World's first! A patient with 25 years of diabetes was cured and autologous regenerated pancreatic islet transplantation was successful

Type 2 diabetes usually begins with insulin resistance in peripheral tissues and gradually loses islet function as pancreatic β-cell mass decreases or β-cell dedifferentiation occurs. More than 30% of patients with type 2 diabetes eventually require insulin therapy to control blood sugar. Islet transplantation is an effective treatment for insulin-dependent diabetes. In kidney transplant patients, metabolic improvements after islet transplantation are associated with the function and long-term survival of the transplanted kidney. In addition, the severe shortage of donor organs also hinders the clinical application of islet transplantation.

Recently, Professor Yin Hao's team from the Second Affiliated Hospital of Naval Medical University (Shanghai Changzheng Hospital) and Professor Cheng Xin's team from the Center for Excellence in Molecular Cell Science of the Chinese Academy of Sciences reported in Nature's Cell Discovery the first case of stem cell-derived "autologous regenerative islet" transplantation to treat type 2 diabetes patients with impaired islet function.

In vitro differentiated “autologous pancreatic islet tissue”

Pancreatic progenitor cells or islet tissue generated from human pluripotent stem cells (hPSCs) have been shown to survive, function, and reverse hyperglycemia in diabetic animal models. A recent clinical trial showed that hPSC-derived pancreatic endoderm cells implanted subcutaneously in patients with type 1 diabetes were able to further mature into meal-responsive β-like cells and secrete insulin, although the level of secretion was not high enough to replace exogenous insulin. The results of stem cell research suggest that non-tumorigenic human endoderm stem cells (EnSCs) appear to be more suitable as precursors for large-scale generation of pancreatic islet cells.

The researchers achieved the in vitro differentiation of autologous EnSCs and the production of autologous pancreatic islet tissue (E-islets), completing the first intrahepatic transplantation in a patient with type 2 diabetes with impaired insulin secretion.

Figure: Schematic summary of the main processes involved in the production, quality control, and safety/effectiveness assessment of E-islets for transplantation.

Case presentation

The patient was a 59-year-old male with a 25-year history of type 2 diabetes. He developed end-stage diabetic nephropathy and received a kidney transplant in June 2017. Since November 2019, he had poor blood sugar control, with blood sugar levels fluctuating between 3.66-14.60mmol/L. Due to concerns about hypoglycemia and poor blood sugar control that would adversely affect the long-term survival of the transplanted kidney, the patient agreed to use autologous E-islets for transplantation treatment.

Patients underwent percutaneous hepatic portal vein infusion and transplantation. Endocrine function and diabetes-specific indicators were tested at baseline, 4, 8, 12, 16, 20, 24, 36 and 48 weeks and at designated time points thereafter, and blood glucose was measured 24 hours a day using a continuous glucose monitoring system (CGM). During the follow-up period, the grafts were well tolerated, with no tumor formation or serious graft-related adverse events.

Three main clinical outcomes were monitored during follow-up for 116 weeks, namely, glycemic indices, reduction in exogenous insulin, and fasting and postprandial circulating C-peptide/insulin levels. Significant changes in patients’ glycemic control were observed as early as the second week after transplantation. Glycemic variability decreased after surgery, as evidenced by **stable fasting glucose concentrations and a significant reduction in postprandial glucose concentrations. Notably, insulin requirements gradually decreased and were completely discontinued by the end of week 11. Oral hypoglycemic agents were gradually reduced from week 44 and discontinued at week 48 (acarbose) and week 56 (metformin). Mean fasting C-peptide levels increased 3-fold after surgery compared with preoperative levels.

Importantly, no episodes of hypoglycemia or severe hyperglycemia were observed during the entire follow-up period of 116 weeks postoperatively.

Future Outlook

In summary, the researchers reported the first use of autologous E-islets to treat patients with type 2 diabetes with impaired islet function. Extracting islet tissue from hPSCs or EnSCs provides an unprecedented new source for tissue replacement therapy. EnSCs are non-tumorigenic in vivo and have the advantages of endoderm specificity and being developmentally closer to the pancreatic lineage, which can achieve effective and large-scale islet tissue regeneration.

Secondly, the study selected patients with type 2 diabetes rather than type 1 diabetes, which not only excluded the interference of autoimmune diseases on E-islets transplantation and functional evaluation, but also expanded the scope of indications for islet transplantation.

The limitation of this study is that it cannot completely rule out the possibility that residual endogenous islets can improve their function after surgery. Therefore, it is necessary to increase the sample size and conduct more trials on patients with type 1 diabetes who have completely lost pancreatic β cells in the future.

Future research is also needed to address the pharmacodynamics of stem cell-derived islets as drugs, apply stem cell-derived islet transplantation to other subtypes of diabetes, and generate "universal islet tissue" that does not require immunosuppression as an off-the-shelf product to treat diabetes.