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It is hoped that this medical procedure will be approved in the US to treat the most needy of patients
Many patients with Type 1 Diabetes experience episodes of severe hypoglycemia despite strict adherence to therapy. This situation of abnormally low blood sugar can lead to loss of consciousness, coma, or even death. New clinical studies show that transplantation of pancreatic islets of Langheran (footnote i), harboring insulin producing β-‐cells, restored normal blood glucose and greatly reduced episodes of dangerous hypoglycemia in the majority of forty-‐eight patients that received the islets. It is hoped that it will be approved in the US for wider application to treat the most needy of patients.
We have already described basic technology regarding islets transplantations and some applications for treatment of T1D patients: Type 1 Diabetes Research Advances To Develop A Cure, See Part 3 for more information.
It is estimated that between 1.5 and 3.0 million people in the Unites States alone have Type 1 Diabetes (T1D), a disease whereby the insulin-‐producing β-‐cells, housed within the islets of Langheran are mistakenly recognized as foreign entities and killed by misguided immune cells infiltrating the islets. Though the majority of patients manage the disease with insulin therapy and a disciplined life-‐ style, thousands of them experience swings of blood glucose levels that can either go dangerously up (hyperglycemia) or down (hypoglycemia), in spite of therapy. Hyperglycemia, if it occurs frequently, speeds up long-‐term complications such as eye disease (Diabetic Retinopathy), nerve damage (Diabetic Neuropathy), kidney damage (Diabetic Nephropathy), and Cardiovascular complications. While hypoglycemia brings about symptoms such as blurry vision, rapid heartbeat, fatigue, shaking, and sweating; in most cases, these complications can be reversed by immediately taking fast acting carbohydrates.
Furthermore, there are many patients that experience impaired awareness of hypoglycemia (IAH) and severe hypoglycemic events (SHEs), which may lead to loss of consciousness, coma, or even death. Even though a strict compliance with the most advanced therapies and a disciplined life-‐style bring benefits to the majority of these individuals, many of them are still at risk of developing complications (footnote ii). These patients become eligible for pancreas or islets transplants; while the pancreas transplant procedure is an invasive and demanding surgery normally performed in patients who also require kidney transplant, the islet transplant procedure is much simpler and less risky. Islets transplant is a technology approved in some foreign countries, but in the US it is only performed as an investigational therapy.
The subject of this narrative is to describe positive results and drawbacks of a phase 3 clinical study (footnote iii) conducted at eight centers in North America (Hering et al., 2016; Reference 1). It involved forty-‐eight adult patients who had T1D for more than 5 years and the absence of stimulated C-‐peptide (no insulin production); moreover, these patients experienced impaired awareness of hypoglycemia (IAH) and severe hypoglycemic events (SHEs), in spite of being treated with state of the art therapy by professionals for a full year prior to the start of the study. They received immunosuppressants to control autoimmunity and alloimmunity (footnote iv) prior to receiving variable amounts of purified human pancreatic islets (PHPI). The total dose of PHPI ranged between 286,565–1,562,425 IEQ/patient (footnote v) given in one infusion (to 22 patients), two infusions (to 25 patients), and three infusions (to 1 patient) into patients’ hepatic portal veins (vi). The multiple infusions were given to patients who did not see improvements 75 days after the first infusion.
The authors reported that 87.5% of the patients in the study reached an HbA1c level of less than 7.0% (53 mmol/mol) at day 365 and did not experience SHEs from day 28 to day 365 after their first islet transplant. This is very important because in the year before treatment none of the patients were able to maintain HbA1c levels less than 7% without experiencing SHEs.Some other benefits that resulted from the PHPI infusions were: A significant restoration of hypoglycemia awareness, an improvement in mean glucose level, an increase in the number of times the patients were within glucose target range of 54–180 mg/dL (3.1–10 mmol/L), and a decrease in the number of times glucose dipped below the very dangerous threshold of 54 mg/dL (3.1 mmol/L). Moreover, 52% of the patients achieved insulin independence, and 80% of those who achieved it were able to keep it at the 2-year mark. Only non-‐life threatening side effects occurred as a consequence of the procedure, although serious procedural bleeding was observed in 5 of the 48 patients.
The authors concluded: “This trial is the first phase 3 trial to show effectiveness of any therapy in restoring both sustained normoglycemia and protection from SHEs in patients with long-‐standing T1D complicated by IAH and recent SHEs” and that, “the clear benefits of islet transplantation must be evaluated in the context of the associated risks”.
Before islet transplantations can be expanded to a significant percentage of T1D patients, the following issues need to be addressed: (1) Not every patient seems to reach insulin independence and adverse conditions may still occur; (2) The lack of pancreas donors; (3) A need for chronic use of toxic immunosuppressive medications to control both autoimmunity and alloimmunity in patients; and (4) A relatively short duration of the transplant.
Nevertheless, it is hoped that this trial, together with similar studies already published or in progress will foster the approval of human islets transplants to more patients who are in most need for this procedure. Moreover, procedures to produce large quantities of β-‐cells from stem cells and from patients’ own cells have been reported by several laboratories. Research to make these procedures safe for transplantations is advancing fast; in addition, studies to re-‐educate the immune system rendered faulty by T1D are aggressively pursued with some positive results. These scientific and technological advances have increased hopes that β-‐cells transplantations will become a safe procedure in the near future.
i-‐ The islets of the Langheran are small (about 0.2 mm diameter) clusters of cells disseminated across the pancreas constituting 1-‐2% of its mass. They contain glycemic regulatory hormones producing cell species such as: (I) β-‐cells that produce insulin and amylin (each islet contains approximately 1,000 β-‐ cells, i.e., they constitute the majority of the cells of the islet); amylin, co-‐secreted with insulin, is involved in preventing spikes in blood glucose after meals by slowing down gastric emptying and fostering satiety; and (II) α-‐cells that produce glucagon that raises the glucose concentration in the blood, thus opposing the insulin glucose-‐lowering activity.
ii-‐it is hoped that the bionic pancreas (under development) will be able to continuously monitor glucose and deliver precise amounts of insulin(to drop glucose) or glucagon (to increase glucose) thereby closely mimicking the natural pancreas and minimize, or avoid all together, glucose ups and lows.
iii-‐ It is a critical study because the data is presented to the Food and Drug Administration for drug’s approval. Usually it involves many diseased people. In these studies the investigators need to gather data that show that the benefits offered by the drug are superior to its side effects, and that the drug performs better than the ongoing standard of cure, if one is already in use.
iv-‐ Autoimmunity is an immune response whereby a person’s immune system attacks the body’s own cells causing their destruction, e.g., in T1D the β-‐cells are destroyed; Alloimmunity is an immune response against a foreign entity (non-‐self), e.g., a transplant from one person to another of an organ like the pancreas, or of pancreas’ islets.
v-‐ Islet equivalents, or IEQ is a way to express the number of islets (one IEQ is equivalent to a pancreatic islet whose diameter is 150 μm).
vi-‐ The portal vein or hepatic portal vein is a blood vessel that conducts blood from the gastrointestinal tract and spleen to the liver
Hering et al. (2016) Phase 3 Trial of Transplantation of Human Islets in Type 1 Diabetes Complicated by Severe Hypoglycemia. Published online before print April 18, 2016, doi: 10.2337/dc15-‐1988.