Ben M. Sörensen

Prediabetes and type 2 diabetes are associated with generalized microvascular dysfunction: the Maastricht Study

Background: Type 2 diabetes (T2DM) is associated with an increased risk of cardiovascular disease. 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] 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 (oral glucose tolerance test; normal glucose metabolism [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 blood pressure-lowering medication, and prior cardiovascular disease. Results: Retinal arteriolar %-dilation was (mean±standard deviation) 3.4±2.8 in normal glucose metabolism, 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% confidence interval –0.56 to 0.15) with further deterioration in T2DM (B=–0.61 [–0.97 to –0.25]) versus normal glucose metabolism (P for trend=0.001). Skin %-hyperemia was (mean±standard deviation) 1235±810 in normal glucose metabolism, 1109±748 in prediabetes, and 937±683 in T2DM. Adjusted analyses showed a lower %-hyperemia in prediabetes (B=–46 [–163 to 72]) with further deterioration in T2DM (B=–184 [–297 to –71]) versus normal glucose metabolism (P for trend=0.001). In addition, higher glycohemoglobin A1c and fasting plasma glucose were associated with lower retinal arteriolar %-dilation and skin %-hyperemia in fully adjusted models (for glycohemoglobin A1c, standardized B=–0.10 [–0.15 to –0.05], P<0.001 and standardized B=–0.13 [–0.19 to –0.07], P<0.001, respectively; for fasting plasma glucose, standardized B=–0.09 [–0.15 to –0.04], P<0.001 and standardized B=–0.10 [–0.15 to –0.04], P=0.002, respectively). Conclusion: 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.

Hyperglycemia Is the Main Mediator of Prediabetes- and Type 2 Diabetes–Associated Impairment of Microvascular Function: 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 = 1,791, 49% women, aged 60 ± 8 years), we determined flicker light–induced retinal arteriolar %-dilation (1) using the Dynamic Vessel Analyzer, heat-induced skin %-hyperemia (1) using laser Doppler flowmetry, and diabetes status using the oral glucose tolerance test (normal glucose metabolism \[NGM\] \[ n = 1,040\], prediabetes [ n = 276], or T2D [ n = 475]) (Table 1). Mediating effects of composite indices on prediabetes- and T2D-associated microvascular dysfunction were estimated by linear regression. View this table: Table 1 General characteristics and retinal and skin measures for the retinal study population according to glucose metabolism status Age- and sex-adjusted analyses showed lower retinal arteriolar %-dilation in prediabetes (B = −0.16 [95% CI –0.53; 0.21]), with further deterioration in T2D (B …

Determinants of microvascular function in individuals with and without type 2 diabetes: a population-based approach

Microvascular dysfunction (impaired functioning of the small blood vessels in the body) is associated with conditions such as heart failure, stroke, cognitive impairment and depression. This dissertation is part of the Maastricht Study and examines the risk factors of microvascular dysfunction in people with and without diabetes. Elevated blood sugar levels, even in people with prediabetes, and ageing are associated with ocular and dermal microvascular dysfunction. Male gender and smoking are associated with dermal microvascular dysfunction. Early and extensive monitoring of elevated blood sugar levels and microvascular dysfunction may prevent many common diseases.

Cardiovascular risk factors as determinants of retinal and skin microvascular function: The Maastricht Study.

Objective Microvascular 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. Methods In 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. Results In 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. Conclusions Associations 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.

Response by Sorensen et al to Letters Regarding Article, "Prediabetes and Type 2 Diabetes Are Associated With Generalized Microvascular Dysfunction : The Maastricht Study"

We appreciate Dr Tsuda and Brzezinski et al for their interest in our study,1 in which we found retinal arteriolar and skin microvascular dysfunction in prediabetes and type 2 diabetes mellitus independent of major cardiovascular risk factors. These findings support the concept that generalized microvascular dysfunction precedes the clinical diagnosis of type 2 diabetes mellitus and may contribute to the development of microvascular complications in (pre)diabetes. Resting albuminuria has long been favored as clinical biomarker for renal disease and is strongly associated with cardiovascular disease risk.2 An explanation is that albuminuria may reflect generalized (microvascular and macrovascular) endothelial dysfunction.3 Data on the association between direct measures of microvascular dysfunction and albuminuria are, however, scarce. Recently, we have shown an association between capillary …

