Diabetes Mellitus. (Editorial).

The discovery of insulin was the turning point in the management of diabetes mellitus. The first patient to receive the pancreatic extract was a 14-year-old boy, Leonard Thompson, who had been admitted in 1922 at the Toronto General Hospital with a blood glucose level of 500 mg/dL and a daily urine volume of 3 to 5 L. The administration of pancreatic extracts induced an immediate improvement in the boy's condition: he "became brighter, looked better and said he felt stronger." This was associated with a rapid reduction in the blood and urine glucose levels (Banting, 1922). The administration of pancreatic extracts to this young patient ushered in a new era in the management of diabetes and a new chapter in the evolution of medicine.

It was only one year earlier, in 1921, in Toronto that a young Canadian surgeon, Frederick Grant Banting, a fourth-year medical student, Charles Herbert Best, and a professor of physiology, John James Richard Macleod, attempted to isolate from the pancreas the hormone that was deficient in patients with diabetes mellitus. Macleod enlisted the help of a chemist, James Bertram Collip, who had special expertise in the extraction and purification of epinephrine. Their discovery earned Banting and Macleod the Nobel Prize in Medicine only one year later, in 1923. Banting decided to share his prize with Charles H. Best, and Macleod did the same with James B. Collip.

Although diabetes mellitus had been known since antiquity, the road leading to the discovery of insulin started to take shape in 1869 when Paul Langerhans, a German medical student, noted that the pancreas contained two distinct groups of cells: the acinar cells that secrete the digestive enzymes and other cells grouped in clusters, the islets of Langerhans. The function of these cells in glucose metabolism was not defined until about twenty years later in 1889 when Oskar Minkowski and Joseph von Mering demonstrated that pancre-atomized dogs developed features similar to patients with diabetes mellitus. Since that time, several attempts were made to extract the hormone from the pancreas.

The extraction of insulin from the pancreas was marred by the proteolytic enzymes that destroyed it whenever an extraction attempt was made. Banting and Best overcame the problem by tying the pancreatic duct. The pancreatic acinar cells self-destroyed, and the islets of Langerhans remained intact. The extraction of insulin could then proceed.

The amino acid sequence of insulin was established in 1960. The hormone started being synthetized in 1963. In 1977 the gene responsible for the formation of insulin was discovered; and only one year later, in 1978, small amounts of human insulin were obtained from E coli after splicing the insulin gene and introducing it into the bacterium. In that same year, Eli Lilly embarked on the production of genetically engineered human insulin.

The availability of insulin ushered another important change in medical care: the pivotal role the patient has to play if the disease is to be well controlled. The patient could no longer assume a passive role; he had to actively collaborate in the treatment of his condition. The patient had to be educated, had to understand what the disease is all about and how insulin could help. The adverse effects of insulin had to be learned, and the patient (and family) had to recognize the early symptoms and signs of hypoglycemia, hyperglycemia, and acidosis. The successful management of diabetic patients requires the active collaboration of the patient and family. This can only be achieved through education and the active collaboration of a team of health care specialists with various areas of expertise.

The ease of administration of insulin and the ease with which the blood glucose levels can be measured have encouraged physicians to try to control them as tightly as possible. Studies confirmed that the tighter the control of the blood glucose level, the better the prognosis. Unfortunately, the tighter the glucose control, the higher the probability the patient will develop bouts of hypoglycemia, which could be quite serious. It soon became obvious that a very delicate balance is needed: the tighter the control, the better the prognosis; and yet too tight a control might be detrimental and even fatal. The two sayings of Hippocrates, "First do no harm" and "Second do good," are very closely intertwined.

Our understanding of the glucose metabolism should make us marvel at the constitution and efficiency of the human body. Throughout our life span, the blood glucose level is maintained within a certain range regardless of the "supply" or "demand." No matter how much the person eats, all the excess carbohydrates are stored. Similarly, when a person fasts, a ready supply of carbohydrates is available to produce just the necessary amount of glucose to meet that person's requirements to perform the tasks at hand. Whenever the person is under stress and a burst of energy is required, carbohydrates are mobilized almost instantaneously to maintain the blood glucose level in the optimum range. This process goes on 24 hours a day, 7 days a week, 52 weeks a year, year in, year out, without any break, without any time off. What a wonderful, efficient organism we have been endowed with!

It gives me great pleasure to introduce Dr. Alan Peiris as the first guest editor of this month's Special CME Feature on diabetes mellitus.

Alan N. Peiris, MD, PhD, MRCP (UK), is Professor of Medicine, Department of Internal Medicine, East Tennessee State University; Staff Physician, Mountain Home Veterans Administration Medical Center; and Medical Director at the Diabetes Center, Johnson City Medical Center, Johnson City, Tenn.

Suggested Reading

(1.) Banting FG, Best CH, Collip JB, et al: Pancreatic extracts in the treatment of diabetes mellitus. Can Med Assoc J 1922; 12:141-146

(2.) Bliss M: The discovery of insulin. University of Chicago Press. Chicago, 1982

(3.) Kahn CR, Shechter Y: Insulin, oral hypoglycemic agents, and the pharmacology of the endocrine pancreas. Goodman and Gilman's The Pharmacological Basis of Therapeutics. Gilman AG, Rall TW, Nies AS, et al (ed). Eighth Edition, 1990. Pergamon Press, pp 1483-1495

(4.) Minkowski 0: Historical development of the theory of pancreatic diabetes. Diabetes 1989; 38:1-6

(5.) The Diabetes Control and Complications Trial Research Group: The absence of a glycemic threshold for the development of long-term complications: the perspective of the Diabetes Control and Complications Trial. Diabetes 1996; 45:1289-1298

(6.) The Diabetes Control and Complications Trial Research Group: The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993; 329:977-986

(7.) The Diabetes Control and Complications Trial Research Group: Lifetime benefits and costs of intensive therapy as practiced in the Diabetes Control and Complications Trial. JAMA 1996; 276: 1409-1415

(8.) The Diabetes Control and Complications Trial Research Group: The relationship of glycemic exposure (HbAlc) to the risk of development and progression of retinopathy in the Diabetes Control and Complications Trial. Diabetes 1995; 44:968-983