Dehydroepiandrosterone Administration Counteracts Oxidative Imbalance and Advanced Glycation End Product Formation in Type 2 Diabetic Patients

Abstract

OBJECTIVE -Dehydroepiandrosterone (DHEA) has been shown to prevent oxidative stress in several in vivo and in vitro models. This study aimed to evaluate the effects of DHEA administration on oxidative stress, pentosidine concentration, and tumor necrosis factor (TNF)-␣/ TNF-␣ receptor system activity in patients with type 2 diabetes.RESEARCH DESIGN AND METHODS -Twenty patients were enrolled in the study and randomly assigned to the DHEA (n ϭ 10) or placebo (n ϭ 10) group. Twenty healthy sexand age-matched subjects with normal glucose levels served as control subjects. DHEA was given as a single daily dose of 50 mg for 12 weeks.RESULTS -Oxidative stress parameters were significantly higher in diabetic patients versus control subjects. Pentosidine levels, as well as soluble TNF receptor (sTNF-R)I and sTNF-RII, were also higher in diabetic patients. After DHEA, plasma levels of reactive oxygen species and hydroxynonenal dropped by 53 and 47%, respectively, whereas the nonenzymatic antioxidants glutathione and vitamin E increased (ϩ38 and ϩ76%, respectively). The same changes in oxidative parameters were detected in peripheral blood mononuclear cells (PBMCs). DHEA treatment also induced a marked decrease of pentosidine plasma concentration in diabetic patients (Ϫ50%). Moreover, the TNF-␣/TNF-␣ receptor system was shown to be less activated after DHEA treatment, in both plasma and PBMCs.CONCLUSIONS -Data indicate that DHEA treatment ameliorates the oxidative imbalance induced by hyperglycemia, downregulates the TNF-␣/TNF-␣ receptor system, and prevents advanced glycation end product formation, suggesting a beneficial effect on the onset and/or progression of chronic complications in type 2 diabetic patients. Diabetes Care 30:2922-2927, 2007T he onset and progression of diabetes complications involves a complex interplay between ranges of pathogenic mechanisms. However, emerging evidence suggests that a single early phenomenon, i.e., the overproduction of superoxide by the respiratory chain, plays a key role in the pathogenesis of both microvascular and macrovascular chronic complications (1-3).The production of advanced glycation end products (AGEs) is among the main mechanisms recruited by oxidative stress and is involved in the pathogenesis of tissue injury (3,4). AGEs progressively accumulate with time at the sites of diabetic microvascular disease and mediate tissue damage by activation of specific receptors at distant sites, via circulation (3,5). Moreover, the AGE/AGE receptor interaction, along with hyperglycemiainduced oxidative stress, possibly serves as a key activator of upstream kinases, leading to increased production of inflammatory cytokines thought to be involved in the progression of chronic diabetes complications (6).Interruption of free radical overproduction by antioxidants counteracts AGE formation (2). Nevertheless, despite convincing experimental results, clinical trials with traditional antioxidants have been disappointing (7)-the activity of the antioxidants used in those trials is limited to...

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