[OP.5A.05] GLUCOSE METABOLISM STATUS IS ASSOCIATED WITH IMPAIRED RETINAL ARTERIOLAR VASODILATATION: THE MAASTRICHT STUDY

Objective: Type 2 diabetes (T2DM) is associated with a ∼2-fold increased risk of cardiovascular disease (CVD). This can be explained, in part, by the finding that large artery dysfunction already occurs before the onset of diabetes (‘ticking clock hypothesis’). Whether a similar phenomenon occurs for microvascular dysfunction is not known. We therefore tested the hypothesis that microvascular dysfunction (MVD) is already present in impaired glucose metabolism (IGM; prediabetes) and worsens further in T2DM by investigating the association between glucose metabolism and MVD using the retinal arteriolar dilator response to flicker light. Design and method: In a population-based cohort study with oversampling of T2DM (n = 2092), we determined flicker-light-induced retinal arteriolar %-dilatation (Dynamic Vessel Analyzer; Imedos, Germany) and glucose metabolism status (OGTT; classified as normal (NGM), IGM or T2DM). Differences were compared with multivariable regression adjusted for age, sex, waist, smoking, systolic-BP, lipid profile, retinopathy, eGFR, (micro)albuminuria, the use of lipid-modifying and/or blood-pressure-lowering medication, and prior CVD. Results: 1192 individuals had NGM (41% men, aged 58 ± 8 years (mean ± SD)), 323 IGM (54% men, aged 61 ± 7 years) and 577 T2DM (69% men, aged 63 ± 8 years). Arteriolar %-dilatation (mean ± SD) was 3.42 ± 2.84 in NGM, 3.01 ± 2.76 in IGM, and 2.34 ± 2.64 in T2DM. Adjusted analyses showed a lower %-dilatation in IGM (&bgr; = −0.20, [CI95% −0.56; 0.15]), which further decreased in T2DM (&bgr; = −0.61, [−0.97; −0.25]) vs NGM, p for trend = 0.001. In addition, higher HbA1c (&bgr; = −0.32, [−0.48; −0.16], p < 0.001) and fasting plasma glucose (FPG) (&bgr; = −0.16, [−0.24; −0.07], p < 0.001) were associated with lower arteriolar %-dilatation in fully adjusted models. Conclusions: Glucose metabolism status, HbA1c, and FPG are associated with reduced flicker-light-induced retinal arteriolar dilatation, independently of major cardiovascular risk factors. These findings support the concept that MVD precedes and thus may contribute to T2DM and T2DM-associated CVD.

Prediabetes and Type 2 Diabetes Are Associated With Generalized Microvascular DysfunctionClinical Perspective: The Maastricht Study

Background: Type 2 diabetes (T2DM) is associated with an increased risk of cardiovascular disease. 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] 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 (oral glucose tolerance test; normal glucose metabolism [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 blood pressure-lowering medication, and prior cardiovascular disease. Results: Retinal arteriolar %-dilation was (mean±standard deviation) 3.4±2.8 in normal glucose metabolism, 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% confidence interval –0.56 to 0.15) with further deterioration in T2DM (B=–0.61 [–0.97 to –0.25]) versus normal glucose metabolism (P for trend=0.001). Skin %-hyperemia was (mean±standard deviation) 1235±810 in normal glucose metabolism, 1109±748 in prediabetes, and 937±683 in T2DM. Adjusted analyses showed a lower %-hyperemia in prediabetes (B=–46 [–163 to 72]) with further deterioration in T2DM (B=–184 [–297 to –71]) versus normal glucose metabolism (P for trend=0.001). In addition, higher glycohemoglobin A1c and fasting plasma glucose were associated with lower retinal arteriolar %-dilation and skin %-hyperemia in fully adjusted models (for glycohemoglobin A1c, standardized B=–0.10 [–0.15 to –0.05], P<0.001 and standardized B=–0.13 [–0.19 to –0.07], P<0.001, respectively; for fasting plasma glucose, standardized B=–0.09 [–0.15 to –0.04], P<0.001 and standardized B=–0.10 [–0.15 to –0.04], P=0.002, respectively). Conclusion: 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.

Prediabetes and Type 2 Diabetes Are Associated With Generalized Microvascular DysfunctionClinical Perspective

Background: Type 2 diabetes (T2DM) is associated with an increased risk of cardiovascular disease. 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] 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 (oral glucose tolerance test; normal glucose metabolism [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 blood pressure-lowering medication, and prior cardiovascular disease. Results: Retinal arteriolar %-dilation was (mean±standard deviation) 3.4±2.8 in normal glucose metabolism, 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% confidence interval –0.56 to 0.15) with further deterioration in T2DM (B=–0.61 [–0.97 to –0.25]) versus normal glucose metabolism (P for trend=0.001). Skin %-hyperemia was (mean±standard deviation) 1235±810 in normal glucose metabolism, 1109±748 in prediabetes, and 937±683 in T2DM. Adjusted analyses showed a lower %-hyperemia in prediabetes (B=–46 [–163 to 72]) with further deterioration in T2DM (B=–184 [–297 to –71]) versus normal glucose metabolism (P for trend=0.001). In addition, higher glycohemoglobin A1c and fasting plasma glucose were associated with lower retinal arteriolar %-dilation and skin %-hyperemia in fully adjusted models (for glycohemoglobin A1c, standardized B=–0.10 [–0.15 to –0.05], P<0.001 and standardized B=–0.13 [–0.19 to –0.07], P<0.001, respectively; for fasting plasma glucose, standardized B=–0.09 [–0.15 to –0.04], P<0.001 and standardized B=–0.10 [–0.15 to –0.04], P=0.002, respectively). Conclusion: 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.