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Pioglitazone Treatment Improves Nitrosative Stress in Type 2 Diabetes

¹ Department of Internal Medicine, The Strelitz Diabetes Institutes, Eastern Virginia Medical School, Norfolk, Virginia
² Department of Pathology and Anatomy, Eastern Virginia Medical School, Norfolk, Virginia

Address correspondence and reprint requests to Aaron I. Vinik, MD, PhD, The Strelitz Diabetes Institutes, Eastern Virginia Medical School, Norfolk, VA 23510. E-mail: vinikai{at}evms.edu

OBJECTIVE—The purpose of this study was to determine the effect of 24 weeks of treatment with 45 mg/day pioglitazone on peripheral skin blood flow (SkBF) and skin nitric oxide (NO) production in vivo in patients with type 2 diabetes.

RESEARCH DESIGN AND METHODS—This was a randomized, parallel, cross-over, double-blind, within- and between-subject study designed to compare vascular responses before and after treatment. We studied 12 subjects with type 2 diabetes (average age 58.6 ± 30.8 years, HbA_1c 7.9 ± 00.4%, BMI 31.3 ± 1.2 kg/m²). SkBF was measured using laser Doppler techniques in response to ischemia reperfusion and local skin warming, and NO production was assessed in vivo using an amperometric NO meter inserted directly into the skin. These measurements were performed before treatment and at 6 and 24 weeks.

RESULTS—The SkBF response was not significantly improved after 24 weeks in either of the groups. NO production was significantly decreased in the pioglitazone-treated group in the basal condition (area under the curve 6.4 ± 1.0 vs. 2.8 ± 0.8, P < 0.01), after local heat stimulation at 40°C (12.9 ± 2.2 vs. 5.7 ± 1.7, P < 0.01), and after nociceptor stimulated flow with local heating at 44°C (36.4 ± 6.3 vs. 16.6 ± 3.4). Differences were not significant in the placebo-treated group.

CONCLUSIONS—Treatment of patients with type 2 diabetes with pioglitazone for 24 weeks reduced skin NO production, thus probably reducing nitrosative stress without a demonstrable effect on SkBF. Because nitrosative stress is considered to be a factor in the pathogenesis of neurovascular dysfunction, these findings warrant further investigation.

Abbreviations: DPN, diabetic polyneuropathy • eNOS, endothelial nitric oxide synthase • MCHC, mean corpuscular hemoglobin concentration • NOCI, nociceptor stimulated flow • ONOO^–, peroxynitrite • PPAR, peroxisome proliferator–activated receptor • ROS, reactive oxygen species • SkBF, skin blood flow • TZD, thiazolidinedione • WBC, white blood cell

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