Diabetic retinopathy is related to both endothelium-dependent and -independent responses of skin microvascular flow

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 [1.45–10.3]) 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.Diabetes affects 285 million individuals worldwide (1), and diabetic retinopathy (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) (4–9) or brachial flow–mediated dilation (FMD) (10–13), 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 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.