Beta-Cell Therapies for Type 1 Diabetes: Transplanting Islet Cells and Bionics
In search for alternatives to insulin replacement, technological solutions, such as the bionic pancreas, may provide safer and more successful treatments.
By Kathryn Bux Rodeman and Betul Hatipoglu, MD
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Despite its successes, pancreas transplant is major surgery and requires lifetime immunosuppression. Research is ongoing into a less invasive procedure that, it is hoped, would require less immunosuppression: transplanting islets by themselves.
For some patients with chronic pancreatitis, the only option to relieve chronic pain, narcotic dependence, and poor quality of life is to remove the pancreas. In the past, this desperate measure would instantly and inevitably cause diabetes, but not anymore. In the 1980s, about 13 years after islets were first isolated, researchers learned how to remove them from the discarded pancreas and give them back to the patient.
Alpha cells and glucagon are a different story; a complication of islet transplant is hypoglycemia. In 2016, Lin et al12 reported spontaneous hypoglycemia in six of 12 patients who maintained insulin independence after autotransplant of islets. Although the transplanted islets had functional alpha cells that could in theory produce glucagon, as well as beta cells that produce insulin and C-peptide, apparently the alpha cells were not secreting glucagon in response to the hypoglycemia. Location may matter. Gupta et al,13 in a 1997 study in dogs, found that more hypoglycemia occurs if islets are autotransplanted into the liver than if they are transplanted into the peritoneal cavity. A possible explanation may have to do with the glycemic environment of the liver.
Islets can also be taken from cadaver donors and transplanted into patients with type 1 diabetes, who do not have enough working beta cells.
Success of allotransplant increased after the publication of observational data from the program in Edmonton in Canada, in which seven consecutive patients with type 1 diabetes (T1D) achieved initial insulin independence after islet allotransplant using steroid-free immunosuppression.14 Six recipients required islets from two donors, and one required islets from four donors, so they all received large volumes of at least 11,000 islet equivalents (IEQ) per kilogram of body weight.
In a subsequent report from the same team,15, 16 (44%) of 36 patients remained insulin-free at one year, and C-peptide secretion was detectable in 70% at two years. But despite the elevated C-peptide levels, only five patients remained insulin-independent by two years. Lower hemoglobin A1c levels and decreases in hypoglycemic events from baseline also were noted.
The Clinical Islet Transplantation Consortium (CITC)16 and Collaborative Islet Transplant Registry (CITR)17 were established in 2004 to combine data and resources from centers around the world, including several that specialize in islet isolation and purification. Currently, more than 80 studies are being conducted.
The CITC and CITR now have data on more than 1,000 allogeneic islet transplant recipients (islet transplant alone, after kidney transplant, or simultaneous with it). The primary outcomes are hemoglobin A1c levels below 7%, fasting C-peptide levels 0.3 ng/mL or higher, and fasting blood glucose of 60 to 140 mg/dL with no severe hypoglycemic events. The best results for islet-alone transplant have been in recipients over age 35 who received at least 325,000 IEQs with use of tumor necrosis factor antagonists for induction and calcineurin inhibitors or mammalian target of rapamycin (mTOR) inhibitors for maintenance.17
The best success for islet-after-kidney transplant was achieved with the same protocol but with insulin given to the donor during hospitalization before pancreas procurement. For participants with favorable factors, a hemoglobin A1c at or below 6.5% was achieved in about 80% at one year after last infusion, with more than 80% maintaining their fasting blood glucose level goals. About 70% of these patients were insulin-independent at one year. Hypoglycemia unawareness resolved in these patients even five years after infusion. Although there were no deaths or disabilities related to these transplants, bleeding occurred in one of 15 procedures. There was also a notable decline in estimated glomerular filtration rates with calcineurin inhibitor-based immunosuppression.17
One of the greatest challenges to islet transplant is the need for multiple donors to provide enough islet cells to overcome the loss of cells during transplant. Pancreases are already in short supply, and if each recipient needs more than one, this makes the shortage worse. Some centers have achieved transplant with fewer donors,18, 19 possibly by selecting pancreases from young donors who had a high body mass index and more islet cells, and harvesting and using them with a shorter cold ischemic time.
The number of viable, functioning islet cells drastically decreases after transplant, especially when transplanted into the portal system. This phenomenon is linked to an instant, blood-mediated inflammatory reaction involving antibody binding, complement and coagulation cascade activation, and platelet aggregation. The reaction, part of the innate immune system, damages the islet cells and leads to insulin dumping and early graft loss in studies in vitro and in vivo. Another factor affecting the survival of the graft cells is the low oxygen tension in the portal system.
