A presentation given by Deborah Butterfield, Founder and Executive Director of the Insulin-Free Foundation and Author of Showdown with Diabetes, at the Japan Society for Pancreas and Islet Transplantation in Tokyo.

I have lived most of my life with diabetes, and now I spend my days working to support science and to advance policy to cure it. Based on these personal and professional experiences, I would like to relate two odysseys, my odyssey with diabetes, which is an all too common story of life with diabetes, and the odyssey of diabetes over the last century and in to this new millennium.

The Century of Insulin

Before insulin was available in the 1920s, the life expectancy of a diabetic person was less than two years. Of course, with the advent of insulin, diabetes became a chronic disease, a disease people could live with indefinitely. Since then, the guiding principle of diabetes management for people with Type 1 diabetes (and some with Type 2) has been to use exogenous insulin to control blood sugar levels. From 1922 to the early 1980's, the standard therapy was two injections daily, testing the urine for sugar, and counting carbohydrates. But, over time the majority of diabetic people progressed to a host of secondary diseases of the eyes, nerves and kidneys.

In the mid-1980s, blood glucose monitors were introduced making it possible for diabetic people to estimate their insulin and dietary requirements more accurately. Increasingly, people used multiple daily injections of insulin to manage their diabetes, with the hope that they could avoid complications. From 1983 to 1993, the landmark Diabetes Control and Complications Trial (DCCT) showed, theoretically, that more normal blood sugar levels achieved with this intensive management could delay the onset and slow the progression of diabetic complications. It also showed that nothing short of consistently normal blood glucose levels could stop or prevent complications. Indeed, in practice, the incidence of long-term diabetic complications has continued to rise (in part due to the increasing incidence of the disease), and deaths and hospitalizations from acute complications associated with hypoglycemia have risen sharply. Clearly, intensive diabetes management and insulin therapy is better than conventional management, but it is not enough to prevent or reverse diabetic complications.

Transplantation: A New Way of Thinking

In the mid-1950s, kidney transplantation was evolving as a therapeutic option for people with end-stage renal disease -- but not for people with diabetes. People with diabetes were excluded from the treatment because the steroid-based immunosuppression protocols required to prevent rejection were believed at that time to complicate diabetes to such a degree that the risks outweighed the benefits. Diabetics became the pariahs of medicine. Diabetologists referred patients to nephrologists, but nephrologists told patients there was nothing they could do to help because of the underlying diabetes.

In 1966 an enterprising group of physicians headed by Drs. Kelly and Lillehei, at the University of Minnesota gave rise to a new way of thinking. In an attempt to help a young diabetic woman who was dying of kidney failure, they transplanted her with a pancreas in addition to a kidney. The hope was that the new pancreas would normalize her blood sugar level so that post-management care of her kidney transplant would be possible. The surgery, in which Dr. Idezuki, Chairman and Professor Emeritus of surgery at Saitama University Hospital participated, was a success. The patient became insulin-free. Although she died three months later of sepsis, her experience opened the door to the era of cures.

During the 1970's, 102 pancreas transplants were performed, but the success rate was only 6.5%. A moratorium was placed on pancreas transplantation while researchers returned to the lab to try to find ways to perfect the technique. The introduction of Cyclosporine A, in combination with improved surgical techniques, elevated pancreas transplantation to become a realistic therapeutic option for diabetic people with kidney disease.

Pancreas Transplants Today

The International Pancreas Transplant Registry (IPTR) located at the University of Minnesota, has received reports on more than 15,000 cases of pancreas transplantation between 1966 and the year 2000. Today there are approximately 200 pancreas transplant centers worldwide. Since 1994, more than 1,000 pancreas transplants per year have been performed in the United States. Between 1987 and the year 2000, success rates improved significantly, once again as the result of advances in new immunosuppression therapies, most notably, Tacrolimus (FK506, Prograf) and Mycophenalate Mofeteil (CellCept, MMF). During this period, the IPTR reports that one-year pancreas graft function rates in the US went from 72% to 85% for simultaneous pancreas-kidney transplants (SPK); from 52% to 76% for pancreas after kidney transplants (PAK); and from 50% to 78% for solitary pancreas transplants (PTA). In April 1993 when I had my first simultaneous pancreas-kidney transplant, fewer than 5,000 pancreas transplants had been recorded.

