Background—Type 2 diabetes (T2DM) is associated with an increased risk of cardiovascular disease (CVD).
This can be partly explained by large artery dysfunction, which already occurs in prediabetes ('ticking clock
hypothesis'). Whether a similar phenomenon also applies to microvascular dysfunction is not known. We
therefore tested the hypothesis that microvascular dysfunction is already present in prediabetes and is more
severe in T2DM. To do so, we investigated the associations of prediabetes, T2DM, and measures of
hyperglycemia with microvascular function measured as flicker light-induced retinal arteriolar dilation and
heat-induced skin hyperemia.
Methods—In The Maastricht Study, a T2DM-enriched population-based cohort study (N=2213, 51% men,
aged ((mean±standard deviation (SD)) 59.7±8.2 years), we determined flicker light-induced retinal arteriolar
%-dilation (Dynamic Vessel Analyzer), heat-induced skin %-hyperemia (laser-Doppler flowmetry) and glucose
metabolism status (OGTT; normal glucose metabolism (NGM), (N=1269), prediabetes (N=335) or T2DM
(N=609)). Differences were assessed with multivariable regression analyses adjusted for age, sex, body
mass index, smoking, physical activity, systolic blood pressure, lipid profile, retinopathy, estimated glomerular
filtration rate, (micro)albuminuria, the use of lipid-modifying and/or blood pressure-lowering medication, and prior CVD.
Results—Retinal arteriolar %-dilation was (mean±SD) 3.4±2.8 in NGM, 3.0±2.7 in prediabetes, and 2.3±2.6 in
T2DM. Adjusted analyses showed a lower arteriolar %-dilation in prediabetes (B=-0.20,95%CI [-0.56;0.15]),
with further deterioration in T2DM (B=-0.61, [-0.97;-0.25]) vs NGM, p for trend=0.001. Skin %-hyperemia was
(mean±SD) 1235±810 in NGM, 1109±748 in prediabetes, and 937±683 in T2DM. Adjusted analyses showed
a lower %-hyperemia in prediabetes (B=-46, [-163;72]), with further deterioration in T2DM (B=-184, [-297;-71])
vs NGM, p for trend=0.001. In addition, higher HbA1c and fasting plasma glucose (FPG) were associated with
lower retinal arteriolar %-dilation and skin %-hyperemia in fully adjusted models (for HbA1c, standardized
B (stB)=-0.10, [-0.15;-0.05], p<0.001 and stB=-0.13, [-0.19;-0.07], p<0.001, respectively; for FPG, stB=-0.09,
[-0.15;-0.04], p<0.001 and stB=-0.10, [-0.15;-0.04], p=0.002, respectively).
Conclusions—Prediabetes, T2DM and measures of hyperglycemia are independently associated with impaired
microvascular function in the retina and skin. These findings support the concept that microvascular dysfunction
precedes and thus may contribute to T2DM-associated CVD and other complications which may in part have a
microvascular origin, such as impaired cognition and heart failure.
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