Diabetes Research Update
In April 2006, Dr. Louis Monnier and colleagues published an article in JAMA that challenged the conventional wisdom about diabetes management and complications. The article suggests that complications can occur not only because of high blood glucose but also because of fluctuations in glucose.
Microvascular complications (like eye, kidney, and nerve problems) and macrovascular complications (like atherosclerosis and cardiovascular disease) have been linked to oxidative stress, a damaging cellular process. In the study, investigators compared the effects of chronic sustained hyperglycemia and acute glucose fluctuations on the activation of oxidative stress. Twenty-one subjects with type 2 diabetes were enrolled in the study along with 21 controls, or people without diabetes. All subjects wore a continuous glucose monitor, the Minimed CGMS system, to measure their glucose levels over three consecutive days. As a gauge of oxidative stress, researchers measured the subjects urine excretion of 8-iso-prostaglandin (8-iso-PGF2a), a marker of free radical production.
The study compared the data collected on the mean urinary excretion rate of 8-iso-PGF2a to the standard measurements of glycemic control. The strongest positive correlation was found between the mean urinary excretion of 8-iso-PGF2 and MAGE, or Mean Amplitude of Glucose Excursion. MAGE is an average of the differences between consecutive peaks and valleys in a glucose trend (e.g., a measure of how much glucose levels are fluctuating).
Levels of free radical production were twice as high in subjects with diabetes than in the control group, and glucose fluctuation was strongly correlated with high free radical production. Superoxide production also correlated strongly with postprandial instability. The authors concluded that glucose fluctuations during postprandial periods and, more generally, during glucose swings exhibited a more specific triggering effect on oxidative stress than chronic sustained hyperglycemia (1681).
The same issue of JAMA published an editorial about the findings. Drs. Michael Brownlee and Irl B. Hirsch, who are well known for their expertise in glycemic variability, wrote: "If confirmed in larger studies, [these findings] have enormous clinical implications." Previous work has suggested that excursions are damaging, even in patients with low glucose levels overall. Dr. Brownlee saw the impact of MAGE in his currently unpublished research on the activity of the endothelial cell enzyme, prostacyclin synthase, which inhibits atherosclerosis. When patients experienced induced hyperglycemic excursions with special hyperglycemic clamps, they saw a dramatic free-radical induced decrease in prostacyclin synthase. Both authors view the work of Monnier as further confirmation that patients with type 2 diabetes should be more strongly encouraged to test frequently.
The bottom line: Dr. Monniers work challenges the standards of treatment, adopted since the DCCT, that have made A1c scores the gold standard of care. The focus on A1c may be too narrow, downplaying the possible damage caused by glucose excursions. We believe that devices like continuous glucose monitors and drugs like Byetta and Symlin can diminish glycemic instability and can minimize excursions. They could play a much larger role in diabetes care if and when this latest research gains more adherents. If nothing else, this research reinforces the imperative of intensive management.
(Monnier D. et al. Activation of Oxidative Stress by Acute Glucose Fluctuations Compared With Sustained Chronic Hyperglycemia in Patients With Type 2 Diabetes. JAMA April 2006. 295 (14): 1681-1687. Saudek, Christopher, et al. Assessing Glycemia in Diabetes Using Self-monitoring Blood Glucose and Hemoglobin A1C. JAMA. 12 Apr 2006. 295(14):1688-1697.)