Sex-specific differences in nonlinear associations between glycaemia and brain health in UK Biobank

Overview

1. Unit for Lifelong Health and Ageing at UCL, London, UK
2. Nuffield Department of Population Health, University of Oxford, Oxford, UK
3. Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, UK

Abstract

Aims: Diabetes and hyperglycaemia are associated with poorer brain health, but most studies focus on diagnosed diabetes and rarely examine non-linear or sex-specific associations between glycaemia and neuroimaging biomarkers. We investigated whether glycaemia shows non-linear associations with brain structure and whether these differ by sex.

Methods: In 36,321 UK Biobank participants, sex-stratified fractional polynomial models assessed associations of random glucose and HbA1c with brain MRI volumes, adjusted for covariates. Restricted cubic splines and range-restricted linear models assessed robustness and estimated sex-specific slopes.

Results: Associations of glycaemia with whole brain and grey matter volumes were inverted J-shaped in both sexes, with lower volumes at higher glycaemia and less consistent evidence of lower volumes at the lower end. Predicted whole brain volume peaked at glucose values between 4.4 and 4.7 mmol/L and HbA1c values between 33 and 37 mmol/mol.

Restricted cubic splines confirmed non-linearity for glucose with whole brain volume (p_non-linearity=0.006) and grey matter (p_non-linearity<0.001), with evidence of sex interaction (p_interaction=0.02–0.03). For HbA1c, splines supported non-linearity for whole brain volume (p_non-linearity=0.006) and grey and white matter volumes (both p_non-linearity<0.001), with little evidence of sex interaction (p_interaction≥0.4). White matter hyperintensity volume showed a J-shaped association for HbA1c (p_non-linearity=0.002), with no evidence of sex interaction. Linear models in the descending range indicated steeper glucose-associated declines in whole brain and grey matter volumes in females than males.

Conclusions: Glycaemia–brain imaging associations were non-linear. Higher glycaemia was associated with less favourable brain structural profiles, with stronger associations for glucose in females. These findings indicate that associations between glycaemia and brain structure extend across the glycaemic spectrum rather than being limited to clinically defined diabetic states.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

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Code availability

The statistical code used for the analyses will be made available on GitHub upon publication.

Ethics approval UK Biobank has approval from the North West Multi-centre Research Ethics Committee (REC reference 11/NW/0382), and all participants provided written informed consent. This research was conducted under UK Biobank Application Number 7661.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

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Data availability

This research was conducted using the UK Biobank Resource under Application Number 7661. UK Biobank data are available to bona fide researchers through application via the UK Biobank Access Management System (www.ukbiobank.ac.uk).

Individual-level data cannot be shared by the authors but can be accessed directly through UK Biobank upon approval. No new primary participant data were collected for this analysis.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 1, 30 September 2026: the first record

Recorded: type, journal, dates, 5 authors, 10 keywords, 2 funders, 26 references.

Cite

This paper

Fatih, N., James, S.-N., Chaturvedi, N., Hughes, A. D., & Garfield, V. (2026). Sex-specific differences in nonlinear associations between glycaemia and brain health in UK Biobank. medRxiv (preprint). https://doi.org/10.64898/2026.03.12.26348052

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