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Acute glucose fluctuations activate oxidative stress
Glucose swings had more specific effect than sustained hyperglycemia in type 2 diabetes.
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A case-control study found that rapid and acute glucose fluctuations are as important as chronic hyperglycemia in the activation of oxidative stress in patients with type 2 diabetes.
Previous research has indicated that “activation of the oxidative stress by hyperglycemia plays a major role in the pathogenesis of diabetic complications,” researchers wrote in the Journal of the American Medical Association. However, the part played by acute glucose fluctuations in the development of these complications is less clear.
Louis Monnier, MD, chief of the division of metabolic diseases at Lapeyronie Hospital in Montpellier, France, and colleagues conducted a study into the respective roles of sustained chronic hyperglycemia and acute glucose fluctuations on the activation of oxidative stress.
Twenty-one patients with type 2 diabetes were enrolled in the study between 2003 and 2005, and 21 age- and sex-matched controls were also included from an earlier study conducted at the University of Montpellier.
Patients at baseline
Nineteen of the 21 patients with diabetes were treated with oral antidiabetic agents (glyburide or a combination of metformin and glyburide); all patients followed a weight-controlling diet for at least three months prior to the start of the study. The mean HbA1c level was 9.6% (range, 7.5% to 12.5%).
Researchers monitored the subcutaneous interstitial glucose levels of all patients with diabetes during a period of three consecutive days, using the MiniMed continuous glucose monitoring system (Medtronic).
“The characteristic glucose pattern of each patient was calculated by averaging the profiles obtained on study days 1 and 2,” researchers wrote. Oxidative stress activation was estimated from measurement of urinary excretion of the F2 isoprostane 8-iso prostaglandin F2 (8-iso PGF2).
Patients with diabetes had a significantly higher excretion rate of 8-iso PGF2a vs. the control patients (P<.001). Excretion rates of 8-iso PGF2 were tested for linear correlations with markers of glucose control, and the strongest correlation was found with the mean amplitude of glycemic excursions (r=0.86, P<.001).
A correlation was also found between 8-iso PGF2 and a measurement of postprandial glucose excursions (r=0.55, P=.009). However, excretion rates did not correlate with fasting plasma insulin, HbA1c, fasting plasma glucose and mean daily glucose concentrations.
Researchers also classified patients into two groups based on treatment: 16 patients were treated with two drugs, and five were treated either with one drug or diet alone.
They found no significant differences in mean amplitude of glycemic excursions between these groups, indicating that this marker had no relationship with therapy for diabetes.
Monnier told Endocrine Today, however, that in unpublished data of a larger population of 130 patients, it appears that mean amplitude of glycemic excursions are stable in type 2 diabetic patients with HbA1c higher than 7% to 8%.
“By contrast, mean amplitude of glycemic excurions are reduced to a minimum of approximately 45 mg/dL when HbA1c is below 6.5% to 7%,” he said.
“The main message of the study is that rapid and acute glucose fluctuations from peaks to nadirs are as important as sustained chronic elevation of blood glucose in the activation of the oxidative stress in type 2 diabetes patients,” Monnier said.
“As activation of oxidative stress is one of the main mechanisms of complications in diabetes, it is therefore highly suggested by our results that the treatment of glycemic disorders should be aimed not only at reducing HbA1c levels but also at flattening glucose variability.”
Monnier said that because patients with type 2 diabetes most often have high glucose variation over the post-breakfast morning period, treatment should specifically target this period of the day using prebreakfast insulin injections or inhalations.
“Future trials devoted to the assessment of therapeutic strategies in type 2 diabetics should take into consideration their potential to minimize glycemic excursions,” Monnier said.
Self-monitoring
Monnier also pointed out the importance of self-monitoring and continuous monitoring of glucose given the results of this study. In an accompanying editorial, Michael Brownlee, MD, of Albert Einstein College of Medicine in New York, and Irl B. Hirsch, MD, of the University of Washington School of Medicine in Seattle, agreed that these and other data were making the need for continuous monitoring more acute.
“These data suggest that in patients with type 2 diabetes, self-monitoring of blood glucose should be performed with increased frequency to monitor glycemic variability, regardless of the effect on HbA1c,” they wrote. “Second, the findings suggest that different therapeutic strategies now in use should be evaluated for their potential to minimize glycemic excursion, as well as for their ability to reduce HbA1c.” – by Dave Levitan
For more information:
- Monnier L, Mas E, Ginet C, et al. Activation of oxidative stress by acute glucose fluctuations compared with sustained chronic hyperglycemia in patients with type 2 diabetes. JAMA. 2006;295:1681-1687.
- Brownlee M, Hirsch IB. Glycemic variability: a hemoglobin A1c-independent risk factor for diabetic complications. JAMA. 2006;295:1707-1708.