How does our body normally maintain proper glucose homeostasis? The body maintains proper glucose homeostasis by using insulin to keep the blood sugar at a constant level. Insulin works by signaling the uptake of glucose into the cells of the body. Without insulin, proper glucose control cannot be achieved. Insulin is manufactured in the islet cells of the pancreas, and is necessary every minute of our lives.
Type 1 Diabetes Definition. The definition of type 1 diabetes is a state of absolute deficiency of insulin. In this scenario, the pancreas is unable to produce sufficient insulin to maintain proper glucose homeostasis in the body. As a result, individuals with type 1 diabetes must rely on insulin taken by injection to stay alive.
Why Does the Pancreas Fail? The exact cause of type 1 diabetes is not known for certain but the available evidence suggests that some type of autoimmune reaction is generally involved. This results in damage to the islet cells that produce insulin, and eventually cause failure of insulin production.
Is there a cure? One way to treat the disease is to have a pancreas transplant. This is a procedure where a whole pancreas is donated from a brain-dead organ donor and transplanted into a person requiring the pancreas. Someone who is living is not able to donate a whole or part of a pancreas as we each have a single pancreas that is required for our survival. A pancreas transplant is a major operation and requires that the individual stay in the hospital for a week or more and be on anti-rejection drug therapy for the rest of their life. Once a person receives a new pancreas that is functioning normally, they are no longer considered diabetic and no longer need to take insulin. Their blood glucose levels are regulated by the islet cells in their new transplanted pancreas.
More Recently. A new procedure has evolved that shows some promise as an alternative to a whole pancreas transplant. This procedure involves the isolation of islet cells from a donated pancreas and the transfer of those cells through a blood vessel to the liver where the cells will live and produce insulin in the recipient’s body. Although these individuals must also be on anti-rejection therapy there are several advantages to this procedure. These advantages include a less invasive procedure, a lower cost, and a much shorter hospital stay.
The Islet Cell Transplant Procedure. There are several steps in the islet transplant procedure that will be outlined as follows:
- The Donor. The islet cells used for the procedure are obtained from a brain-dead donor.
- Before the Transplant. The process prior to transplantation includes an assessment by the transplant physicians with a physical examination, eye examination, and blood work.
- The Transplant. The Transplant. The transplant is performed by a radiologist in the hospital. A catheter is placed in a vein in the abdomen. Islet cells are injected into the vein and end up in the liver where they will live. This procedure is performed using a local anesthetic in the skin of the abdomen, similar to the anesthetic in a dentist’s office. It is otherwise painless.
- After the Transplant. Recipients of a transplant will be seeing the transplant physicians and team on a regular basis after the transplant. They will be taking medications to keep the islet cells functioning and free of rejection. The exact medications used are currently being studied and are changing and improving with time and research.
How many transplants are required? From previous research, it appears that most people will require more than one islet transplant for successful treatment. Some people have required up to three transplants.
Risks of Transplantation. The risks associated with any transplant are infections and increased risk of developing cancers. These risks are side effects of the medications used to prevent transplant rejection. It is not clear at this point how common these risks will be in people receiving islet transplants. So far, there have been no reports of any such complications. However, this is a risk that all people who receive a transplant will be made aware of and will need to accept.
The Hypothesis for the Islet Cell Transplant Study Program. Intuitively we may assume that the islet cell transplant will definitely make a huge improvement in health and quality of life. That may not be true! Will it delay complications? What about the anti-rejection drugs? In terms of costs are the benefits to the patient really there? It may be found to be a great improvement in diabetes care, but we will not know if this in fact is true until studies are performed to look at this question.
Who is eligible for the research study? The trial population to be enrolled will include approximately 50 subjects, male and female, between 20 and 80 years of age who have Type 1 diabetes. Patients must also have some problems with their eyes and kidneys, related to diabetes, but those patients who have heart trouble or are considering pregnancy will be excluded. Patients must also reside in the greater Vancouver area.
How are patients evaluated for eligibility? Patients are evaluated by the islet transplantation physicians. Eye examination, urine tests, and blood work, will be monitored on a regular basis. Before transplantation, all patients will be treated with the best medical treatments for diabetes that we currently have which includes controlling blood sugars well with insulin injections, and treating any other medical problems such as high blood pressure or high cholesterol.
What is optimal medical therapy? Glycemic Control (blood sugars)
- Target fasting or pre-meal blood sugars by glucometer 4-7 mmol/L
- Target HbA1c <0.70 to be followed every 3 months.
These targets are based on the Diabetes Control and Complication Trial (DCCT), which demonstrated an approximately 50 percent reduction in eye, nerve, and kidney complications with intensive treatment for hyperglycemia.
