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© American Diabetes Association ®, Inc., 2006
Editorial |
The Color Blue: Musings After 68 Years in the Diabetes Wars
Driving from California through Arizona on the way home to Texas in August 1938, we made frequent stops because my 8-year-old brother said he had to go to the toilet. "Go see what is going on," my mother directed me, then age 12. "We are stopping too often."
I reported back that Johnny was peeing a lot, and it was like water. "Oh! I hope it's not diabetes like my cousin Norman," my Mom replied. This was the first time I had heard the word diabetes. Later, she told us a brief story of 16-year-old cousin Norman, who had diabetes and had died in a coma in Connecticut while on the way to see a famous doctor in Boston, Mass., in 1919.
The day after we arrived home, my mother and brother visited our family doctor.
After Johnny came home from the hospital in Dallas, I learned to test his urine for sugar.
I was the resident chemist at our house because I had an amateur chemistry set from which I had made invisible ink, a chemical that smelled like rotten eggs, and some handsome dyes for cloth. I would put a teaspoon of a blue liquid called Benedict's solution into a test tube and add 10 drops of urine. Then, I'd place it in boiling water for 5 minutes. The solution might stay blue or it might turn green, yellow, orange, or brick red. Rarely, the solution stayed blue but had a red sediment at the bottom of the tube. Later, I became skilled enough to skip the boiling water and just hold the tube over a gas flame until a color developed. Rarely did it boil over; after all, I was a chemist. I learned that our favorite color was blue, for that meant no sugar in the urine.
Thus, my initiation into diabetes.
In time, I learned how to boil syringes, sharpen needles, draw and give insulin, and give my brother sugar or something sweet if he felt funny or was sweating and shaking. This was Diabetes 101. Testing the urine, giving the insulin, and struggling at the dinner table to be sure the right kind and amount of food was eaten became a daily routine. No more cakes or Nehi pop; we made our own sugar-free root beer, and a gram scale found a place at our table. Favorite foods always seemed to weigh heavy. No more sweets at dessert; the family ate as Johnny ate.
Years passed, World War II ended, and I started medical school. Diabetes lay dormant in my mind as many other facts forced their way forward. On a surgical rotation at Michael Reese Hospital in Chicago, I learned from a mentor that a researcher named Rachmiel Levine was studying how insulin worked. Later, at Presbyterian Hospital in Chicago, I learned that most physicians did not feel comfortable caring for diabetic patients. The attending physician often said, "Call in Rollin Woodyatt. He'll help us with this patient."
After ruling out a career in obstetrics and gynecology, I spent time with Dr. Woodyatt and saw how important patient teaching was to good diabetes care. I also learned that it was labor-intensive and could not be left to written handouts, but must be applied personally by the physician and the nurse/dietitian. I also saw regular insulin used at mealtime along with morning protamine zinc insulin (as Dr. Woodyatt said, "to keep the blood sugar from being too high after a meal"). Here I learned of the debate among physicians on the degree to which the blood glucose should be made normal. Dr. Woodyatt wanted the blood glucose levels as close to normal as feasible in order to ward off aggressive infections and lessen the risk of eye and kidney complications. I recall him commenting once, "Those who leave the blood sugar high are in error. We don't see these problems in people whose blood sugars are normal." The goal was the color blue, which suggested normal blood sugar because the urine was free of glucose.
Additionally, there were white points counted for carbohydrate consumed (along with blue points for protein and red points for fat). A gram scale was present at every bedside. The more white points eaten, the more regular insulin needed. Urine was tested before meals; the color blue was still the goal. When yellow, orange, or red occurred, more regular insulin was given. A fasting blood glucose was usually taken each morning. Most patients spent 2 weeks in the hospital; there was much to learn.
Time flew after graduation: internship, a spell in the U.S. Navy, residency, then a career decision. I wanted to learn more about the care of diabetic people. I chose a fellowship at the New England Deaconess Hospital/Joslin Clinic in Boston, Mass., where I worked with great mentors and saw many, many patients, young and old, those new to diabetes and those who were veterans of the diabetes wars. I was immersed in diabetes care. The way to learn quality care of diabetes is to see many patients with a variety of problems and to have experienced mentors readily at hand. Every diabetic person is a unique human being with unique problems to be solved.
Were there newer therapies? Not really. By then, it was NPH insulin rather than PZI plus regular insulin before meals, and the color blue—though still a hotly debated stance—was the goal.
There was a pregnancy clinic every Tuesday morning, where 20 patients visited with the incomparable Priscilla White, doyenne of clinical diabetologists, leading figure in the care of diabetic children and pregnant women with diabetes, a beloved physician. Monday mornings were foot rounds on Deaconess 2 with surgeons and podiatrists. Newly admitted patients were reviewed every 8:00 A.M., and staff rounds were every evening. We learned on the hospital wards and also at the office. At the end of my fellowship, a rumor came from Germany that pills for diabetic patients might be available soon.
Then it was October 1, 1955. Good-bye, Boston; Hello, Henry Ford Hospital in Detroit, Mich. Was there anything new or different in the Midwest? There were PZI/regular insulin mixes. How much regular insulin do you add to PZI to have some quick-acting effect? The naive attempt to control diabetes with one injection of insulin daily with the new lente triad was short lived. The color blue was still the goal and still debated, especially with the pediatricians, whose nightmare was hypoglycemia. By 1957, we had sulfonylureas available: no BZ55, but tolbutamide and later chlorpropamide. A little later came phenformin, a biguanide.