A Personal Odyssey: From a Condition to a Disability

I was diagnosed with Type 1 diabetes in 1970 at 10 years of age. My doctor taught me that diabetes is manageable, and that if I was diligent about diabetes management, I would live a normal, healthy life. Perhaps he knew that diabetes most often led to complications, often despite good management practices, but how do you explain to a 10-year old child that there is a 40% chance that in 20 years her kidneys would fail, and an 80% chance of retinopathy? How can you tell her that her life expectancy dropped by 30% with her diagnosis?

When I was diagnosed, not much had changed since the discovery of insulin. Although I can't know for certain because we didn't have an accurate method for monitoring, I believe my blood sugar levels were within a reasonable range. Blood glucose monitors were introduced in the mid-1980s. I both loved and hated my blood glucose monitor. I felt more in control knowing precisely what my blood glucose level was at any time. I tested often and managed my diabetes intensively with an average of six injections per day. Yet knowing what dose of insulin to take was not then, and is not now, a precise science. It is not a simple analog of food, exercise, and insulin; rather it is a complex and seemingly random theory of chaos with a few discernable known variables. I was frustrated by my inability to achieve perfect control, and visits to the doctors that gave me no new strategies or tools, but simply repeated the mantra that diabetes could be controlled simply by being "compliant" with a prescribed regimen of insulin, blood sugar tests, and diet.

If you were to plot average blood sugar results on a graph relative to the incidence of complications, the graph would show that long-term diabetic complications decrease, but don't stop, as average blood sugars improve. As average blood sugars approach normal levels where long-term complications could be prevented, the risk of severe hypoglycemia increases significantly. This leaves only a brief window of opportunity where there is neither a risk of severe hypoglycemia or long-term progression to secondary diabetic complications. When I was 23, the first changes in the blood vessels in my eyes were observed, and I became even more compulsive about diabetes management, believing that I could get through that narrow window and avoid both long-term and acute complications with sheer discipline and will. I thought then that the retinopathy was an isolated event, one bout with complications that was corrected with laser surgery.

Four years later I experienced a strange tingling in my legs. At first I thought nothing of it, but the discomfort intensified and became shooting pains that felt as though my nerves had been plugged into an electrical outlet. At night, pain played up and down my legs and no aspirin or creams could stop the agony. Over time the pain went away and was replaced by numbness. Still, I thought of the retinopathy and problems with my nerves as unrelated events; but the next year, when I was 28, the first signs of kidney disease appeared. It was then that I realized the retinopathy and neuropathy had been part of a progressive process and that the symptoms appearing in my eyes, nerves and kidneys were expressions of a deeper, more insidious process taking place at the microvascular level.

Following my first symptoms of retinopathy in 1989, every visit to the doctor had, without exception, left me with more restrictions and less optimism about my future health. Rather than the old banalities that I could live a "normal and healthy life," my doctors said, "Complications after this many years are very common." Their counsel about how to manage my diabetes was always a variation on the theme of intensive use of insulin. I knew then that there was nothing more that they, or insulin, could do to stop the progression. I had been doing the best I could with intensive insulin therapy for 20 years; modifying my regimen yet again may lead to incremental improvements in my blood sugar results for a day, or a week; or, until the next cold, travel, or deadline at work sent me out of control. I needed something more. I needed a fundamental shift in my approach to diabetes. No amount of laser surgery could stop retinopathy; no low protein diets or hypertension medicines could reverse nephropathy; and intensive insulin therapy could not stop the progression either. It was then that I heard about pancreas transplantation, the only treatment that could offer consistently normal non-diabetic blood glucose levels.

