Prediabetes and Type 2 Diabetes Are Associated With Generalized Microvascular Dysfunction: The Maastricht Study.

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. 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. 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). 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.

Sörensen BM ，Houben AJ ，Berendschot TT ，Schouten JS ，Kroon AA ，van der Kallen CJ ，Henry RM ，Koster A ，Sep SJ ，Dagnelie PC ，Schaper NC ，Schram MT ，Stehouwer CD ... -  《-》

Type 2 diabetes and HbA(1c) are independently associated with wider retinal arterioles: the Maastricht study.

Li W ，Schram MT ，Berendschot TTJM ，Webers CAB ，Kroon AA ，van der Kallen CJH ，Henry RMA ，Schaper NC ，Huang F ，Dashtbozorg B ，Tan T ，Zhang J ，Abbasi-Sureshjani S ，Ter Haar Romeny BM ，Stehouwer CDA ，Houben AJHM ... -  《-》

Different Measures of Hyperglycemia Are Negatively Associated With Skin Microvascular Flowmotion: The Maastricht Study.

Zhao X ，Schalkwijk C ，Kroon A ，Schram MT ，Stehouwer C ，Houben A ... -  《-》

Both Prediabetes and Type 2 Diabetes Are Associated With Lower Heart Rate Variability: The Maastricht Study.

Low heart rate variability (HRV), a marker for cardiac autonomic dysfunction, is a known feature of type 2 diabetes, but it remains incompletely understood whether this also applies to prediabetes or across the whole glycemic spectrum. Therefore, we investigated the association among prediabetes, type 2 diabetes, and measures of glycemia and HRV. In the population-based Maastricht Study (n = 2,107; mean ± SD age 59 ± 8 years; 52% men; normal glucose metabolism [n = 1,226], prediabetes [n = 331], and type 2 diabetes [n = 550, oversampled]), we determined 24-h electrocardiogram-derived HRV in time and frequency domains (individual z-scores, based upon seven and six variables, respectively). We used linear regression with adjustments for age, sex, and major cardiovascular risk factors. After adjustments, both time and frequency domain HRV were lower in prediabetes and type 2 diabetes as compared with normal glucose metabolism (standardized β [95% CI] for time domain: -0.15 [-0.27; -0.03] and -0.34 [-0.46; -0.22], respectively, P for trend <0.001; for frequency domain: -0.14 [-0.26; -0.02] and -0.31 [-0.43; -0.19], respectively, P for trend <0.001). In addition, 1-SD higher glycated hemoglobin, fasting plasma glucose, and 2-h postload glucose were associated with lower HRV in both domains (time domain: -0.16 [-0.21; -0.12], -0.16 [-0.21; -0.12], and -0.15 [-0.20; -0.10], respectively; frequency domain: -0.14 [-0.19; -0.10], -0.14 [-0.18; -0.09], and -0.13 [-0.18; -0.08], respectively). Both prediabetes and type 2 diabetes were independently associated with lower HRV. This is further substantiated by independent continuous associations between measures of hyperglycemia and lower HRV. These data strongly suggest that cardiac autonomic dysfunction is already present in prediabetes.

Coopmans C ，Zhou TL ，Henry RMA ，Heijman J ，Schaper NC ，Koster A ，Schram MT ，van der Kallen CJH ，Wesselius A ，den Engelsman RJA ，Crijns HJGM ，Stehouwer CDA ... -  《-》

Sex differences in the association of prediabetes and type 2 diabetes with microvascular complications and function: The Maastricht Study.

de Ritter R ，Sep SJS ，van der Kallen CJH ，van Greevenbroek MMJ ，de Jong M ，Vos RC ，Bots ML ，Reulen JPH ，Houben AJHM ，Webers CAB ，Berendschot TTJM ，Dagnelie PC ，Eussen SJPM ，Schram MT ，Koster A ，Peters SAE ，Stehouwer CDA ... -  《Cardiovascular Diabetology》