(Pre)diabetes, higher levels of glucose variability, and glycemia are continuously associated with corneal neurodegeneration – The Maastricht Study

Abstract

Purpose : Neurodegeneration is a hallmark complication of type 2 diabetes (T2D). In the cornea, early morphological changes of nerve fibers are demonstrable using corneal confocal microscopy. We aim to assess the association of glucose metabolism status (GMS), indices of glucose variability, and continuous measures of glycemia with corneal nerve measures.

Methods : Population-based cross-sectional data from The Maastricht Study of N=3,471 participants (mean age 59.4 years, 48.4% men, 14.7% with prediabetes, and 21% with T2D). We used linear regression analyses to study the associations, after adjustment for demographic, and cardiovascular risk factors, between GMS n=3,471 (prediabetes, and T2D vs normal GMS), indices of glucose variability (incremental glucose peak n=1,201, and continuous glucose monitoring n=509), and continuous measures of glycemia (fasting plasma glucose n=3,470, 2-hour post-load glucose n=3,328, HbA_1c n=3,468, skin autofluorescence n=3,254, and duration of T2D n=574) with a composite Z-score of corneal nerve fiber measures, and with individual corneal nerve measures (corneal nerve branch density, fiber density, fiber length, and fractal dimension). We used P for trend analyses for GMS.

Results : After full adjustment, a more adverse GMS was associated with a lower composite Z-score of corneal nerve measures (beta [95%CI], prediabetes vs normal GMS -0.08 [-0.17; 0.03]; T2D vs normal GMS status -0.14 [-0.25; -0.04]; P for trend = 0.001). Analogously, higher levels of incremental glucose peak per SD, -0.04 [-0.12; 0.05], continuous glucose monitoring-assessed SD per SD, -0.09 [-0.24; 0.06], fasting plasma glucose per SD, -0.09 [-0.13; -0.05], 2-hour post-load glucose -0.07 [-0.11; -0.03], HbA_1c -0.08 [-0.11; -0.04], skin autofluorescence -0.05 [-0.08; -0.01], and duration of T2D -0.09 [-0.17; -0.00] were all associated with a lower composite Z-score of corneal nerve measures. In general, directionally similar associations were observed for individual corneal nerve measures.

Conclusions : This is the first population-based study to show that a more adverse GMS and higher levels of glucose variability and measures of glycemia are linearly and independently associated with corneal neurodegeneration; these data suggest that glycemia-associated corneal neurodegeneration is a continuous process that already starts before the onset of T2D.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.