by David Sutherland, M.D., Ph.D.
Director, Diabetes Institute for Immunology and Transplantation
University of Minnesota, Minneapolis, Minnesota
(Copyright 2002, by INSULIN FREE TIMES magazine
(www.insulinfreetimes.org), reprinted
with permission)
Currently, the only two treatments that sustain life for people with type 1
diabetes are exogenous insulin provided by injections or pumps, and beta-cell
transplantation with ongoing immunosuppression. Beta-cell transplantation may
be achieved by transplanting the complete pancreas organ or by transplanting
the insulin-producing cells alone.
Besides providing the highest daily quality of life possible, a principal objective of today's treatments for insulin-dependent diabetes is to reduce secondary complications, or in the case of a transplant, to reduce the side effects of the immunosuppressive drugs. It is known that the lower the average blood sugar level, the lower the incidence of secondary complications. Unfortunately, other than consistent and sustained perfect blood sugar levels, there is no threshold below which complications do not occur, and attempts to provide such control with current insulin delivery systems give an unacceptable incidence of dangerous hypoglycemic events. Theoretically, a closed loop, insulin-pump system with an insulin secretion rate that is adjusted continuously by an implanted glucose sensor could do so; but a practical device does not yet exist.
Today, only beta-cell transplantation offers the consistent and sustained perfect blood sugar levels that are known to protect against the chronic and acute complications caused by diabetes. To achieve this state, however, a person with diabetes must weigh the risks of surgery and immunosuppression against the risks of insulin treatment, including secondary complications and the relentless burden of modern diabetes management.
For diabetic kidney transplant recipients, the addition of a beta-cell transplant is not debatable: kidney recipients are already obligated to take immunosuppression, so the choice is whether to be a transplant recipient with diabetes, or a transplant recipient without diabetes. Clearly, most people faced with this choice, will choose to be free of diabetes. The long-term success rates for kidney transplants is better if a pancreas is added, whether at the same time as the kidney, or later. The only possible debate for the person with diabetes and kidney failure is whether to choose dialysis to avoid immunosuppression, or immunosuppressive treatment in order to have a successful kidney transplant. Nephrologists routinely advise immunosuppression, and their patients routinely benefit from that advice.
For people with diabetes who do not have kidney disease, the primary benefit of beta-cell transplantation in conjunction with immunosuppression is insulin-independence, just as a dialysis-free state is the principal benefit of immunosuppression for a non-diabetic kidney recipient. Of course, secondary complications of diabetes are also prevented or ameliorated for the beta-cell recipient. In either case, to be dialysis-free or insulin-independent may be worth the price of immunosuppression.
What are the risks of a beta-cell transplant? Even for the surgically invasive
pancreas transplant, the mortality rate is less than 1%, and may be lower than
the mortality rate caused by insulin-induced hypoglycemia over time. The risk
of requiring additional surgery to treat complications following a pancreas
transplant is now approximately 10%. The immunosuppressive risk of lymphoma
is less than 1%, and the risk of kidney disease progressing because of the side
effects of certain anti-rejection drugs is approximately 10%, no higher than
the incidence of progressive secondary complications in the intensive insulin
treatment arm of the Diabetes Control and Complications Trial (DCCT). In some
patients, pre-existing kidney disease may even reverse.
The time has come for diabetologists to view diabetes as nephrologists have viewed kidney disease; internal organ or cellular replacement, even with the need for immunosuppression, can be preferable, for an individual patient, particularly those burdened by an unsatisfactory response to the needle-intensive approach. The rate of insulin-independence for a pancreas transplant alone is nearly 80%; and continued insulin-independence five years post-transplant for transplants done since the introduction of new immunosuppressants in the mid-1990s are greater than 50%. With the immunosuppressants introduced in the mid-1990s, nearly 80% of pancreas-alone recipients have remained insulin-independent at one year, and over 50% are still insulin-independent at 5 years.
When donors and recipients are carefully selected to meet certain criteria, the success rate for islet transplants is approaching that of pancreas transplants. Currently, insulin-producing beta cells are destroyed to such a degree during the islet isolation process that to succeed using islets from a single donor requires using a pancreas from a large donor for recipients with a low body mass index or low insulin requirements.
In order to use the limited number of donors available to achieve insulin-independence in the largest number of recipients, with no more surgery than necessary, a common waiting list and allocation system for beta cell transplants is being implemented; candidates with low body mass index or low insulin requirements will receive islets isolated from the pancreases of donors with high body mass indexes, while those with high insulin requirements will receive a vascularized, whole pancreas organ from pancreas donors with low body mass indexes.
With either technique (whole organ or cellular), if the transplant fails, immunosuppression is stopped. If it continues to function, the side effects of immunosuppression over time have not been shown to occur in greater incidence or severity than the side effects of diabetes. Quality-of-life studies in beta-cell transplant recipients have uniformly shown a preference for immunosuppression over diabetic treatment, and nearly all who lose graft function opt for a retransplant.
Beta-cell transplantation, even with immunosuppression, should be applied to
the extent organs are available for the treatment of diabetes. Indeed, the use
of immunosuppression to prevent the loss of native insulin-producing beta cells
in the pancreas of people with type 1 diabetes with a sufficient mass of cells
to still be insulin-independent at the time of diagnosis should be revisited
with the modern immunosuppressive agents now available.