Diabetic Retinopathy Is Related to Both Endothelium-Dependent and -Independent Responses of Skin Microvascular Flow

Diabetes Care, Jun 2011

OBJECTIVE Endothelial dysfunction has been hypothesized as a possible pathogenic factor in the development of diabetic retinopathy (DR). We examined the relationship of DR to endothelium-dependent and endothelium-independent responses in skin microvascular flow.

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Diabetic Retinopathy Is Related to Both Endothelium-Dependent and -Independent Responses of Skin Microvascular Flow

THANH T. NGUYEN MBBS PHD JONATHAN E. SHAW CAROL ROBINSON PHD RYO KAWASAKI PHD JIE JIN WANG PHD ANDREAS J. KREIS TIEN Y. WONG PHD OBJECTIVE-Endothelial dysfunction has been hypothesized as a possible pathogenic factor in the development of diabetic retinopathy (DR). We examined the relationship of DR to endothelium-dependent and endothelium-independent responses in skin microvascular flow. RESEARCH DESIGN AND METHODS-Participants consisted of 224 individuals with diabetes: 85 with type 1 diabetes and 139 with type 2 diabetes. Sodium nitroprusside (SNP) and acetylcholine (ACh) were delivered across the skin by iontophoresis. Laser Doppler flowmetry was used to assess the skin microcirculation response to SNP (endothelium-independent response) and ACh (endothelium-dependent response). The presence and severity of DR were graded from retinal photographs using a standard protocol. RESULTS-Of 224 participants, 64.3% had DR. After multivariable adjustment, participants with reduced responses to SNP or ACh were more likely to have DR, with an odds ratio (OR) of 2.33 (95% CI 1.09-5.01) for SNP and 2.20 (1.05-4.61) for ACh, comparing participants with responses below and above the median values. Participants with reduced responses (below the median) to both SNP and ACh were nearly four times more likely to have DR (OR 3.86 [1.4510.3]) than those with SNP and ACh both above the median values. CONCLUSIONS-The presence of DR was associated with a reduction in skin microcirculation responses to iontophoresis of both SNP and ACh, suggesting that vascular processes associated with both endothelial dysfunction and endothelial function-independent mechanisms may be pathogenically related to DR. - D uals worldwide (1), and diabetic iabetes affects 285 million individretinopathy (DR) is the leading cause of blindness in the working-age population in most developed countries (2). Although it has been suggested that endothelial dysfunction may underlie the pathogenesis of DR (3), the few clinical and epidemiologic studies to date have found inconsistent associations of DR with indirect serum markers of endothelial function (e.g., soluble vascular adhesion molecule-1) (49) or brachial flow mediated dilation (FMD) (1013), a more direct measurement of endothelial dysfunction (14). Drug delivery to the skin by iontophoresis, accompanied by laser Doppler technology to measure microvascular flow, has been validated as a measure of endothelial function in the skin microcirculation (15). Responses of the skin c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c microcirculation to sodium nitroprusside (SNP) and acetylcholine (ACh) are measures of endothelium-independent and endothelium-dependent responses, respectively. Studies have shown a strong correlation between endothelial function assessed by FMD of the brachial artery and ACh increase in skin blood flow (r = 0.92, P , 0.0001) (16). Further study has shown that impaired skin microvascular response is associated with a range of cardiovascular risk factors and diseases (15). In this study, we examined the relationship of DR with skin microvascular dysfunction as measured by iontophoresis and laser Doppler flowmetry in a clinical sample of patients with diabetes. Our aim was to establish whether DR was associated with systemic microvascular dysfunction evidenced in the skin and whether this was primarily driven by endothelial dysfunction. RESEARCH DESIGN AND METHODSWe conducted a case control study of DR among 224 individuals with diabetes, consisting of 85 with type 1 diabetes and 139 with type 2 diabetes. Participants were recruited from the diabetic eye clinics at the International Diabetes Institute, Melbourne, Australia, between October 2006 and April 2008. Detailed examination of the participants has been previously reported (3). In brief, individuals with known diabetes who were seen at the diabetic eye clinics and treated with oral hypoglycemic mediations and/or insulin were eligible. Participants were excluded if aged older than 70 years, currently pregnant, had a previous mastectomy (with axillary clearance), previous vitreal surgery, had an arteriovenous fistula on the arm/forearm, a history of skin cancer on the arm/forearm, epilepsy, glaucoma, and/or had cataract on examinations for this study. All participants underwent a standardized clinical examination, analysis of blood chemistry, retinal photographs, and assessment of skin microvascular dysfunction. Tenets of the Declaration of Helsinki were followed, institutional review board approval was granted, and written informed consent was obtained from all participants. Skin microcirculation endothelial function Skin microcirculation endothelial function was measured using a laser Doppler flowmetry technique that assessed the skin microcirculation responses to iontophoresis of SNP and ACh (15). Iontophoresis delivers the SNP and ACh vasodilators across the skin using (...truncated)


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Thanh T. Nguyen, Jonathan E. Shaw, Carol Robinson, Ryo Kawasaki, Jie Jin Wang, Andreas J. Kreis, Tien Y. Wong. Diabetic Retinopathy Is Related to Both Endothelium-Dependent and -Independent Responses of Skin Microvascular Flow, Diabetes Care, 2011, pp. 1389-1393, 34/6, DOI: 10.2337/dc10-1985