and insulin injections are completely stopped by the 11th week; Oral hypoglycemic agents were also tapered from week 44 onwards and discontinued at week 48 (acarbose) and week 56 (metformin).
This study showed that the patient's blood sugar was very effectively controlled for more than two years after transplantation, demonstrating that non-tumorigenic human endodermal stem cell-derived islet tissue is expected to restore islet function in patients with severe type 2 diabetes without serious adverse effects.
▎Professor Yin Hao, Director of the Organ Transplantation Center of Shanghai Changzheng Hospital. The study was conducted by his team and the team of Professor Cheng Xin from the Center for Excellence in Molecular and Cell Science, Chinese Academy of Sciences. In 2012, Cheng Xin, the chief scientist of the joint team, established endodermal stem cells and their improved types of endoderm stem cells for the first time in the world. It has also successfully established a large-scale directional differentiation system under GMP conditions, which can realize large-scale production. On this basis, after more than ten years of painstaking research, the team reprogrammed the peripheral blood mononuclear cells (PBMCs) into autologous induced pluripotent stem cells (iPSCs) from patients' blood, and used the world's first technology to transform them into "seed cells", that is, endoderm stem cells, and finally recreate pancreatic islet tissue in vitro.
Stem cell-derived islet transplantation still faces problems such as low survival rate and "carcinogenic mutations".
The successful cure of a 25-year-old diabetic is undoubtedly exciting news.
Since a single islet β cell senses extracellular glucose changes and secretes insulin, this type of transplant does not require a very complex surgical procedure like transplantation of entire organs such as the heart and kidney, and it is expected that a functional cure can be achieved if the islet containing β cells is transplanted to a site that is conducive to adequate exchange with the bloodstream.
However, Ding Guoshan, academic leader of the Department of Organ Transplantation at Shanghai Changzheng Hospital, said: "Judging from the preliminary research results, this research result is a discovery with considerable impact on the treatment of diabetes in the future, especially the treatment of severe diabetes, and the scientific research significance and potential clinical application value are quite huge." At present, the research results are still preliminary, and more cases and more in-depth clinical trials need to be accumulated, and through continuous research progress and further analysis, the next step can really be a new cure for the majority of diabetic patients who have been dependent on insulin injection for a long time, and there is still a long way to go."
At present, this type of stem cell-derived islet transplantation still faces some major problems:
The first is the issue of survival rates. Due to the high metabolic demands of insulin production and secretion, β cells are particularly susceptible to stress, and in early studies of islet transplantation, more than 50% of islet tissue died after transplantation, mainly due to the stress response of transplantation (hypoxia, nutrient deficiencies, inflammation, etc.).
Another issue is the long-term safety of stem cell products. We mentioned above the teratoma risk of hPSCs, which is also the risk of all stem cell differentiation, the direction of cell differentiation is still not completely controllable, and the accumulation of unsafe genetic mutations (especially oncogenic mutations) may pose a significant safety risk to this type of stem cell transplantation (including stem cell differentiated islet transplantation).
In 2015, a clinical trial in Japan using induced pluripotent stem cells (iPSCs) for macular degeneration was suspended due to genetic variation.
The most concerned risk comes from post-transplant rejection.
In fact, in 2021, the Stem Cell Institute of Harvard University also completed a clinical trial for diabetes, achieving the world's first cure for type 1 diabetes using stem cell therapy.
▎According to the analysis of islet transplantation data, only 11% of the 237 human islet transplants performed between 1990 and 1999 did not require insulin injection for one year after surgery. For example, the University of Alberta in Canada reported that 33 diabetic patients had a success rate of 85% after islet transplantation using the Edmonton Protocol alone, but most recipients needed to undergo two or more transplants. The rate of people who did not need insulin therapy at 5 years after surgery decreased to 10%.
But the American patient who uses this stem cell therapy to "cure" type 1 diabetes needs to take immunosuppressants all the time, otherwise his immune system will reject the transplanted pancreatic islet cells.
This is also a problem that the patient at Shanghai Changzheng Hospital, who is a kidney transplant patient and also needs anti-rejection drugs after surgery in 2017.
In addition to allogeneic transplantation, even if intermediate stem cells such as iPSCs are used and the stem cells are generated from the patient's own body, they may still be recognized by the patient's immune system as foreign objects and attacked.
Although the use of anti-rejection drugs from other organ transplants, such as some immunosuppressants, can protect these transplanted islet tissues, long-term use of these drugs can also have adverse effects, such as increased risk of infection and cancer.
It is unclear whether the risk of these adverse effects is higher or lower than the benefit of controlling blood glucose.
Diabetic patients need to beware of informal treatment methods that are abducted in the name of stem cells
Of course, researchers in various countries are also trying to solve these problems, such as using some immunomodulatory biomaterials and special packaging methods to protect the transplanted pancreatic islet tissue, so that pancreatic β cells can contact small molecules such as glucose and release insulin, but not with the host's immune cells.
These are some of the challenges faced by stem cell transplantation in the treatment of diabetes, and they are not unsolvable, but more and more in-depth clinical studies are needed.
It is also important to know that these studies are still in a very early stage, and there are many risks involved, and we should also beware of other informal treatment methods that are abducted in the name of stem cells.
All in all, the Chinese researchers' study is a global advance in the field of diabetes treatment, giving hope for a cure for patients with type 2 diabetes.