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.
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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)