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 cardiovascular disease and other complications, which may in part have a microvascular origin such as impaired cognition and heart failure.

This is the first population-based study that provides direct evidence that microvascular endothelial dysfunction is associated with albuminuria, and that this association is stronger in individuals with than in those without type 2 diabetes.

Microvascular dysfunction (MVD) is a common pathophysiological change that occurs in various diseases, such as type 2 diabetes mellitus (T2DM), heart failure, dementia, and depression. Recent technical advances have enabled noninvasive measurement and quantification of microvascular changes in humans. In this paper, we describe the protocols of the microvascular measurements applied in the Maastricht Study, an ongoing prospective, population-based cohort study of persons aged 40–75 years being carried out in the southern part of the Netherlands (baseline data assessment, November 2010–January 2020). The study includes a variety of noninvasive measurements in skin, retina, brain, and sublingual tissue, as well as plasma and urine biomarker assessments. Following this, we summarize our main findings involving these microvascular measurements through the end of 2018. Finally, we provide a brief perspective on future microvascular investigations within the framework of the Maastricht Study.

Prediabetes and type 2 diabetes (T2D) are associated with microvascular dysfunction (1), which may explain their increased risk of microvascular complications. However, mechanisms remain poorly understood. We investigated to what extent prediabetes-and T2D-associated microvascular dysfunction is potentially attributable to (composite indices of) hyperglycemia, insulin resistance, blood pressure, arterial stiffness, lipid profile, and/or low-grade inflammation.In the Maastricht Study (2), a T2D-enriched population-based cohort study (n 5 1,791, 49% women, aged 60 6 8 years), we determined flicker lightinduced retinal arteriolar %-dilation (1) using the Dynamic Vessel Analyzer, heat-induced skin %-hyperemia (1) Qualitatively similar patterns of mediation were found in additional analyses (available on request) in which we additionally adjusted for smoking, BMI, and (micro)vascular complications, used absolute retinal arteriolar diameter and skin blood flow as outcomes, investigated arterial stiffness as a potential mediator, or used a composite index of long-term hyperglycemic measures (glycated hemoglobin A 1c and skin autofluorescence).These findings suggest that hyperglycemia itself, rather than the cardiovascular risk context associated with prediabetes and T2D, is the main contributor to both prediabetes-and T2D-associated retinal and skin microvascular dysfunction. This supports an early detrimental effect of hyperglycemia on the retinal and skin microvascular responses. Impairments in both these responses reflect decreased availability of nitric oxide and are likely a reflection of microvascular endothelial dysfunction, possibly in conjunction with neuronal dysfunction (3,4).Our study had some limitations. First, data were cross-sectional; therefore, we cannot exclude reverse causality. Second, inflammatory markers drawn from venous plasma, compared with local

ObjectiveMicrovascular dysfunction is an important underlying mechanism of microvascular diseases. Determinants (age, sex, hypertension, dyslipidemia, hyperglycemia, obesity, and smoking) of macrovascular diseases affect large-artery endothelial function. These risk factors also associate with microvascular diseases. We hypothesized that they are also determinants of microvascular (endothelial) function.MethodsIn The Maastricht Study, a type 2 diabetes-enriched population-based cohort study (n = 1991, 51% men, aged 59.7±8.2 years), we determined microvascular function as flicker light-induced retinal arteriolar %-dilation and heat-induced skin %-hyperemia. Multiple linear regression analyses were used to assess the associations of cardiovascular risk factors (age, sex, waist circumference, total-to-high-density lipoprotein (HDL) cholesterol ratio, fasting plasma glucose (FPG), 24-h systolic blood pressure, and cigarette smoking) with retinal and skin microvascular function.ResultsIn multivariate analyses, age and FPG were inversely associated with retinal and skin microvascular function (regression coefficients per standard deviation (SD) were -0.11SD (95%CI: -0.15;-0.06) and -0.12SD (-0.17;-0.07) for retinal arteriolar %-dilation and -0.10SD (-0.16;-0.05) and -0.11SD (-0.17;-0.06) for skin %-hyperemia, respectively. Men and current smokers had -0.43SD (-0.58;-0.27) and -0.32SD (-0.49;-0.15) lower skin %-hyperemia, respectively. 24-h systolic blood pressure, waist circumference, and total-to-HDL cholesterol ratio were not statistically significantly associated with these microvascular functions.ConclusionsAssociations between cardiovascular risk factors and retinal and skin microvascular function show a pattern that is partly similar to the associations between cardiovascular risk factors and macrovascular function. Impairment of microvascular function may constitute a pathway through which an adverse cardiovascular risk factor pattern may increase risk of diseases that are partly or wholly of microvascular origin.

