(Pre)diabetes, glycemia, and daily glucose variability are associated with retinal nerve fiber layer thickness in The Maastricht Study

Abstract

Retinopathy and neuropathy in type 2 diabetes are preceded by retinal nerve fibre layer (RNFL) thinning, an index of neurodegeneration. We investigated whether glucose metabolism status (GMS), measures of glycaemia, and daily glucose variability (GV) are associated with RNFL thickness over the entire range of glucose tolerance. We used cross-sectional data from The Maastricht Study (up to 5455 participants, 48.9% men, mean age 59.5 years and 22.7% with type 2 diabetes) to investigate the associations of GMS, measures of glycaemia (fasting plasma glucose [FPG], 2-h post-load glucose [2-h PG], HbA1c, advanced glycation endproducts [AGEs] assessed as skin autofluorescence [SAF]) and indices of daily GV (incremental glucose peak [IGP] and continuous glucose monitoring [CGM]-assessed standard deviation [SD]) with mean RNFL thickness. We used linear regression analyses and, for GMS, P for trend analyses. We adjusted associations for demographic, cardiovascular risk and lifestyle factors, and, only for measures of GV, for indices of mean glycaemia. After full adjustment, type 2 diabetes and prediabetes (versus normal glucose metabolism) were associated with lower RNFL thickness (standardized beta [95% CI], respectively − 0.16 [− 0.25; − 0.08]; − 0.05 [− 0.13; 0.03]; Ptrend = 0.001). Greater FPG, 2-h PG, HbA1c, SAF, IGP, but not CGM-assessed SD, were also associated with lower RNFL thickness (per SD, respectively − 0.05 [− 0.08; − 0.01]; − 0.06 [− 0.09; − 0.02]; − 0.05 [− 0.08; − 0.02]; − 0.04 [− 0.07; − 0.01]; − 0.06 [− 0.12; − 0.01]; and − 0.07 [− 0.21; 0.07]). In this population-based study, a more adverse GMS and, over the entire range of glucose tolerance, greater glycaemia and daily GV were associated with lower RNFL thickness. Hence, early identification of individuals with hyperglycaemia, early glucose-lowering treatment, and early monitoring of daily GV may contribute to the prevention of RNFL thinning, an index of neurodegeneration and precursor of retinopathy and neuropathy.

Thinner inner retinal layers are associated with lower cognitive performance, lower brain volume, and altered white matter network structure—The Maastricht Study

“…In particular, retinal thicknesses were also associated with hippocampal volume, which is an important clinical measure that can be used to assess neurodegeneration as part of the amyloid beta, tau, and neurodegeneration (ATN) classification framework proposed by the National Institute on Aging and Alzheimer's Association (NIA‐AA) 44 . Also in support of this concept, we additionally found that retinal neurodegeneration and cerebral neurodegeneration have shared risk factors 45,46 . We recently showed in The Maastricht Study, using data from up to ∼5600 individuals, that most risk factors for dementia, including hyperglycemia and hypertension, were associated with retinal neurodegeneration, as quantified from lower RNFL thickness and worse retinal sensitivity 45,46 .…”

“… 44 Also in support of this concept, we additionally found that retinal neurodegeneration and cerebral neurodegeneration have shared risk factors. 45 , 46 We recently showed in The Maastricht Study, using data from up to ∼5600 individuals, that most risk factors for dementia, including hyperglycemia and hypertension, were associated with retinal neurodegeneration, as quantified from lower RNFL thickness and worse retinal sensitivity. 45 , 46 Of note, however, as we found relatively weak associations of retinal neuronal variables with brain variables, retinal neuronal imaging biomarkers may by themselves (as singular biomarkers) not be sufficiently informative to use in a clinical care setting.…”

“… 45 , 46 We recently showed in The Maastricht Study, using data from up to ∼5600 individuals, that most risk factors for dementia, including hyperglycemia and hypertension, were associated with retinal neurodegeneration, as quantified from lower RNFL thickness and worse retinal sensitivity. 45 , 46 Of note, however, as we found relatively weak associations of retinal neuronal variables with brain variables, retinal neuronal imaging biomarkers may by themselves (as singular biomarkers) not be sufficiently informative to use in a clinical care setting. Future studies should aim to evaluate the added value of retinal imaging biomarkers on top of (a combination of) other non‐invasive and scalable biomarkers for dementia (such as blood‐based biomarkers for amyloid beta and tau in Alzheimer's disease).…”

(Pre)diabetes and a higher level of glycaemic measures are continuously associated with corneal neurodegeneration assessed by corneal confocal microscopy: the Maastricht Study

“…linear) process that starts before the onset of type 2 diabetes [ 3 , 4 ]. Indeed, we have previously demonstrated linear associations of adverse glucose metabolism status and higher levels of glycaemic measures with lower retinal nerve fibre layer thickness [ 5 ], more brain structural abnormalities [ 6 , 7 ], worse peripheral nerve function [ 8 ] and lower heart rate variability [ 9 ], which are all measures of neurodegeneration and/or neural dysfunction. Additionally, chronic hyperglycaemia accelerates the formation of advanced glycation end-products (AGEs), which are considered a major initiator of neurodegeneration [ 10 ].…”

“…AGEs are protein-bound compounds that exhibit intrinsic fluorescence properties, which can be measured non-invasively as skin autofluorescence (SAF) [ 11 ]. We have shown previously that AGEs assessed as SAF are associated with lower retinal nerve fibre layer thickness [ 5 ].…”