For this reason, sites such as the pancreas, gastric submucosa, genitourinary tract, muscle, omentum, bone marrow, kidney capsule, peritoneum, anterior eye chamber, testis and thymus are being explored.20
To create a more supportive environment for the transplanted cells, biotechnicians are trying to encapsulate islets in a semipermeable membrane that would protect them from the immune system while still allowing oxygen, nutrients, waste products, and, critically, insulin to diffuse in and out. Currently, no site or encapsulated product has been more successful than the current practice of implanting naked islets in the portal system.20
Without advances in transplant sites or increasing the yield of islet cells to allow single-donor transplants, islet cell allotransplant will not be feasible for most patients with T1D.
Use of animal kidneys (xenotransplant) is a potential solution to the shortage of human organs for transplant.
In theory, pigs could be a source. Porcine insulin is similar to human insulin (differing by only one amino acid), and it should be possible to breed “knockout” pigs that lack the antigens responsible for acute humoral rejection.21
On the other hand, transplant of porcine islets poses several immunologic, physiologic, ethical, legal and infectious concerns. For example, porcine tissue could carry pig viruses, such as porcine endogenous retroviruses.21 Additionally, even if the pigs are genetically modified, patients will still require immunosuppressive therapy.
A review of 17 studies of pig islet xenotransplant into nonhuman primates found that in five of the studies (four using diabetic primates) the grafts survived at least three months.22 Of these, one study used encapsulation, and the rest used intensive and toxic immunosuppression.
More research is needed to make xenotransplant a clinical option.
Stem cells provide an exciting potential alternative to the limited donor pool. During the past decade, several studies have shown success using human pluripotent stem cells (embryonic stem cells and human-induced pluripotent stem cells), mesenchymal stem cells isolated from adult tissues and directly programmed somatic cells. Researchers have created stable cultures of pluripotent stem cells from embryonic stem cells, which could possibly be produced on a large scale and banked.23
Human pluripotent stem cells derived from pancreatic progenitors have been shown to mature into more functional, islet-like structures in vivo. They transform into subtypes of islet cells including alpha, beta and delta cells, ghrelin-producing cells, and pancreatic polypeptide hormone-producing cells. This process takes two to six weeks. In mice, these cells have been shown to maintain glucose homeostasis.24 Phase 1 and 2 trials in humans are now being conducted.
Pagliuca et al25 generated functional human pancreatic beta cells in vitro from embryonic stem cells. Rezania et al24 reversed diabetes with insulin-producing cells derived in vitro from human pluripotent stem cells. The techniques used in these studies contributed to the success of a study by Vegas et al,26who achieved successful long-term glycemic control in mice using polymer-encapsulated human stem cell-derived beta cells.
Reversal of autoimmunity is an important step that needs to be overcome in stem cell transplant for T1D. Nikolic et al27 have achieved mixed allogeneic chimerism across major histocompatibility complex barriers with nonmyeloablative conditioning in advanced-diabetic nonobese diabetic mice.
However, conditioning alone (i.e., without bone marrow transplant) does not permit acceptance of allogeneic islets and does not reverse autoimmunity or allow islet regeneration.28 Adding allogeneic bone marrow transplant to conditioned nonobese diabetic mice leads to tolerance to the donor and reverses autoimmunity.
While we wait for advances in islet cell transplant, improved insulin pumps hold promise. One such experimental device, the iLet (Beta Bionics, Boston, MA), designed by Damiano et al, consists of two infusion pumps (one for insulin, one for glucagon) linked to a continuous glucose monitor via a smartphone app.
The monitor measures the glucose level every five minutes and transmits the information wirelessly to the phone app, which calculates the amount of insulin and glucagon required to stabilize the blood glucose: more insulin if too high, more glucagon if too low. The phone transmits this information to the pumps.
Dubbed the “bionic” pancreas, this closed-loop system frees patients from the tasks of measuring their glucose multiple times a day, calculating the appropriate dose, and giving multiple insulin injections.
The 2016 summer camp study29 followed 19 preteens wearing the bionic pancreas for five days. During this time, the patients had lower mean glucose levels and less hypoglycemia than during control periods. No episodes of severe hypoglycemia were recorded.
El-Khatib et al30 randomly assigned 43 patients to treatment with either the bihormonal bionic pancreas or usual care (a conventional insulin pump or a sensor-augmented insulin pump) for 11 days, followed by 11 days of the opposite treatment. All participants continued their normal activities. The bionic pancreas system was superior to the insulin pump in terms of the mean glucose concentration and mean time in the hypoglycemic range (P < .0001 for both results).
As the search continues for better solutions, advances in technology such as the bionic pancreas could provide a safer (i.e., less hypoglycemic) and more successful alternative for insulin replacement in the near future.
This abridged article was originally published in the Cleveland Clinic Journal of Medicine.