Type 2 diabetes and depression via microvascular dysfunction, neurodegeneration, inflammation, advanced glycation end products (AGEs), and arterial stiffness

Diabetes Obes Metab. 2025 Sep;27(9):4847-4858. doi: 10.1111/dom.16527. Epub 2025 Jun 19.

Abstract

Aims: 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.

Materials and 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 of 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 6091 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 a higher risk of clinically relevant depressive symptoms is partly mediated by microvascular dysfunction, neurodegeneration, AGEs and arterial stiffness.

Keywords: cardiovascular disease; diabetes complications; population study; type 2 diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Biomarkers / blood
  • Depression* / epidemiology
  • Depression* / etiology
  • Depression* / physiopathology
  • Diabetes Mellitus, Type 2* / complications
  • Diabetes Mellitus, Type 2* / epidemiology
  • Diabetes Mellitus, Type 2* / physiopathology
  • Diabetes Mellitus, Type 2* / psychology
  • Diabetic Angiopathies* / epidemiology
  • Diabetic Angiopathies* / physiopathology
  • Female
  • Glycation End Products, Advanced* / blood
  • Glycation End Products, Advanced* / metabolism
  • Humans
  • Inflammation* / complications
  • Inflammation* / epidemiology
  • Inflammation* / physiopathology
  • Male
  • Microvessels / physiopathology
  • Middle Aged
  • Netherlands / epidemiology
  • Neurodegenerative Diseases* / epidemiology
  • Neurodegenerative Diseases* / physiopathology
  • Prospective Studies
  • Vascular Stiffness* / physiology

Substances

  • Glycation End Products, Advanced
  • Biomarkers