Islet Cell Transplantation for Type 1 Diabetes

People with type I diabetes may develop complications from long-term use of insulin and develop hypoglycemia, or severe low blood sugar. Now researchers have developed a therapy that may help protect type I diabetics from this life-threatening condition.

As mom to 10-year-old twins Kendall and Garrett, Erika Totten is never off-duty. But just a few years ago, a chronic condition caused her health to go downhill. Insulin no longer controlled her type I diabetes.

Totten told Ivanhoe, "My speech would be really slurred. I'd kind of just be all over the place from one topic to another."

Erika was severely hypoglycemic and would suffer side effects from low blood sugar without warning.

"I actually crashed my car with them in it," she said. "My three-year-old daughter, if she hadn't told the policeman that ‘mommy has bad sugar' he wouldn't have even known. He probably would have thought I was drunk driving because that's apparently what it looks like."

Michael Rickels, MD, MS, Associate Professor of Medicine at the Perelman School of Medicine, University of Pennsylvania, is studying a cutting edge therapy for severe type I diabetics; a transplant of special pancreatic cells.

Dr. Rickels told Ivanhoe, "The benefits of being able to maintain their glucose levels in a near normal and stable range without hypoglycemia would outweigh the downsides of immunosuppression."

Islet cells are removed from a donor pancreas, processed, and infused into a patient's liver. The islets contain cells that produce insulin. Doctors at Penn tested the procedure in a small number of patients.

"Two months from transplant, seven of the 11 patients were able to taper off their insulin therapy," Dr. Rickels explained.

Erika is one patient who is now insulin-free. "It's a miracle. I don't know how else to explain it. It really has changed my life completely," she told Ivanhoe.

Dr. Rickels says four of the patients needed a second infusion of islets before they were able to stop taking insulin. Transplant therapy for type I diabetes is still investigational. Dr. Rickels says long-term studies need to be completed so researchers can understand how long the results may last and what side effects can be anticipated.

Contributors to this news report include: Cyndy McGrath, Supervising Producer/Field Producer; Cortni Spearman, Assistant Producer; Jamison Koczan, Editor and Kirk Manson, Videographer.

BACKGROUND: Type 1 diabetes occurs when the immune system destroys beta cells in your pancreas. Beta cells are responsible for making insulin which is the hormone that helps move sugar, or glucose into your body's tissues. Your body's cells use this as fuel. Type 1 diabetes accounts for about 5-10 percent of diabetes cases and is usually diagnosed in teens and children. It is caused by a lack of insulin as a result of the beta cells of the pancreas being attacked by the immune system. Type 2 diabetes occurs in about 90-95 percent of diabetes cases and is caused by insulin resistance, in which the body has plenty of insulin but is unable to use it properly often as a result of an unhealthy lifestyle. 

COMPLICATIONS FROM INSULIN: Insulin is a hormone that controls blood sugar. Because diabetics need to deliver insulin for the rest of their life, they can develop complications over time due to these treatments. Some side effects include:

·     Low blood sugar (hypoglycemia)- could result in coma or death

·     High blood sugar (hyperglycemia)- could lead to heart diseases, blindness and other long-term complications

·     Weight gain

·     Lumps or scars where you've had too many insulin injections

·     A rash at the site of injection or over the entire body

NEW TECHNOLOGY: In a study at the University of Pennsylvania, researchers have concluded that after receiving pancreatic islet cell transplantation, patients who have developed low blood sugar (hypoglycemia) as a complication of insulin treatments over time are able to regain normal internal recognition of the condition. Hypoglycemia is a life threatening complication of insulin treatment for type 1 diabetes and can occur when the body's defense mechanisms against low blood sugar are broken down over a long period of time. This can cause shakiness, irritability, confusion, lightheadedness, shortness of breath, and even seizures or loss of consciousness. Michael R. Rickels, MD, MS, Associate Professor of Medicine at the University of Pennsylvania Perelman School of Medicine said, "Patients who were suffering from hypoglycemia unawareness, when a patient has low blood sugar but feels no symptoms, were able to internally recognize the condition and automatically increase their own blood sugar to normal levels six months after undergoing islet cell transplantation."