Blood Pressure Control. Hypertension (blood pressure >140/90 mmHg) should be treated to attain target blood pressure <125/70 mmHg to prevent progression of renal disease.Treatment for high blood pressure is important because elevated diastolic blood pressure is a risk factor for the development of macular edema, and elevated systolic blood pressure is a risk factor for loss of vision.
Lipid Control (Blood fats). All patients will be treated to target values for the following fasting lipid profile:
- LDL-C level <2.5 mmol/L
- Total Cholesterol:HDL-C ratio <4
- Triglyceride level <2.0 mmol/L
Based on 10 year risk of coronary artery disease >30%, or a history of cardiovascular disease, or diabetes from the Recommendations for the Management and Treatment of Dyslipidemia , CMAJ, May 16, 2000; 162(10) 1441-1447.
Renal Protection (Kidneys). All patients with >300 mg/day of albumin in their urine and microalbuminuria (30-299 mg/day albumin in their urine) will receive ACE inhibitor treatment even in the absence of hypertension. Based on Should All Patients with Type 1 Diabetes Mellitus and Microalbuminuria Receive Angiotensin-Converting Enzyme Inhibitors? A Meta-Analysis of Individual Patient Data. Annals of Internal Medicine. March 2001, volume 134, pages 370-379.
Patients will be randomly selected from the group to receive an islet transplant.Of the group of 50, there will be 10 people at a time who will carry pagers so that they can be contacted in the case a transplant becomes immediately available.
Study Flow Chart
- Meet Inclusion Criteria
- Retinopathy Assessment
- Cardiovascular Assessment
- Transplantation Team Assessment
- Exclusion Criteria and Assessment
- Trial of Optimal Medical Therapy (3 months)
- Collect Data on End Points on Optimal Medical Therapy
- Await random selection for islet cell transplantation.
The Islet Cell Transplant Study (Blood fats). Despite medical treatment, complications related to diabetes still occur. This study will determine the rate of progression of complications related to type 1 diabetes in subjects with microalbuminuria and retinopathy on optimal medical therapy. The subjects will receive optimal medical treatment which includes: glycemic control, blood pressure control, lipid profile control, and all patients will be treated with an ACE inhibitor.
Trial Schedule
- Planned inclusion of first subject: started March 11, 2002
- Planned inclusion of last subject: When 50 patients have been recruited.
The study has started enrolling patients at this time. We anticipate that the first transplant will take place near the end of 2002 or early 2003.
Rationale for the Trial. These subjects will ultimately await random selection for pancreatic islet cell transplantion. The data collected in the first part of the study will ultimately be used to compare against data after islet cell transplantation.
The primary endpoints (key data measurements collected) are glycemic control, glycemia frequency, and progression of complications:
- rate of progression from microalbuminuria to proteinuria (kidney damage)
- rate of progression of diabetic non-proliferative retinopathy to proliferative retinopathy (eye damage).
The secondary endpoints of the study are:
- renal failure (elevated creatinine)
- end stage renal disease
- myocardial infarction (heart attacks).
Subjects will be randomly selected into the treatment arm or control arm. All subjects will be treated to the targets for optimal medical therapy (see previous page). Subjects in the treatment arm will randomly receive a transplant when there is a pancreas available. Randomization is similar to flipping a coin, and not controlled by the investigators. Both cohorts will be followed for primary and secondary endpoints (described earlier).
All study participants will be closely followed before the transplant as well as afterwards to determine whether the transplant has improved their quality of life as well as prevented progression of diabetes related problems.
Summary
Pancreatic islet cell transplantation is a potential new promising treatment for patients with type 1 diabetes. Currently, there are no clinical studies to show that pancreatic islet transplantation is better than the current optimal medical treatment for type 1 diabetes. There is also no long-term data on the effects of islet transplantation in the progression of complications related to diabetes. These complications include decrease in kidney function, diabetes-related eye disease, cardiovascular disease, and death. Currently, there is also no data on long-term safety of pancreatic islet transplantation. Studies to answer these questions have not yet been performed.
The study we are now starting will try to answer these questions. We will be comparing patients who receive optimal medical treatment for type 1 diabetes to patients who receive pancreatic islet cell transplantation. We hope to determine what differences in outcome and complications are seen between these two treatments. Should pancreatic islet transplantation be shown to be a superior treatment for type 1 diabetes than our current optimal medical therapy, we hope to be able to provide this treatment in improving the health of patients with type 1 diabetes.
Michelle Fung is a clinical fellow specializing in endocrinology and metabollism.