The Choice

I was advised against pursuing a pancreas transplant, indeed, I was advised to wait until my kidneys failed, at which time I could go on dialysis and then get a kidney transplant. My doctors believed that immunosuppression was worse than diabetes, so I should delay getting a transplant for as long as possible -- perhaps delaying until islet cells would be available. So I waited and watched for four more years as my kidneys deteriorated, the bleeding in my eyes proliferated, I needed leg braces to walk, I vomited several times per day because my food wouldn't digest, and my blood sugar levels swung from dangerously low to dangerously high; I could no longer sense the lows. Perhaps science would advance, perhaps immunosuppression would be worse than diabetes, but I was in my early thirties and I didn't want the life that lay before me on that path. I chose to go for a pancreas and kidney transplant with the hope that I could stop the underlying disease, correct the kidney failure, and once again look forward to a future where each day could be better than the day before.

On April 6, 1993, I traveled to Wisconsin for my transplant. Twenty-four hours after the surgery I was able to walk down the hallway of the hospital. Although it was still too soon after surgery to eat, I was insulin-free - my blood sugar levels were normal - non-diabetic. For 23 years my life had been sustained with insulin injections, indeed more than 25,000 injections. What I remember most about the few weeks that followed my surgery was the feeling of "future", as if the dark horizon of sickness and disability had been moved years into the future. But two weeks later my dream was shattered by acute rejection, infection, more rejection, and more infection. It was a cycle from which the only escape was to lose my life or lose the transplanted organs. In the middle of June, the transplanted organs were removed. It had been a difficult struggle to stop diabetes from intruding on my life again, but I had lost. The success rates from SPK at the hospital were 85%, but I had ended up in the 15% for whom the transplant would fail. The emotional fall was hard. My horizons imploded and I felt empty and lost. Diabetes management with insulin had not stopped my rapid decline to disability, nor had my kidney-pancreas transplant.

Several weeks later I returned to my home in New York City and went back to work so I could pay my bills. Diabetes and my complications continued to progress just as they had before my transplant, and I knew that to overcome my disabilities and protect my future health, I must attempt the transplant once more. I traveled to the University of Minnesota for a consultation with Professor David Sutherland, and was once again added to the national waiting list for a kidney and pancreas transplant.

During the summer of 1994 while I waited, I had a heart attack and spent two weeks in a cardiac intensive care unit at New York University Hospital. Before my first transplant, my biggest fear had been of the transplant - the surgery, the immunosuppression drugs, and perhaps a fear of the unknown. As I lay in the cardiac intensive care unit, my biggest fear was that I would no longer be eligible for a transplant. My fear of being diabetic had beome greater than my fear of transplantation.

A Personal Odyssey: From Disability to Insulin-Independence

One month after being discharged from New York University Hospital, I received a call that a kidney and pancreas had been donated by the family of a 36-year-old woman who had died in a car accident and been declared brain-dead. As I learned later through correspondence with an intermediary, her family found great honor and some sense of peace from knowing that her organs gave life, health, and hope to five people.

Immediately I flew to Minneapolis and underwent my second transplant. That was almost seven years ago! My life today is one of activity and health. I am married now and my husband and I travel widely for business and pleasure. My autonomic neuropathy reversed completely, my peripheral neuropathy has improved greatly, my eyes have improved, and above all, my spirit is now free from the fears of restrictions of living with a disease that was attacking one vital organ system after another.

The Insulin-Free Foundation

My lack of knowledge when first I expressed the propensity to secondary complications had almost cost my life. Had my family not seen an article in the media about pancreas transplantation, I may not have known of the option. In 1996, my husband and I founded the Insulin-Free Foundation to provide information to help people to understand the potential progressive nature of diabetes, to recognize the warning signs of progressive complications, and to know their options with regard to today's treatment choices, and those in development.

The importance of this message to diabetic people, their families, caretakers, and friends is quantified in the two million hits and 600,000 impressions we receive on our websites every month, and by the hundreds of letters and telephone calls we receive from diabetic people. Pancreas transplantation, and now advances in islet transplantation, not only are important treatment options to people today, they represent tangible advances in science to a population of millions of diabetics worldwide who are united in their yearning for a cure.

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