By Vinny Negi
When the body is unable to control blood glucose levels, diabetes develops. The body produces no insulin at all in one type of diabetes. This autoimmune condition, known as type 1 diabetes, or T1D, is brought on by the body’s defense mechanism killing its own insulin-producing cells because it believes they are alien. Patients with type 1 diabetes typically lose 32 years of healthy life.
Insulin shots for life are the current treatment for type 1 diabetes. Despite its effectiveness, low blood glucose levels can induce symptoms like shakiness, irritability, hunger, confusion, and dizziness in patients using insulin. Seizures or unconsciousness may occur in severe situations. By regulating insulin release, real-time blood glucose monitors and injectable devices can help prevent low blood sugar levels, however some patients are not able to use them.
By providing these patients with fresh cells that produce insulin and cells that keep their blood glucose levels from dropping too low, a procedure known as islet transplantation can help them better control their blood sugar. The availability of donors and the requirement for immunosuppressive medications, however, limit it.The percentage of T1D patients who qualify for islet transplants is only around 10%.
Making islets from stem cells has helped my colleagues and I overcome transplantation obstacles in our work as adiabetes researchers.
The background of islet transplantation
After more than a century of research, the FDA approved islet transplantation for Type 1 diabetes in 2023.
Beta cells, another name for insulin-producing cells, are found in areas of the pancreas known as the islets of Langerhans. They are found in cell clusters that generate various hormones related to metabolism, including ghrelin, which signals hunger, somatostatin, which suppresses insulin and glucagon, and glucagon, which raises blood glucose levels. While examining the microscopic structure of the pancreas, anatomist Paul Langerhans made the discovery of islets in 1869 after seeing that these cell clusters dyed differently from other cells.
Since pathologist Gustave-Doyard Laguesse originally hypothesized the function islets play in hormone production in the late 19th century, the path to islet transplantation has been fraught with difficulties. Researchers tried using a sheep pancreas transplant in 1893 to heal a 13-year-old boy who was dying of diabetes. Three days following the treatment, the boy passed away, despite a minor improvement in his blood glucose levels.
Insulin and glucagon are among the hormones secreted by the pancreatic islets of Langerhans, which are yellow in color.Getty Images/Science Photo Library/Steve Gschmeissner
When researcher Paul E. Lacy successfully transplanted islets in a diabetic rat in 1972, interest in islet transplantation was rekindled. Following that, numerous research teams attempted islet transplantation on humans, with little to no success.
Using immunosuppressive medications and a significant number of islets from two to three donors at once, transplant surgeon James Shapiro and his team successfully transplanted islets in seven patients in Edmonton, Canada, in 1999. These patients were able to control their diabetes for a year without the need of insulin thanks to the Edmonton protocol.
By 2012, more than 1,800 patients had received islet transplants using this method, and over 90% of them had survived after seven years of monitoring. The Edmonton protocol serves as the foundation for the first islet transplant therapy to be authorized by the FDA.
Islets derived from stem cells
Nowadays, islet transplantation is seen as a minor procedure in which islets are inserted via catheter into a liver vein. Despite its apparent simplicity, the surgery has several drawbacks, such as a high cost and a shortage of donor islets. Immunosuppressive medications must be used for the rest of one’s life after a transplant in order for the foreign islets to survive and function in the body. However, using immunosuppressants also makes other infections more likely.
Researchers are investigating the use of stem cells to produce an infinite supply of islets in order to get around these obstacles.
Scientists are employing two types of stem cells for islet transplants: induced pluripotent stem cells, or iPSCs, and embryonic stem cells, or ESCs. In the lab, both varieties can develop into islets.
Each has advantages and disadvantages.
Because ESCs are derived from dead human embryos, there are ethical questions surrounding them. Immunosuppressive medications would still be needed for ESC transplantation, which would restrict its application. In order to shield ESC islets from the body’s immune system, scientists are trying to either encapsulate them or cause mutations in them.
On the other hand, the patient’s skin, blood, or fat cells are used to create iPSCs. Immunosuppressive medications are not required because the transplant uses the patient’s own cells. However, a significant obstacle is the expense of producing iPSC islets for every patient.
It is possible to live a long life with Type 1 diabetes.
Challenges of stem cell islets
Theoretically, iPSCs could eliminate the need for immunosuppressive medications, but clinical testing is still required.
Since the cells used to produce stem cells may also have the same disease-causing mutation of their islet cells, T1D patients with genetic mutations that cause the condition are now unable to use iPSC islets. Numerous gene-editing technologies could potentially eliminate the mutations and produce functioning islets of induced pluripotent stem cells.
The cost of islet transplantation is a significant concern, in addition to the difficulty of genetic modification. Due to increased manufacturing costs, stem cell-derived islet transplantation is more costly than insulin therapy.
The establishment of biobanks for iPSC matching is one attempt to increase the process’s scale and reduce its cost. By removing the need to create newly modified islets for every patient, this would enable iPSC islets to be used for several patients, lowering expenses. The same batch of cells may be utilized for all patients, which is another benefit of embryonic stem cell islets.
After transplantation, there is also a chance that these stem cell islets will develop into malignancies. Thus far, there has been very little evidence of cancer in human clinical trials and rodent lab investigations. This implies that there is little probability that these cells will develop into a tumor.
However, before stem cell islets can be employed in clinical settings, more rounds of research and development are needed. I think a few more modifications can help researchers overcome diabetes and save lives, but it’s a long journey.
Vinny Negiis is a University of Pittsburgh Endocrinology and Metabolism Research Scientist.
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