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New perspectives of treatment for type 1 diabetes: pancreatic islets derived from pluripotent stem cells
“The daily management of type 1 diabetes is entirely entrusted to the person suffering from it. Patients must learn to predict how much they will eat, and therefore how much sugar they will intake, and how much insulin, and at what time, they need to inject themselves to keep their glycemia under control. It is a constant mental effort that involves calculating, anticipating, and predicting — all tasks normally done by the pancreas, whose endocrine cells are naturally calibrated to finely tune glycemia. When this physiological control is lost, as it happens in type 1 diabetes, it is as if we had to remind ourselves in every moment to breathe.”
This is how Lorenzo Piemonti, Head of the Regenerative Medicine and Transplant Unit, Group Leader of the Beta Cell Biology Lab at IRCSS San Raffaele Hospital in Milan, and Professor at Vita-Salute San Raffaele University, describes the mental toll that an invisible disease like type 1 diabetes can represent for people living with it.
A few months ago, on June 20, The New England Journal of Medicine published a phase 1–2 study that demonstrated the safety and efficacy of a novel, allogeneic, stem cell-derived islet-cell therapy that rendered 10 patients with type 1 diabetes independent from exogenous insulin one year after a single infusion.
Pancreatic islets
These results were achieved within the framework of a larger, ongoing study, involving research institutes in the United States, Canada, and Europe, including Italy, where the IRCCS San Raffaele Hospital in Milan is the only participating center.
“One year after receiving a single dose of the therapy, 10 patients suffering from type 1 diabetes no longer needed exogenous insulin to keep their glycemia under control. These results, if confirmed on a larger sample of people, suggest the possibility of an alternative therapy for type 1 diabetes” explains the Professor.
Putting the research into context
Injection of exogenous insulin with automated delivery systems (insulin pumps) represents the current standard of care for type 1 diabetes. These devices have been saving lives for years. However, insulin pumps cannot replicate the fine and rapid tuning of glycemia done by a healthy pancreas.
Sometimes, especially after a meal, insulin-delivery systems might be unable to readily calibrate the exact dose of insulin needed for glycemic control: this can lead to the injection of inappropriately large amounts of the hormone.
As a result, hypoglycemia can ensue, which, when not managed, can cause collapse, coma, seizures and injury. When episodes of hypoglycemia become recurrent, about 30-40% of patients with type 1 diabetes become unaware of their onset, which further complicates intervention.
To better mimic the physiological control of glycemia, strategies based on replacement of beta cells (cells of the pancreatic islets that produce and release insulin) have been developed. These include the transplantation of the whole pancreas and transplantation of pancreatic islets alone.
Islet transplantation lowers the surgery risk associated with transplantation of the whole pancreas, which is complicated by organ anatomy, histology, and exocrine secretions.
Currently, islet transplantation is a well-established practice that allows finer and more stable control of glycemia.
However, while being more effective than exogenous insulin injections in maintaining glycemic control, islet transplantation does not resolve the problem of donor organ availability. This is because more than one pancreas is necessary to obtain the right number of cells that eventually engraft, survive, and function in the recipient patient.
Here, is where therapies based on the use of stem cell derived islets could make a difference.
First, pluripotent stem cells are potentially unlimited sources of differentiated cells, including pancreatic islets.
Second, the clinical experience with primary islet transplantation provides the guidelines to achieve successful engraftment and functioning also of islets that are differentiated from pluripotent stem cells.
The study in the New England Journal of Medicine
In the study published last June in the New England Journal of Medicine, 14 patients with severe type 1 diabetes, who suffered from recurrent episodes of hypoglycemia, received a single infusion of allogeneic stem cell-derived islets through the portal vein, a procedure already in use for transplantation of primary pancreatic islets.
Infused islets eventually engrafted in the liver, where they functioned without altering normal hepatic activity. However, the patients have to take immunosuppressive medications to avoid rejection of infused cells.
One year after the single infusion, no severe hypoglycemic events were recorded for any of the treated patients, who showed overall restoration of physiological-like glycemic control. The treatment was safe for all the patients, as no serious adverse events were reported.
Upon infusion, the patients showed increased serum levels of C peptide, which was undetectable at the baseline recorded before treatment. The increase of C peptide concentration up to detection levels indirectly indicates that infused islets had successfully engrafted and started functioning.
