Abstract
BACKGROUND: Whether gradations in glycemia across non-diabetes, prediabetes, and diabetes relate to tear-film homeostasis and dry eye disease (DED) remains uncertain, and explicitgraded association evidence is limited. METHODS: In a single-center cross-sectional study (April 2024-March 2025), we enrolled 300 adults by quota (n = 100 per stratum). Same-day hemoglobin A1c (HbA1c) and fasting plasma glucose (FPG) classified strata and were also modeled continuously. Co-primary outcomes were non-invasive tear break-up time (NIBUT) and Schirmer I (no anesthesia). Secondary outcomes included fluorescein tear break-up time (TBUT), ocular surface disease index (OSDI), National Eye Institute (NEI) staining, meiboscore, tear meniscus height, bulbar redness, tear osmolarity, and matrix metalloproteinase-9 (MMP-9). DED was defined as OSDI ≥13 plus ≥1 sign [NIBUT <10 s, osmolarity ≥308 mOsm/L or intereye difference ≥8 mOsm/L, or NEI staining score ≥2 (beyond trace)]. Multivariable analysis of covariance (ANCOVA) and logistic regression adjusted for prespecified demographic, clinical, and environmental covariates. Restricted cubic splines tested non-linearity, and Benjamini-Hochberg false discovery rate (FDR) controlled multiplicity for secondary endpoints. RESULTS: Mean NIBUT was 11.8, 10.5, and 9.2 s, and Schirmer I was 13.8, 12.1, and 10.4 mm across non-diabetes, prediabetes, and diabetes (both p-trend < 0.001). Adjusted differences versus non-diabetes were -1.20 and -2.50 s for NIBUT and -1.60 and -3.10 mm for Schirmer (all p ≤ 0.006). Per 1% higher HbA1c, NIBUT decreased by 0.72 s and Schirmer by 1.15 mm, and DED odds increased (aOR 1.31; all p < 0.001) with no significant non-linearity. DED proportion within strata was 24.0%, 34.0%, and 51.0% (prediabetes aOR 1.60, p = 0.049; diabetes aOR 2.90, p = 0.001). Osmolarity abnormality and MMP-9 positivity rose across strata and with HbA1c, remaining significant after FDR control. Using FPG instead of HbA1c yielded concordant effects. CONCLUSIONS: Higher glycemic status, including prediabetes, was associated with shorter NIBUT, lower Schirmer, and higher odds of DED and inflammatory signs, although the absolute between-stratum differences were modest in magnitude. Longitudinal studies are needed to assess the temporality and the practical relevance of these cross-sectional associations.