Indra LM Steensa,b, Miranda T Schrama,b,c,d,e, Alfons JHM Houbena,b, Tos TJM Berendschotf, Annemarie Kosterg,h, Hans Bosmag,h, Simone JPM Eussena,g,i, Bastiaan E de Galana,b,j; Thomas T van Slotenk
a CARIM Cardiovascular Research Institute Maastricht, Maastricht University (UM), Maastricht, The Netherlands. b Department of Internal Medicine, Maastricht University Medical Center+ (MUMC+), Maastricht, The Netherlands. c Heart and Vascular Center, MUMC+, Maastricht, The Netherlands. d School of Mental Health and Neuroscience, MUMC+, Maastricht, MD, The Netherlands. e Department of Epidemiology, Erasmus MC, Rotterdam, the Netherlands. f Department of Ophthalmology, MUMC+, Maastricht, the Netherlands. g CAPHRI Care and Public Health Research Institute, UM, The Netherlands. h Department of Social Medicine, UM, Maastricht, The Netherlands. i Department of Epidemiology, UM, Maastricht, The Netherlands. j Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands. k Department of Vascular Medicine, Diabetology and Endocrinology, University Medical Center Utrecht, Utrecht, The Netherlands.
i.steens@maastrichtuniversity.nl
Background: Type 2 diabetes increases the risk of depression, but the mechanisms underlying this association are incompletely understood. We investigated whether microvascular dysfunction, neurodegeneration, low-grade inflammation, advanced glycation end products (AGEs) and arterial stiffness, pathologies that are more common in diabetes, explain, or mediate, the association between type 2 diabetes and incident clinically relevant depressive symptoms.
Methods: We used prospective data from The Maastricht Study, a population-based cohort study. Diabetes status and potential mediators were assessed at baseline. Clinically relevant depressive symptoms (PHQ-9 score ≥10) were assessed at baseline and each year during a median of 8.1 (IQR 4.2, 10.1) years of follow-up. Mediation analysis was employed to investigate the mediating effect by microvascular dysfunction (retinal, blood and MRI biomarkers), neurodegeneration (retina and MRI biomarkers), low-grade inflammation (blood biomarkers), AGEs (skin and blood biomarkers) and arterial stiffness (tonometry and ultrasound biomarkers).
Results: Data of 6,091 participants (age, 59.4 years [SD 8.6]; 51.3% women; 23.6% type 2 diabetes) were available. Type 2 diabetes was associated with a higher incidence of clinically relevant depressive symptoms (HR:1.37; 95%CI 1.13, 1.65). This association was partly mediated by microvascular dysfunction (proportion mediated:10.4% [95%CI: 3.6%, 17.2%]); neurodegeneration (proportion mediated: 12.1% [95%CI: 3.9%, 20.3 %]); AGEs (proportion mediated: 5.4% [95%CI: 3.0%, 8.8 %]; and arterial stiffness (proportion mediated: 8.4% [95%CI: 3.3%, 13.5%]); but not by low-grade inflammation.
Conclusions: The association between type 2 diabetes and higher risk of clinically relevant depressive symptoms is partly mediated by microvascular dysfunction, neurodegeneration, AGEs and arterial stiffness.