The etiology of late-life depression (LLD) is still poorly understood. Microvascular dysfunction (MVD) has been suggested to play a role in the etiology of LLD, but direct evidence of this association is scarce. The aim of this study was to investigate whether direct and indirect markers of early microvascular dysfunction are associated with prevalent and incident LLD in the population-based Maastricht Study cohort. We measured microvascular dysfunction at baseline by use of flicker light-induced retinal vessel dilation response (Dynamic Vessel Analyzer), heat-induced skin hyperemic response (laser- Doppler flowmetry), and plasma markers of endothelial dysfunction (endothelial dysfunction; sICAM-1 [soluble intercellular adhesion molecule-1], sVCAM-1 [soluble vascular adhesion molecule-1], sE-selectin [soluble E-selectin], and vWF [Von Willebrand Factor]). Depressive symptoms were assessed with the 9-item Patient Health Questionnaire (PHQ-9) at baseline and annually over 4 years of follow-up (n=3029; mean age 59.6±8.2 years, 49.5% were women, n=132 and n=251 with prevalent and incident depressive symptoms [PHQ-9≥10]). We used logistic, negative binominal and Cox regression analyses, and adjusted for demographic, cardiovascular, and lifestyle factors. Retinal venular dilatation and plasma markers of endothelial dysfunction were associated with the more prevalent depressive symptoms after full adjustment (PHQ-9 score, RR, 1.05 [1.00–1.11] and RR 1.06 [1.01–1.11], respectively). Retinal venular dilatation was also associated with prevalent depressive symptoms (PHQ-9≥10; odds ratio, 1.42 [1.09–1.84]), after full adjustment. Retinal arteriolar dilatation and plasma markers of endothelial dysfunction were associated with incident depressive symptoms (PHQ-9≥10; HR, 1.23 [1.04–1.46] and HR, 1.19 [1.05–1.35]), after full adjustment. These findings support the concept that microvascular dysfunction in the retina, and plasma markers of endothelial dysfunction is involved in the etiology of LLD and might help in finding additional targets for the prevention and treatment of LLD.

Objective Physical activity may provide a means for the prevention of cardiovascular disease via improving microvascular function. Therefore, this study investigated whether physical activity is associated with skin and retinal microvascular function. Methods In The Maastricht Study, a population‐based cohort study enriched with type 2 diabetes (n = 1298, 47.3% women, aged 60.2 ± 8.1 years, 29.5% type 2 diabetes), we studied whether accelerometer‐assessed physical activity and sedentary time associate with skin and retinal microvascular function. Associations were studied by linear regression and adjusted for major cardiovascular risk factors. In addition, we investigated whether associations were stronger in type 2 diabetes. Results In individuals with type 2 diabetes, total physical activity and higher‐intensity physical activity were independently associated with greater heat‐induced skin hyperemia (regression coefficients per hour), respectively, 10 (95% CI: 1; 18) and 36 perfusion units (14; 58). In individuals without type 2 diabetes, total physical activity and higher‐intensity physical activity were not associated with heat‐induced skin hyperemia. No associations with retinal arteriolar %‐dilation were identified. Conclusion Higher levels of total and higher‐intensity physical activity were associated with greater skin microvascular vasodilation in individuals with, but not in those without, type 2 diabetes.

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