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).


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 cardiovascular disease and other complications, which may in part have a microvascular origin such as impaired cognition and heart failure.
From the CARIM School for Cardiovascular Diseases, Maastricht University, The Netherlands (B.M.S., A.J.H.M.H., A.A.K., C.J.H.v.d.K., R.M.A.H., S.J.S.S., P.C.D., N.C.S., M.T.S., C.D.A.S.); Department of Internal Medicine, Maastricht University Medical Center+, The Netherlands (B.M.S., A.J.H.M.H., A.A.K., C.J.H.v.d.K., R.M.A.H., S.J.S.S., N.C.S., M.T.S., C.D.A.S.); CAPHRI School for Public Health and Primary Care, Maastricht University, The Netherlands (A.K., P.C.D., N.C.S.); Department of Epidemiology, Maastricht University, The Netherlands (P.C.D.); Department of Social Medicine, Maastricht University, The Netherlands (A.K.); and University Eye Clinic Maastricht, Maastricht University Medical Center+, The Netherlands (T.T.J.M.B., J.S.A.G.S.).
Ben M
BM
Sörensen
From the CARIM School for Cardiovascular Diseases, Maastricht University, The Netherlands (B.M.S., A.J.H.M.H., A.A.K., C.J.H.v.d.K., R.M.A.H., S.J.S.S., P.C.D., N.C.S., M.T.S., C.D.A.S.); Department of Internal Medicine, Maastricht University Medical Center+, The Netherlands (B.M.S., A.J.H.M.H., A.A.K., C.J.H.v.d.K., R.M.A.H., S.J.S.S., N.C.S., M.T.S., C.D.A.S.); CAPHRI School for Public Health and Primary Care, Maastricht University, The Netherlands (A.K., P.C.D., N.C.S.); Department of Epidemiology, Maastricht University, The Netherlands (P.C.D.); Department of Social Medicine, Maastricht University, The Netherlands (A.K.); and University Eye Clinic Maastricht, Maastricht University Medical Center+, The Netherlands (T.T.J.M.B., J.S.A.G.S.).
Alfons J H M
AJ
Houben
From the CARIM School for Cardiovascular Diseases, Maastricht University, The Netherlands (B.M.S., A.J.H.M.H., A.A.K., C.J.H.v.d.K., R.M.A.H., S.J.S.S., P.C.D., N.C.S., M.T.S., C.D.A.S.); Department of Internal Medicine, Maastricht University Medical Center+, The Netherlands (B.M.S., A.J.H.M.H., A.A.K., C.J.H.v.d.K., R.M.A.H., S.J.S.S., N.C.S., M.T.S., C.D.A.S.); CAPHRI School for Public Health and Primary Care, Maastricht University, The Netherlands (A.K., P.C.D., N.C.S.); Department of Epidemiology, Maastricht University, The Netherlands (P.C.D.); Department of Social Medicine, Maastricht University, The Netherlands (A.K.); and University Eye Clinic Maastricht, Maastricht University Medical Center+, The Netherlands (T.T.J.M.B., J.S.A.G.S.).
Tos T J M
TT
Berendschot
From the CARIM School for Cardiovascular Diseases, Maastricht University, The Netherlands (B.M.S., A.J.H.M.H., A.A.K., C.J.H.v.d.K., R.M.A.H., S.J.S.S., P.C.D., N.C.S., M.T.S., C.D.A.S.); Department of Internal Medicine, Maastricht University Medical Center+, The Netherlands (B.M.S., A.J.H.M.H., A.A.K., C.J.H.v.d.K., R.M.A.H., S.J.S.S., N.C.S., M.T.S., C.D.A.S.); CAPHRI School for Public Health and Primary Care, Maastricht University, The Netherlands (A.K., P.C.D., N.C.S.); Department of Epidemiology, Maastricht University, The Netherlands (P.C.D.); Department of Social Medicine, Maastricht University, The Netherlands (A.K.); and University Eye Clinic Maastricht, Maastricht University Medical Center+, The Netherlands (T.T.J.M.B., J.S.A.G.S.).
Jan S A G
JS
Schouten
From the CARIM School for Cardiovascular Diseases, Maastricht University, The Netherlands (B.M.S., A.J.H.M.H., A.A.K., C.J.H.v.d.K., R.M.A.H., S.J.S.S., P.C.D., N.C.S., M.T.S., C.D.A.S.); Department of Internal Medicine, Maastricht University Medical Center+, The Netherlands (B.M.S., A.J.H.M.H., A.A.K., C.J.H.v.d.K., R.M.A.H., S.J.S.S., N.C.S., M.T.S., C.D.A.S.); CAPHRI School for Public Health and Primary Care, Maastricht University, The Netherlands (A.K., P.C.D., N.C.S.); Department of Epidemiology, Maastricht University, The Netherlands (P.C.D.); Department of Social Medicine, Maastricht University, The Netherlands (A.K.); and University Eye Clinic Maastricht, Maastricht University Medical Center+, The Netherlands (T.T.J.M.B., J.S.A.G.S.).
