Islet Transplantation for Treating Difficult-to-Manage Type 1 Diabetes in Adults

Decades of research supported by NIDDK and other NIH Institutes recently led to the landmark U.S. Food and Drug Administration (FDA) approval of an entirely new type of therapy for people with type 1 diabetes whose disease cannot be managed using current therapies: islet transplantation. Among its many potential benefits, the procedure may allow someone to go from having difficult-to-manage diabetes to being completely insulin-independent, while substantially lowering the risk of having their glucose (sugar) levels fall dangerously low (hypoglycemia). Before the approval, islet transplantation was only available to people participating in a research study. Now, this therapy is approved for adults with the disease who are unable to approach target hemoglobin A1c levels (a measure of average blood glucose levels over time) because of current repeated episodes of severe hypoglycemia despite intensive diabetes management and education.

Insulin is a life-saving treatment for people with type 1 diabetes, whether taken by injection, insulin pump, or an artificial pancreas device. To estimate how much insulin their body may need, people with the disease must closely monitor their diet, exercise, and daily routine. Despite careful management of diabetes, it is difficult to mimic the exquisite blood glucose control of the pancreas. While taking insulin treats excess glucose in the blood (hyperglycemia), too much insulin can lead to a lack of glucose in the brain and to dangerous situations, including coma and death. Despite vigilant insulin administration, some people have episodes of severe hypoglycemia with memory loss, confusion, altered or irrational behavior, difficulty in awakening, seizures, or loss of consciousness. Such episodes may make activities like driving or caring for young children unsafe. Repeated episodes can lead to impaired awareness of hypoglycemia, where a person does not realize that they have dangerously low blood glucose levels and/or is unable to self-administer treatment, typically by consuming high-sugar foods or drinks or taking a glucose tablet.

To address these challenges, NIDDK vigorously supports research to improve diabetes management. This includes research to advance glucose management technologies, such as artificial pancreas devices that automate insulin delivery in response to blood glucose levels, as well as to develop cell-based approaches, such as islet transplantation, to replace the insulin-producing β (beta) cells that have been destroyed in type 1 diabetes. In islet transplantation, islets (which contain β cells and other cell types) are isolated from donor cadaveric pancreases and transplanted into people with type 1 diabetes. The transplanted islets then start to produce insulin in response to blood glucose levels.

The approval of islet transplantation for people with recurrent severe hypoglycemia is the culmination of decades of collaborative work between NIDDK and the National Institute of Allergy and Infectious Diseases (NIAID), as well as non-governmental organizations and businesses, with oversight and advice from the FDA. The Immune Tolerance Network (ITN), led by NIAID with support from NIDDK and JDRF, tested an approach pioneered in Canada, called the Edmonton Protocol, for injecting transplanted islets into a major vein in the liver and keeping them alive with a novel combination of immunosuppressive drugs. Often, ITN found, the islets survived for months or even years and either reduced the recipient’s need for injected insulin or eliminated it entirely. NIDDK and NIAID continued and built on ITN’s work through the Clinical Islet Transplantation Consortium (CIT) with support from the Special Statutory Funding Program for Type 1 Diabetes Research.

The CIT has achieved remarkable successes, such as documenting the complete elimination of severe hypoglycemic events in the majority of study participants and demonstrating that islet transplantation enabled them to achieve near-normal average blood glucose levels while improving their quality of life—results that paved the way to the recent FDA approval. Notably, ITN and CIT also identified important limitations to islet transplantation procedures. For example, although the surgery itself is less invasive than the transplant of an intact pancreas, complications from the procedure may still occur. More importantly, the medications needed to suppress immune rejection of the islets must be continued for the life of the transplant, and they come with significant risks. Their use increases susceptibility to bacterial and viral infections; can cause fatigue, decreased kidney function, mouth sores, and gastrointestinal problems; and may increase the long-term risk of developing certain cancers. These immunosuppressants are also thought to affect the long-term viability of the transplanted islets, as studies suggest that they are toxic to the islets over time. Thus, an important future research goal is the achievement of “immunological tolerance” for the transplanted cells, meaning that immunosuppression drugs would only be needed for a short time or even not at all.

Because of its current limitations, and because the needed cadaver-derived islets are in short supply, islet transplantation is only appropriate for a small subset of people with type 1 diabetes. NIDDK is currently supporting research to characterize and generate new sources of insulin-producing cells and to eliminate the need for immunosuppressive medicines. For example, in one strategy, called encapsulation, islets (including those from donors as well as progenitor cell-derived islet-like clusters and organoids grown in the laboratory) are coated with a material that protects them from being attacked by the recipient’s immune system and promotes their healthy functioning. To help overcome the shortage of cadaveric islets, research is building on an NIDDK- supported landmark discovery that progenitor cells could be used to produce large quantities of β-like cells in the laboratory. Further development of this breakthrough is being pursued by industry, including the conduct of human clinical trials testing encapsulated and unencapsulated cells. Both the cell source and biomaterials have been developed from fundamental NIDDK-funded research. These industry trials are utilizing clinical trial approaches and experiences developed by NIDDK-supported research on cadaver-derived islet transplantation that led to the FDA licensure, and are expected to benefit from the now established pathway to product licensure made possible by the CIT and the FDA approval.

Overall, this FDA approval is an important milestone in developing a cell-based therapy as a diabetes treatment, helping people with type 1 diabetes who have recurrent hypoglycemia and cannot manage their disease using other approved therapies. This approval also establishes a regulatory framework that future, more broadly applicable cell therapies could follow once they become available. Continued research to identify and test cells and biomaterials, in parallel with research toward generating and preserving sufficient numbers of islets/cells for implantation, will yield knowledge necessary to achieve further progress.