The patients spent more than 70% of their time in the target glucose range (70-180 mg/dl) and maintained levels of glycated hemoglobin below 7%.
10 patients showed full independence from exogenous insulin administration after 1 year of follow-up, while 2 patients had reduced their independence from the hormone by 70% and 36%, respectively.
“Overall, these results indicate that a single infusion of allogeneic stem cell-derived islets effectively restored physiological-like control of glycemia in patients. This study sets the foundations for future clinical trials aimed at confirming these results both in a larger sample of people and over a longer period”, comments Professor Piemonti.
The previous study in Cell
The study in the New England Journal of Medicine is not the first one testing the use of stem-cell derived islets to treat type 1 diabetes.
Last October 2024, a group of researchers from the University of Peking (China) had published in Cell the 1-year results of a phase I clinical trial that evaluated the feasibility of autologous transplantation of stem-cell derived islets in one patient with severe type 1 diabetes.
This time, islets were differentiated from patient’s own adipose-derived mesenchymal stromal cells that were reprogrammed to pluripotency by chemical induction. This procedure uses small-molecule, abiotic chemicals, instead of genetic overexpression of conventional transcription factors, to reprogram somatic cells to pluripotent stem cells.
Islets differentiated from chemically induced pluripotent stem cells were then transplanted under the abdominal anterior rectus sheath of the patient, instead of being infused through the portal vein. This delivery route enables better control of the transplant, which engrafts in an area that is more accessible to imaging techniques and monitoring than the liver.
Also in this study, islets derived from chemically induced pluripotent stem cells led to improved and sustained glycemic control in the patient at 1 year follow-up.
C peptide serum levels increased above the detection limit, indicating successful islet engraftment. Glycated hemoglobin fell below 7% and remained stable at 1 year follow-up. The patient spent more than 98% of her time in the target glucose range and achieved sustained independence from exogenous insulin injection as early as 75 days post transplantation.
“However, also this patient had to receive immunosuppressive medication to avoid rejection of the transplant and relapse of autoimmunity. Since the publishing of these results in Cell, two additional patients have been successfully transplanted with autologous stem-cell derived islets in the abdominal anterior rectus sheath. The treatment has been reported to be safe and effective also for them. Still, both patients had to receive sustained immunosuppression”, comments Professor Piemonti. “
The caveat of immunosuppression thus remains, which exposes patients to a higher risk of developing infections and kidney dysfunctions.
Looking ahead: a future without immunosuppression
For these reasons, research in the field of cell therapy for type 1 diabetes aims at a future without immunosuppression. The idea is to make transplanted cells invisible to the patients' immune system, so that they cannot be attacked.
Research is progressing along two alternative paths:
- The cells to be transplanted are embedded in a gel matrix enriched with inhibitors of the local immune response. This local inhibition is expected to protect transplanted cells, allowing them to survive and function without the side effects associated with systemic immunosuppression. This strategy proved to be promising in non-human primates. The next step will be to test it in humans.
- The cells to be transplanted are treated with genome editing techniques to remove the antigens of class I and II and inhibit auto- and allo- immunity, respectively. Additionally, cells to be transplanted are treated to inhibit innate immunity by Natural Killer cells. This strategy has been tested in a single patient in Sweden, in whom pancreatic cells, which had been made invisible to the immune system, were transplanted into muscle tissue of the forearm. Three months after transplantation, the cells have not been rejected yet.
Of the two approaches, the genome-editing-based strategy seems to be the most promising one. Current research is actively working to optimize the safe, effective, and large-scale production of these genetically engineered cells.
“We cannot predict when research will lead to a cell therapy for type 1 diabetes that no longer requires immunosuppression. It is plausible to expect intermediate phases characterized by milder immunosuppressive regimens, before being able to get rid of them entirely, but we must be cautious in making predictions. On the other hand, considering the incredible innovations that happened in research over the past twenty years, we can say that the first generation of type 1 diabetes patients who will receive large-scale treatment with pancreatic islets derived from stem cells has already been born. Our next commitment will be to make this treatment available and sustainable for the greatest number of people with type 1 diabetes,” concludes Professor Piemonti.
Written by: Laura Celotto
Published on: 14/11/2025