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

Indra L M Steens; Miranda T Schram; Alfons J H M Houben; Tos T J M Berendschot; Annemarie Koster; Hans Bosma; Simone J P M Eussen; Bastiaan E de Galan; Thomas T van Sloten

doi:10.1111/dom.16527

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

Indra L M Steens
, Miranda T Schram
, Alfons J H M Houben
, Tos T J M Berendschot
, Annemarie Koster
, Hans Bosma
, Simone J P M Eussen
, Bastiaan E de Galan
, Thomas T van Sloten

Research output: Contribution to journal › Article › Academic › peer-review

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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.

Original language	English
Pages (from-to)	4847-4858
Number of pages	12
Journal	Diabetes, Obesity & Metabolism
Volume	27
Issue number	9
Early online date	19 Jun 2025
DOIs	https://doi.org/10.1111/dom.16527
Publication status	Published - Sept 2025

Keywords

cardiovascular disease
diabetes complications
population study
type 2 diabetes

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Diabetes Obesity Metabolism - 2025 - Steens - Type 2 diabetes and depression via microvascular dysfunction Final published version, 1.35 MBLicence: CC BY-NC

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Steens, I. L. M., Schram, M. T., Houben, A. J. H. M., Berendschot, T. T. J. M., Koster, A., Bosma, H., Eussen, S. J. P. M., de Galan, B. E., & van Sloten, T. T. (2025). Type 2 diabetes and depression via microvascular dysfunction, neurodegeneration, inflammation, advanced glycation end products (AGEs), arterial stiffness. Diabetes, Obesity & Metabolism, 27(9), 4847-4858. https://doi.org/10.1111/dom.16527

@article{7b69cadade3f43f08860aa227e563a9d,

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

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",

author = "Steens, \{Indra L M\} and Schram, \{Miranda T\} and Houben, \{Alfons J H M\} and Berendschot, \{Tos T J M\} and Annemarie Koster and Hans Bosma and Eussen, \{Simone J P M\} and \{de Galan\}, \{Bastiaan E\} and \{van Sloten\}, \{Thomas T\}",

note = "Publisher Copyright: {\textcopyright} 2025 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley \& Sons Ltd.",

year = "2025",

month = sep,

doi = "10.1111/dom.16527",

language = "English",

volume = "27",

pages = "4847--4858",

journal = "Diabetes, Obesity \& Metabolism",

issn = "1462-8902",

publisher = "John Wiley \& Sons Inc.",

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Steens, ILM, Schram, MT, Houben, AJHM, Berendschot, TTJM, Koster, A, Bosma, H, Eussen, SJPM, de Galan, BE & van Sloten, TT 2025, 'Type 2 diabetes and depression via microvascular dysfunction, neurodegeneration, inflammation, advanced glycation end products (AGEs), arterial stiffness', Diabetes, Obesity & Metabolism, vol. 27, no. 9, pp. 4847-4858. https://doi.org/10.1111/dom.16527

Type 2 diabetes and depression via microvascular dysfunction, neurodegeneration, inflammation, advanced glycation end products (AGEs), arterial stiffness. / Steens, Indra L M; Schram, Miranda T; Houben, Alfons J H M et al.
In: Diabetes, Obesity & Metabolism, Vol. 27, No. 9, 09.2025, p. 4847-4858.

Research output: Contribution to journal › Article › Academic › peer-review

TY - JOUR

T1 - Type 2 diabetes and depression via microvascular dysfunction, neurodegeneration, inflammation, advanced glycation end products (AGEs), arterial stiffness

AU - Steens, Indra L M

AU - Schram, Miranda T

AU - Houben, Alfons J H M

AU - Berendschot, Tos T J M

AU - Koster, Annemarie

AU - Bosma, Hans

AU - Eussen, Simone J P M

AU - de Galan, Bastiaan E

AU - van Sloten, Thomas T

PY - 2025/9

Y1 - 2025/9

N2 - 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.

AB - 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.

KW - cardiovascular disease

KW - diabetes complications

KW - population study

KW - type 2 diabetes

UR - https://www.scopus.com/pages/publications/105008674427

U2 - 10.1111/dom.16527

DO - 10.1111/dom.16527

M3 - Article

C2 - 40536118

SN - 1462-8902

VL - 27

SP - 4847

EP - 4858

JO - Diabetes, Obesity & Metabolism

JF - Diabetes, Obesity & Metabolism

IS - 9

ER -

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

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