Abraham A
AA
Kroon
From the CARIM School for Cardiovascular Diseases, Maastricht University, The Netherlands (B.M.S., A.J.H.M.H., A.A.K., C.J.H.v.d.K., R.M.A.H., S.J.S.S., P.C.D., N.C.S., M.T.S., C.D.A.S.); Department of Internal Medicine, Maastricht University Medical Center+, The Netherlands (B.M.S., A.J.H.M.H., A.A.K., C.J.H.v.d.K., R.M.A.H., S.J.S.S., N.C.S., M.T.S., C.D.A.S.); CAPHRI School for Public Health and Primary Care, Maastricht University, The Netherlands (A.K., P.C.D., N.C.S.); Department of Epidemiology, Maastricht University, The Netherlands (P.C.D.); Department of Social Medicine, Maastricht University, The Netherlands (A.K.); and University Eye Clinic Maastricht, Maastricht University Medical Center+, The Netherlands (T.T.J.M.B., J.S.A.G.S.).
Carla J H
CJ
van der Kallen
From the CARIM School for Cardiovascular Diseases, Maastricht University, The Netherlands (B.M.S., A.J.H.M.H., A.A.K., C.J.H.v.d.K., R.M.A.H., S.J.S.S., P.C.D., N.C.S., M.T.S., C.D.A.S.); Department of Internal Medicine, Maastricht University Medical Center+, The Netherlands (B.M.S., A.J.H.M.H., A.A.K., C.J.H.v.d.K., R.M.A.H., S.J.S.S., N.C.S., M.T.S., C.D.A.S.); CAPHRI School for Public Health and Primary Care, Maastricht University, The Netherlands (A.K., P.C.D., N.C.S.); Department of Epidemiology, Maastricht University, The Netherlands (P.C.D.); Department of Social Medicine, Maastricht University, The Netherlands (A.K.); and University Eye Clinic Maastricht, Maastricht University Medical Center+, The Netherlands (T.T.J.M.B., J.S.A.G.S.).
Ronald M A
RM
Henry
From the CARIM School for Cardiovascular Diseases, Maastricht University, The Netherlands (B.M.S., A.J.H.M.H., A.A.K., C.J.H.v.d.K., R.M.A.H., S.J.S.S., P.C.D., N.C.S., M.T.S., C.D.A.S.); Department of Internal Medicine, Maastricht University Medical Center+, The Netherlands (B.M.S., A.J.H.M.H., A.A.K., C.J.H.v.d.K., R.M.A.H., S.J.S.S., N.C.S., M.T.S., C.D.A.S.); CAPHRI School for Public Health and Primary Care, Maastricht University, The Netherlands (A.K., P.C.D., N.C.S.); Department of Epidemiology, Maastricht University, The Netherlands (P.C.D.); Department of Social Medicine, Maastricht University, The Netherlands (A.K.); and University Eye Clinic Maastricht, Maastricht University Medical Center+, The Netherlands (T.T.J.M.B., J.S.A.G.S.).
Annemarie
A
Koster
From the CARIM School for Cardiovascular Diseases, Maastricht University, The Netherlands (B.M.S., A.J.H.M.H., A.A.K., C.J.H.v.d.K., R.M.A.H., S.J.S.S., P.C.D., N.C.S., M.T.S., C.D.A.S.); Department of Internal Medicine, Maastricht University Medical Center+, The Netherlands (B.M.S., A.J.H.M.H., A.A.K., C.J.H.v.d.K., R.M.A.H., S.J.S.S., N.C.S., M.T.S., C.D.A.S.); CAPHRI School for Public Health and Primary Care, Maastricht University, The Netherlands (A.K., P.C.D., N.C.S.); Department of Epidemiology, Maastricht University, The Netherlands (P.C.D.); Department of Social Medicine, Maastricht University, The Netherlands (A.K.); and University Eye Clinic Maastricht, Maastricht University Medical Center+, The Netherlands (T.T.J.M.B., J.S.A.G.S.).