FOR MORE INFORMATION ON THIS REPORT, PLEASE CONTACT:

Anna Duerr

Senior medical communications officer

215-796-4829

Anna.duerr@uphs.upenn.edu

If this story or any other Ivanhoe story has impacted your life or prompted you or someone you know to seek or change treatments, please let us know by contacting Marjorie Bekaert Thomas at mthomas@ivanhoe.com

Michael Rickels, M.D., M.S., Associate Professor of Medicine at the University of Pennsylvania talks about a way to use islet cells to treat diabetes.

Interview conducted by Ivanhoe Broadcast News in April 2015

Can you tell me what the difference is between Type 1 and Type 2 diabetes?

Dr. Rickels: Type 2 diabetes is the more common form of diabetes. It was originally described as adult onset diabetes because it typically presents itself later in life. Important risk factors are aging and being overweight which can contribute to insulin resistance making it difficult for the pancreas to maintain enough insulin production to control glucose levels in the body. This is different from Type 1 diabetes which was traditionally termed juvenile onset diabetes because it most often presents itself in children and is caused by an auto immune disorder.  For reasons that are still unknown, the body's immune system destroys the insulin producing beta cells in the pancreas and patients become deficient of any production of the hormone insulin and must depend on insulin administration for correcting high blood glucose concentrations.

What is the standard treatment for somebody with Type 1?

Dr. Rickels: The standard treatment for Type 1 diabetes is insulin replaced either through multiple daily injections or delivery through a continuous subcutaneous insulin infusion, also called an insulin pump, which delivers short acting insulin that varies in its rate of delivery depending on the daily circumstances of the patient.

What's the downside for patients with Type 1 diabetes with this kind of treatment? Obviously its life saving, they need this, but are there risks? Are there medical downsides to this treatment?

Dr. Rickels: You're absolutely correct. Without insulin, Type 1 diabetes is a fatal diagnosis.  With insulin, patients are able to live full lives but often with complications of high blood sugar.  They can affect the eyes, kidneys and nerves, making diabetes the leading cause of adult onset blindness, kidney failure and amputations. To avoid the high blood sugars that are associated with these complications, patients need to be more and more aggressive with their insulin management. The downside of that is too much insulin causes an acutely life threatening condition of hypoglycemia or low blood sugar where the brain is not receiving a sufficient level of glucose to function.  If insulin is  available at too high of a level for the body's requirements at a given time, the blood sugar level will drop to a dangerous level that can result in loss of consciousness, seizure and even death, so the downside of being aggressive with insulin therapy is increasing the risk of hypoglycemia.

Tell me about the research that you've been involved with.

Dr. Rickels: We've been particularly interested in helping those patients who, over years of having Type 1 diabetes, have lost their own physiological defenses against low glucose. Normally, our liver provides sugar when our blood sugar is low so that we can correct the blood glucose and prevent a life threatening episode. But in Type 1 diabetes, as the insulin producing beta cells are ultimately lost, there is a corresponding defect to the glucagon producing alpha cells in the pancreas which counteract the action of insulin on the liver and would normally help the liver make glucose when the blood sugar is low.  In Type 1 diabetes, while the alpha cells are present, they don't release glucagon in response to hypoglycemia because they need a signal from their neighboring beta cells. The emergency treatment of a severe hypoglycemic reaction can be the injection of glucagon but this is  available only as a single time rescue administration and not something that patients can rely on day to day to prevent such episodes from occurring.

Tell me about the cell transplantation that you're looking at.

Dr. Rickels:  For patients who've lost all insulin secretion from their pancreas due to Type 1 diabetes, transplanting islet cells that are isolated from a deceased donor pancreas is a means of replacing what is absent physiologically in their bodies, allowing us to restore insulin secretion to control high blood glucose, and also glucagon secretion to support their liver's ability to make glucose when their blood sugar is low.