During this period, Dr. Levine, the researcher at Michael Reese, brilliantly showed how insulin worked by permitting glucose entry into the insulin-sensitive cells. We learned of insulin receptors. Thrilling reports from Solomon Berson and Rosalyn Yalow changed our thinking about diabetes as we realized that not all diabetic people were totally deficient of insulin. The classification of insulin-deficient and lipoplethoric diabetes, then popular, made biochemical sense.
For patients with diabetes, however, the message was unchanged. Maybe some could take pills, but all of the young, skinny people whom you would have liked to spare injections still needed them daily. The color blue remained the goal. Blood glucose levels were measured once at the quarterly visit. A 24-hour collection of urine was measured for glucose. These were our guideposts for glycemic control. However, our concerns grew about eyes and kidneys, less so about heart disease and cholesterol and blood pressure. How much did we really learn from these patients at their visits, and how much did we help them?
By my 20th anniversary in practice, advances in diabetes care were evident: the era of hypophysectomy for vasoproliferative retinopathy had ended with the successful application of retinal photocoagulation. There was nothing new on the oral agent front, although phenformin was gone because of the risk of lactic acidosis. We learned more about unsaturated fats and the virtues of lower cholesterol and used many antihypertensive drugs that helped keep patients' blood pressure nearer to normal.
For diabetic patients, three important technological advances emerged in the 1970s: the development of computerized pumps to deliver insulin beneath the skin, the finding by an Iranian hematologist of a novel hemoglobin moiety called glycated hemoglobin, and the availability of small capillary blood glucose monitors that diabetic people could use to measure their blood glucose at home. Goodbye to the color blue. Now, rather than testing the urine for glucose as an indirect means of assessing blood glucose, our patients could measure their blood glucose directly. No need to look for the color blue.
During this period, Paul Lacy and others were steadily gaining experience with whole pancreas and islet cell transplantation—the rainbow in the sky for insulin-dependent diabetic patients. Ultimately, the former operation would follow the more frequently required renal transplant for diabetic patients, who too often were developing renal failure from diabetic nephropathy.
The first patient with diabetes to receive a transplanted kidney at Henry Ford Hospital did so on 31 October 1974. It was a great success. She lived a full life for 14 years before succumbing to a massive heart attack.
At the same time came the wonders from the science of recombinant DNA. We had human insulin in plentiful amounts; no longer was there a fear of an insulin shortage. Later, there were insulin analogs, swifter, fast-acting insulins that could control blood glucose rises after meals better than Woodyatt or Joslin could have achieved with regular insulin. Industry made smaller and more accurate insulin pumps for those who would use them. The Iranian finding of glycated hemoglobin made it possible to monitor the quality of glycemic control over time.
These advances permitted the initiation in 1982 of the Diabetes Control and Complications Trial, which proved a decade later the importance of quality glycemic control and its need to be applied whenever feasible. The implications of the color blue had been confirmed. One could, with confidence, test blood glucose directly and adjust diet, insulin, and exercise to try to keep the levels of blood glucose close to normal.
Have there been changes in the care of people with diabetes? Of course. Have the changes been for the better? Of course. Are more advances expected? Of course. Will more changes occur, and will the lives of diabetic people be made easier? Of course. Do all diabetic people benefit from these advances? No.
When I had a ruptured cervical disc removed in 1981, my good friend Roger Smith, the Chairman of Surgery at the Henry Ford Hospital, stopped by my room, gave me a mystery to read, and said, "Fred, I'm glad you had a surgical disease." It has been my hope that, in my lifetime, I would see diabetes become a surgical disease, a disease that can be corrected safely and permanently by a skillful surgeon. Then, I could advise patients to visit a surgical colleague and seek surcease from the daily toil of diabetes care.
In my view, this will occur, but not at once or in the near future. There are immunological problems that require resolution. We need to find a way to obtain more islet cells than are now available. And what of those people with insulin resistance and diabetes? What is for them? They represent the majority (and a growing number) of diabetic people everywhere who need help that a transplant will not immediately provide.
Knowledge about diabetes jumped ahead in only one generation from Oscar Minkowski in 1889 and Eugene Opie in 1901, who pointed to the islets in the pancreas described in 1869 by Paul Langerhans as the site of the deficient state causing diabetes, to the Canadians' miraculous isolation of insulin during 1921-1922. Joslin, paraphrasing Ezekiel, reported that the dry bones of the insulin-lacking, dying diabetic person sprung to life and fleshed out when given the newly discovered insulin. Much has happened since 1922, yet our course remains incomplete. Our innate impatience pains us and at times clouds our hope.
So what is today's agenda? We will have inhaled insulin, new means of lowering the blood glucose, and the potential for continuous subcutaneous glucose monitoring with real-time data to lessen the specter of hypoglycemia unawareness. No bolts of lightning, but steady progress. More research, both clinical and basic, will be supported. As Nobel laureate Rosalyn Yalow remarked, research may not supply the answers you seek, but no research will surely yield no advances. Sixty-eight years ago, the color blue meant a normal or near-normal blood sugar level. We now know that what the color blue promised is what we seek.
Although it may take several generations, we know the goal. We run a relay race; we pass the torch from generation to generation. We do our best when we carry the torch, but we are not disappointed that the goal is not reached during our turn. It would be arrogant to think that the end of the race might happen on our watch. The joy is in the run and the help we can offer to our diabetic friends. Through it all, we seek what the color blue had implied.
Footnotes
Fred W. Whitehouse, MD, is Division Head, Emeritus of the Division of Endocrinology and Metabolism at Henry Ford Medical Group and Hospital in Detroit, Mich. He is an associate editor of Diabetes Spectrum.
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