Simone J S
SJ
Sep
From the CARIM School for Cardiovascular Diseases, Maastricht University, The Netherlands (B.M.S., A.J.H.M.H., A.A.K., C.J.H.v.d.K., R.M.A.H., S.J.S.S., P.C.D., N.C.S., M.T.S., C.D.A.S.); Department of Internal Medicine, Maastricht University Medical Center+, The Netherlands (B.M.S., A.J.H.M.H., A.A.K., C.J.H.v.d.K., R.M.A.H., S.J.S.S., N.C.S., M.T.S., C.D.A.S.); CAPHRI School for Public Health and Primary Care, Maastricht University, The Netherlands (A.K., P.C.D., N.C.S.); Department of Epidemiology, Maastricht University, The Netherlands (P.C.D.); Department of Social Medicine, Maastricht University, The Netherlands (A.K.); and University Eye Clinic Maastricht, Maastricht University Medical Center+, The Netherlands (T.T.J.M.B., J.S.A.G.S.).
Pieter C
PC
Dagnelie
From the CARIM School for Cardiovascular Diseases, Maastricht University, The Netherlands (B.M.S., A.J.H.M.H., A.A.K., C.J.H.v.d.K., R.M.A.H., S.J.S.S., P.C.D., N.C.S., M.T.S., C.D.A.S.); Department of Internal Medicine, Maastricht University Medical Center+, The Netherlands (B.M.S., A.J.H.M.H., A.A.K., C.J.H.v.d.K., R.M.A.H., S.J.S.S., N.C.S., M.T.S., C.D.A.S.); CAPHRI School for Public Health and Primary Care, Maastricht University, The Netherlands (A.K., P.C.D., N.C.S.); Department of Epidemiology, Maastricht University, The Netherlands (P.C.D.); Department of Social Medicine, Maastricht University, The Netherlands (A.K.); and University Eye Clinic Maastricht, Maastricht University Medical Center+, The Netherlands (T.T.J.M.B., J.S.A.G.S.).
Nicolaas C
NC
Schaper
From the CARIM School for Cardiovascular Diseases, Maastricht University, The Netherlands (B.M.S., A.J.H.M.H., A.A.K., C.J.H.v.d.K., R.M.A.H., S.J.S.S., P.C.D., N.C.S., M.T.S., C.D.A.S.); Department of Internal Medicine, Maastricht University Medical Center+, The Netherlands (B.M.S., A.J.H.M.H., A.A.K., C.J.H.v.d.K., R.M.A.H., S.J.S.S., N.C.S., M.T.S., C.D.A.S.); CAPHRI School for Public Health and Primary Care, Maastricht University, The Netherlands (A.K., P.C.D., N.C.S.); Department of Epidemiology, Maastricht University, The Netherlands (P.C.D.); Department of Social Medicine, Maastricht University, The Netherlands (A.K.); and University Eye Clinic Maastricht, Maastricht University Medical Center+, The Netherlands (T.T.J.M.B., J.S.A.G.S.).
Miranda T
MT
Schram
From the CARIM School for Cardiovascular Diseases, Maastricht University, The Netherlands (B.M.S., A.J.H.M.H., A.A.K., C.J.H.v.d.K., R.M.A.H., S.J.S.S., P.C.D., N.C.S., M.T.S., C.D.A.S.); Department of Internal Medicine, Maastricht University Medical Center+, The Netherlands (B.M.S., A.J.H.M.H., A.A.K., C.J.H.v.d.K., R.M.A.H., S.J.S.S., N.C.S., M.T.S., C.D.A.S.); CAPHRI School for Public Health and Primary Care, Maastricht University, The Netherlands (A.K., P.C.D., N.C.S.); Department of Epidemiology, Maastricht University, The Netherlands (P.C.D.); Department of Social Medicine, Maastricht University, The Netherlands (A.K.); and University Eye Clinic Maastricht, Maastricht University Medical Center+, The Netherlands (T.T.J.M.B., J.S.A.G.S.). cda.stehouwer@mumc.nl.
Coen D A
CD
Stehouwer
D000328:Adult; D000368:Aged; D001786:Blood Glucose / Q000378:metabolism; D001794:Blood Pressure; D015992:Body Mass Index; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000473:pathology / Q000503:physiopathology; D015444:Exercise; D005260:Female; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D006940:Hyperemia / Q000097:blood / Q000473:pathology / Q000503:physiopathology; D008055:Lipids / Q000097:blood; D008297:Male; D055806:Microvessels / Q000473:pathology / Q000503:physiopathology; D008875:Middle Aged; D011236:Prediabetic State / Q000097:blood / Q000473:pathology / Q000503:physiopathology; D012042:Registries; D012171:Retinal Vessels / Q000473:pathology / Q000503:physiopathology; D012907:Smoking / Q000473:pathology / Q000503:physiopathology
D001786:Blood Glucose; D006442:Glycated Hemoglobin; D008055:Lipids; C517652:hemoglobin A1c protein, human
cardiovascular disease; diabetes mellitus type 2; epidemiology; microvascular dysfunction; pathophysiology