What is an islet cell?

Dr. Rickels: The majority of the pancreas is made up of what's called exocrine tissue which is our glandular tissue that secrets digestive enzymes. Sprinkled throughout the exocrine tissue are these islands of endocrine cells which secrete into the blood stream. Included in those islands, or islets, as they were described by the pathologist Langerhans, are the beta cells that secrete the hormone insulin and the alpha cells which secrete the hormone glucagon.  When we talk about isolating islet cells, we are isolating not only the insulin producing beta cells that are lost in Type 1 diabetes, but also the associated glucagon producing alpha cells that, while present in Type 1 diabetes, remain defective when not part of in intact islet.

Can you explain to me how the transplantation works?

Dr. Rickels: The transplantation is intended for our patients who have had many years of Type 1 diabetes and have reached the point of having defective glucose counter regulation, where they're at increased risk for the development of hypoglycemia or low blood glucose. As a consequence of that, they may be unaware of their glucose being low and have had severe hypoglycemic episodes where they've been unconscious and required emergency treatment. For these individuals, islets are procured from a deceased donor pancreas that is brought to an islet isolation facility where the pancreas itself is digested so that the endocrine producing islet cells can be separated from the exocrine portions of the pancreas organ. Those isolated islet cells are then purified so that what's transplanted is mainly the missing islet tissue and not the bulk of the glandular material of the pancreas. In order to accomplish the transplant, patients are brought to the interventional radiology suite where an interventional radiologist can pass a needle and, via the needle a catheter, which is a small plastic tube, through the skin and across the liver into one of the veins leading into the liver. The catheter is advanced to what's called the portal vein which is the main vein draining the organs in the abdomen. That leads to many branches that distribute throughout the liver. There the purified islet product is dripped from a blood product bag and the islets progress from the portal vein and disperse throughout all its branches in the liver. So while you previously had islets sprinkled throughout the pancreas you now have islets that are sprinkled throughout the organ of the liver.

What happens from there? Does it start to build up within the body?

Dr. Rickels: There's a lot that goes into the care of the islets as well as the recipient around the time of transplantation.  The major limitation of this procedure is that patients require immune suppression medications, like all organ transplant recipients to prevent rejection of the islets as a foreign tissue in their body. The term "alloimmune rejection" refers to a recipient's immune system fighting against someone else's tissue. What's also important in Type 1 diabetes is that because it's an autoimmune disorder, there is also a threat of the autoimmune process recurring in the transplanted islets. The immune suppression is designed to prevent both alloimmune rejection as well as recurrent autoimmunity from taking place in the transplanted cells.

How long does it take before the body gets used to having the cells in there?

Dr. Rickels: We know from the isolation procedure that the islets will not work fully right after they're transplanted. They require a rich source of oxygen which they don't have initially, though there is blood flow from the portal vein that provides the islets with some oxygen immediately after transplantation. They will eventually re-grow an arterial blood supply from the liver's arterial system, and that provides them with the high oxygen levels they need to function completely. Our patients will remain on insulin during the transplantation procedure and for at least two months following the procedure while their islet cells are allowed to rest during this period of engraftment.

Once patients are through these two months what are the results?

Dr. Rickels: In the most recent study that we've participated in and completed we transplanted eleven patients as part of a study involving forty eight total patients receiving transplants across eight institutions in North America.  Two months after the procedures, seven of the eleven patients were able to taper off their insulin therapy after receiving islets from one donor pancreas.  The remaining four were each able to taper off insulin use but not with perfect blood glucose control.  They were eligible to receive a second infusion of islets, after which they were all able to come off insulin therapy.

So you're saying that seven of the eleven are off insulin all together and their bodies are functioning normally as you and I would?

Dr. Rickels: After the second infusion all eleven were able to come off insulin for varying periods of time.

What does that mean to a patient who's been dependent on that for the majority of their life?

