Dr. Anthony Cerami figured out a way to measure the average blood glucose levels over a few months. Around 1970, Dr Cerami was studying sickle-cell anemia at the Rockefeller University. Sickle cell anemia is an inherited disorder in which the gene for the hemoglobin molecule has a mutation.
Hemoglobin is a protein. It is contained within the red blood cells. In fact, a red blood cell can be thought of as just a big fluffy bag full of hemoglobin. Every protein has a job. In the case of hemoglobin, its function is to bind oxygen in the lungs and transport oxygen throughout the body, then release the oxygen in peripheral tissues.
The mutation in the hemoglobin gene changes just one amino acid link in the hemoglobin protein chain. Recall that the insulin from pigs has a similar one amino acid difference to the human insulin protein. In the case of insulin, the two different forms function equivalently in humans. In the case of hemoglobin, this one amino acid change causes the red blood cell, normally a fluffy bag of hemoglobin, to transform, under certain conditions, into a stretched out bag full of rigid rods of hemoglobin. These rigid bags of hemoglobin get stuck in the smallest blood vessels of the body, impeding blood flow and depriving those tissues of oxygen.
Dr Cerami, in his studies of sickle cell anemia, became familiar with all the different modifications that occur to hemoglobin. He thought that one modification to hemoglobin, called glycosylated hemoglobin might be of particular interest to diabetes. Glycosylated hemoglobin is a compound formed when glucose attaches to the hemoglobin protein. His idea was that if one measured the fraction of hemoglobin that was glycosylated, then this would be an accurate measure of the time average blood glucose level. This was because the rate at which glycosylated hemoglobin forms is a simple function of the concentration of glucose in the surrounding area.
He tested this hypothesis with an experiment. Patients with diabetes were often admitted to the hospital when their glucose was out of control. Nurses and dietitians would work with the patients to get their glucose levels under control and within the normal range of 70-100 mg/dl. For five of these patients, Dr. Cerami measured the fraction of glycosylated hemoglobin upon entry when their glucose levels were out of control, along with some direct measurements of glucose levels. Then, after some weeks, he would retake these measurements.
The results were striking. The five patients, upon entry, had average blood glucose levels of 343 mg/dl and 9.8% of their hemoglobin was glycosylated. After their blood glucose was under control, the average blood glucose levels had dropped to 84 mg/dl and 5.8% of their hemoglobin was glycosylated. Furthermore, measurements at intermediate time points showed that the fraction of glycosylated hemoglobin had steadily declined.
Red blood cells, and the hemoglobin inside them, are created in the bone marrow. They circulate through the blood system for three to four months, then are removed from circulation by the spleen. During these three or four months in circulation, the hemoglobin gradually accumulates glucose. Thus the measurement of glycosylated hemoglobin, now called Hemoglobin A1C, is an average over several months. The measurement is generally a good indicator of the average blood glucose levels over that time period. However, the measurement can be significantly altered by changes in the average lifetime of the red blood cell.