Clinical Implications of Glucose Variability: Chronic Complications of Diabetes

Abstract

Glucose variability has been identified as a potential risk factor for diabetic complications; oxidative stress is widely regarded as the mechanism by which glycemic variability induces diabetic complications. However, there remains no generally accepted gold standard for assessing glucose variability. Representative indices for measuring intraday variability include calculation of the standard deviation along with the mean amplitude of glycemic excursions (MAGE). MAGE is used to measure major intraday excursions and is easily measured using continuous glucose monitoring systems. Despite a lack of randomized controlled trials, recent clinical data suggest that long-term glycemic variability, as determined by variability in hemoglobin A1c, may contribute to the development of microvascular complications. Intraday glycemic variability is also suggested to accelerate coronary artery disease in high-risk patients.

Keywords: Glucose variability; Macrovascular complications; Microvascular complications.

Fig. 1. Twenty-four-hour glycemic curves of two patients with diabetes (red and blue lines). The two patients exhibit different patterns of glycemic variation; however, standard deviations calculated across all four points, before each meal and at bedtime (arrows), do not reflect this because the glucose measures are similar between the two patients at those points.

Fig. 2. Continuous glucose monitoring in a patient with type 1 diabetes mellitus. Qualifying excursions are shown as blue arrows (only the inflection components in this case). Each inflection incorporates several excursions smaller than 1 standard deviation (SD) within a given day (44 mg/dL for day 1 and 65 mg/dL for day 2). The averaged excursion (that is, mean amplitude of glycemic excursion [MAGE]) is (A) 85.0 mg/dL for day 1 and (B) 156.5 mg/dL for day 2. MAGE calculated from the entire 48-hour time course (SD, 56.5 mg/dL) was 131.5 mg/dL; this level was similar across each day of the study period (120.7 mg/dL). Similar MAGE values could also be calculated from the descending limbs.

Fig. 3. Glycemic measures in a randomized controlled trial comparing prandial and basal insulin in patients with cardiovascular disease (HEART2D study). Seven-point mean self-monitoring of blood glucose profiles at baseline (dotted line) and throughout the study (solid line) are indicative of the treatment strategy. Only the change in the mean absolute glucose level, an alleged measure of glucose variability, was significantly different between treatments, with no observable differences in standard deviation or mean amplitude of glycemic excursion. Therefore, accurate interpretation of the relationship between glycemic variability and the endpoint of combined cardiovascular events in this trial is prudent. Adapted from Raz et al. [47], with permission from American Diabetes Association. ^aP<0.05 between treatment.