Dr. Rickels: Many of our patients will tell us that they're cured and we remind them that they're not, that they are now taking two medicines each day to suppress their immune system and that without those medicines they would lose their islet cells and be dependent on insulin again. It is important that they continue monitoring their glucose and we encourage them to maintain a healthy lifestyle in terms of their diet, activity and body weight because having an islet transplant is not like having a normal pancreas. There are still important factors of diabetes treatment that need to be followed, although it's an incredible change in terms of their quality of life and functioning.

Can you give me an example of how they feel better, in terms of quality of life?

Dr. Rickels: One example would be patients who were never able to exercise intensively because of the extreme swings in their blood sugar levels. They are now able to run a marathon or compete in a triathlon and take on challenges that they never felt safe undertaking before.

What's the next step?

Dr. Rickels: We would like to see patients who receive the islet transplantation experience relief from their problems with hypoglycemia, even if they were to require some insulin to maintain a normal blood sugar level. With further follow up of our patients, we want to ensure long term durability of this procedure to protect them from hypoglycemia. This could be a future cell therapy for our patients with Type 1 diabetes.

What are the implications then for this research?

Dr. Rickels: The implications in the short term would be to have a treatment option for our patients who are most severely affected by Type 1 diabetes, having the most difficulty with swings in blood sugar and experiencing severe episodes of hypoglycemia.  While there are associated risks of immune suppression therapy in those selected individuals, the benefits of being able to maintain their glucose levels in a near normal and stable range without hypoglycemia would outweigh the downsides and would really be the only treatment that could significantly impact the challenges they face with Type 1 diabetes. In the long run there is work across the transplant community to find safer immune suppression medicines and even someday the ability to induce immunologic tolerance where immune suppression might only be required for a short period of time.

Are you able to speak at all to Erica's case?

Dr. Rickels: I've known Erica very well through this trial and for almost the last eight years now. Her transplant occurred over six years ago, but we first met when Erica came in for evaluation for our islet transplantation protocol. At the time Erica used an insulin pump to deliver insulin continuously and monitored her blood glucose up to nine times a day, following all of our recommendations for counting carbohydrates, correcting hyperglycemia and avoiding hypoglycemia. But she had, as we would call it, labile glucoses. Her swings from high to low were so unpredictable that she was having frequent episodes of severe hypoglycemia. Her average glucose was difficult to have close to the recommended range for preventing complications of diabetes and she was experiencing several severe episodes requiring glucagon given either at home by her husband or when out by emergency medical services.  Also, at the time, having two small children and a job as a social worker that required her to be out in the community created concerns and worries.

And now?

Dr. Rickels: And now Erica, the first patient who participated in this protocol, was able to taper off insulin therapy after two months of receiving islets form a single donor pancreas. She has remained off insulin since that time and is keeping her blood glucose in the near normal range that is required to prevent future complications of diabetes.

Is there anything I didn't ask you that you think people need to know?

Dr. Rickels: The hope for the outcome of this research is that for the small percentage of Type 1 diabetics who are really challenged in controlling this disease, this really can be a life changing treatment.  This mechanistically gets at the heart of the problem when insulin therapy cannot be altered in the body yet with providing a cell based treatment where insulin secretion is turned off as it should be and also the glucagon secretion can be activated as it should be. Restoring the ability of the liver to counteract low glucose means that even patients who may require insulin to maintain near normal glucose levels are still protected from hypoglycemia. Those who really benefit from this procedure are those who have that debilitating complication.

Do you have statistics on how many Americans have Type 1?

Dr. Rickels: Presently at least 1.25 million. The numbers are always changing. Traditionally we believe about ten percent of diabetics have Type 1 diabetes, but the incidence of Type 2 diabetes is increasing alarmingly. Interestingly, the incidence of Type 1 diabetes is also increasing and we're still unsure as to why. We're not sure what factors in our environment may be contributing to increased autoimmunity, but that is also true for other immune and allergic related disorders in our society.  By 2050, 5 million people in America are expected to have Type 1 diabetes.

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