Revolutions in the care of diabetes with the help of dogs and lizards.

During the last century, diabetes has changed in character from a relatively rare disease which was uniformly fatal, characterized by weight loss and best treated with a low-calorie, high-protein diet (type 1), to a common disease characterized by obesity and treated with agents that promote weight loss and a low-calorie diet (type 2). Type 1 diabetes is characterized by an absolute insulin deficiency. Dr. Banting discovered the therapeutic use of insulin to treat type 1 diabetes in depancreatectomized dogs. (1) The first therapeutic insulin preparations were impure and produced many reactions, but for the early patients, they were life saving. Purification resulted in usable Regular insulin, and patients had to take multiple injections each day. In 1938, the development of NPH insulin allowed patients to take fewer injections a day. (2) This longer-acting insulin stayed at the injection site because of the combination with protamine (NPH). Other longer acting insulins were developed. The absorption in these insulins was variable, and they did not cover glucose changes with meals adequately. They were combined with Regular insulin for improved control. Insulin was obtained from animal sources until 1978, when the first recombinant DNA human insulin was announced. (2) Human insulin was synthesized by bacteria in an extremely pure form and became the major source of insulin for human therapy. The last great advance in insulin therapy was the development of insulin analogues designed to have specific properties. The first of these was Lispro, approved by the FDA in 1996, (2) which allowed more physiologic coverage of consumed carbohydrates. More analogues followed with glargine peakless insulin being approved in 2000 (2) and radically changing the therapy of type 1 diabetes. Patients now have 24-hour basal coverage with less hypoglycemia and an insulin that is soluble until injected. (3)

So type 1 diabetes can be managed, but the majority of patients presently have type 2 diabetes, due to obesity and insulin resistance. Oral hypoglycemic agents, including sulfonylureas, metformin, and thiazolidinediones, are commonly used for therapy. However, all but metformin cause weight gain, and the vast majority of patients require insulin as the disease progresses. Insulin causes weight gain as well. Recently, gastrointestinal hormones have been studied as a means of promoting both weight loss and glucose control in patients with type 2 diabetes. An analogue of glucagon-like peptide was discovered in the saliva of the Gila monster by Dr. John Eng. (4)

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Exendin 4 was studied and shown to decrease postprandial blood glucose and promote lower caloric intake and weight loss in patients with type 2 diabetes, a major achievement.

Revolutions in Diabetes Monitoring Paralleled the Changes in Therapy

The most empowering milestone for patients was the advent of glucose determination using a drop of blood obtained from a finger, allowing patients to monitor their own glucose and adjust their medications. The first easily usable meter was the Accu-Chek marketed in 1983 for glucose self monitoring. (5) Urine glucose monitoring was available but was inaccurate, particularly in type 2 diabetes. A correlation of glucose level to complications of diabetes was provided by the HbA1c measurement which reflects the "average" glucose. (6) This measurement was instrumental in demonstrating that control of blood glucose was a key factor in the prevention of diabetes complications, particularly microvascular complications. The Diabetes Control and Complications Trial in patients with type 1 diabetes (7) correlated HbAlc with the onset and progression of microvascular complications, and the United Kingdom Prospective Diabetes Study (8) showed that decreasing the HbA1c in the patient with type 2 diabetes was also important to prevent complications.

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The discoveries in the care and prevention of diabetes have been astounding. No longer is a diagnosis of diabetes akin to a death sentence. The disease can now be controlled. Unfortunately, the majority of patients with diabetes are far from their HbA1c goal of <7.0% (ADA) or <6.5% (AACE). Despite all the instruments of change and control that have occurred in the last century, patients and their health care providers are still not aggressive enough in implementing change to reach the goal of normal blood glucose.

References

1. Madeb R, Koniaris G, Schwartz SI. The discovery of insulin: the Rochester, New York, Connection Ann Intern Med 2005;143:907-912.

2. King KM. A history of insulin from discovery to modern alternatives. Br J Nurs 2003;12:1137-1141.

3. Ratner RE, Hirsch IB, Neifing JL, et al. Less hypoglycemia with insulin glargine in intensive insulin therapy for type 1 Diabetes: US Study Group of Insulin Glargine in type 1 Diabetes. Diabetes Care 2000;23:639-643.

4. Trecroci D. Byetta now available for type 2s. Diabetes Health 2005; 36-37.

5. Mendosa D. Meter Memories and History of Blood Glucose Meters. http://www.mendosa.com/history.htm.

6. Nathan DM, Singer DE, Hurxthal K, et al. The clinical information value of the glycosylated hemoglobin assay. N Engl J Med 1984;310:341-346.

7. DCCT 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.

8. UKPDS Study Group. Intensive blood-glucose control with sulphonyl-ureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33): UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:837-853.

A moment's insight is sometimes worth a lifetime's experience.
--Oliver Wendell Holmes

Veronica Piziak, MD, PHD, and Ethan Moses III, MS

From the Department of Endocrinology, Scott and White Clinic, Texas A & M Health Science Center, Temple, TX.

Reprint requests to Veronica Piziak, MD, PhD, Chief of Endocrinology, Scott and White Clinic, Texas A & M Health Science Center, 2401 South 31st Street, Temple, TX 76508. Email: [e-mail]

Accepted March 1, 2006.