Glycemic Excursions/Fluctuations
What it Means and Why We Should Care
June 21, 2010
Irl B. Hirsch, MD
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In 1993, diabetes care was revolutionized by the first results of the Diabetes Complications and Control Trial (DCCT). Following more than 1400 patients with type 1 diabetes for approximately six years, this trial demonstrated that reducing levels of glycosylated hemoglobin – A1C (glucose control) – to approximately 7% reduces the risk of microvascular complications from diabetes compared to an A1C of about 9%. A1C is still a “gold standard” for the monitoring of diabetes health, but we know that, over time, two people with very similar A1C levels can have very different health outcomes.
A1C is formed when hemoglobin becomes glycosylated through exposure to high levels of glucose in the blood. The red blood cells that contain hemoglobin live for about three months in circulation, so A1C is a measure of overall exposure to glucose in the blood over the course of several months. We know, however, that blood glucose varies over a time course of minutes, rising, for instance, after a meal. Do these more rapid fluctuations matter to the progression of the disease? We have several reasons to believe that they do.
Increases in blood glucose are believed to cause microvascular damage through the formation of reactive oxygen species (ROS). These volatile molecules, in turn, interact with the cells that form blood vessels to disrupt their normal functioning. Researchers have studied ROS production in cells exposed to different levels of glucose, as well as under conditions in which glucose levels are frequently altered. In many cases, alternating glucose levels have caused more cell damage than constant exposure to high levels. Animal studies also support the importance of oscillations in blood glucose as compared to sustained high levels.
Evidence of the importance of glycemic excursions in people has been less clear, and the subject of much debate in the field. A few correlative studies have shown that markers of ROS damage have been found when patients are exposed to greater glycemic variability. However, we are now in a position to test this hypothesis more directly.
With the advent of improved technology for rapid and direct glucose monitoring, patients can now assess their blood glucose levels over days, hours and even minutes. Real-time continuous glucose monitoring (rt-CGM) is now being studied as a tool for patients to exert greater control over their blood sugar. In a recent study from the Junvenile Diabetes Research Foundation, adults who used rt-CGM had a significant reduction in A1C compared with control patients. Children and adolescents who wore the device 6 or 7 days each week had similar improvements in control. This technology can also be used to test whether the frequency of glycemic excursions is an independent risk factor for microvascular complications.
If this hypothesis is proven to be correct, we will need to develop a new gold standard – a number that combines the impact of A1C and glycemic variability to improve our ability to stratify the risks for patients with diabetes.
Irl B. Hirsch is Professor of Medicine, Division of Metabolism, Endocrinology and Nutrition at the University of Washington School of Medicine.
For more related articles, click Diabetes Perspectives.