Figures (1)  Tables (4)

    • Figure 1. 

      Nonlinear curve of changes in retinal sublayer thickness with T2D progression and risk. (a) Changes in retinal sublayer thickness with the development of diabetic over time based on restricted cubic spline (RCS). (b) Risk of T2D along with the change in retinal thickness, based on the RCS curve.

    • Healthy Pre-T2D T2D without any complications T2D and microvascular complications T2D and macrovascular and microvascular
      complications      		 p-Value
      n = 18,019 n = 3,415 n = 1,043 n = 283 n = 302
      Age 54.0 (47.0–61.0) 60.0 (54.0–64.0) 60.0 (54.0–64.0) 63.0 (56.0–66.0) 62.5 (58.2–66.0) < 0.001
      Sex < 0.001
      Female 9,968 (55.3%) 1,899 (55.6%) 444 (42.6%) 121 (42.8%) 75 (24.8%)
      Male 8,051 (44.7%) 1,516 (44.4%) 599 (57.4%) 162 (57.2%) 227 (75.2%)
      Education level < 0.001
      College/university 7,047 (39.1%) 1,046 (30.6%) 296 (28.4%) 58 (20.5%) 60 (19.9%)
      Other 10,972 (60.9%) 2,369 (69.4%) 747 (71.6%) 225 (79.5%) 242 (80.1%)
      Race < 0.001
      Other 1,233 (6.84%) 581 (17.0%) 196 (18.8%) 54 (19.1%) 51 (16.9%)
      White 16,786 (93.2%) 2,834 (83.0%) 847 (81.2%) 229 (80.9%) 251 (83.1%)
      Smoking status < 0.001
      Never 10,419 (58.1%) 1,807 (53.4%) 507 (49.0%) 129 (46.4%) 100 (33.1%)
      Previous/current 7,502 (41.9%) 1,575 (46.6%) 527 (51.0%) 149 (53.6%) 202 (66.9%)
      Drinking status < 0.001
      Never 664 (3.70%) 232 (6.84%) 73 (7.03%) 32 (11.4%) 33 (10.9%)
      Previous/current 17,293 (96.3%) 3,158 (93.2%) 966 (93.0%) 249 (88.6%) 269 (89.1%)
      Health status < 0.001
      Worse 14,716 (82.1%) 2,390 (70.9%) 531 (51.4%) 105 (37.4%) 94 (31.1%)
      Better 3,209 (17.9%) 981 (29.1%) 503 (48.6%) 176 (62.6%) 208 (68.9%)
      Physical activity level < 0.001
      High 6,663 (37.0%) 1,104 (32.3%) 281 (26.9%) 62 (21.9%) 85 (28.1%)
      Low 2,272 (12.6%) 520 (15.2%) 190 (18.2%) 66 (23.3%) 63 (20.9%)
      Moderate 6,160 (34.2%) 1,084 (31.7%) 361 (34.6%) 89 (31.4%) 90 (29.8%)
      Townsend index −1.80 (−3.41 to 0.71) −1.56 (−3.30 to 1.25) −1.04 (−3.23 to 1.80) −0.55 (−2.79 to 2.22) −1.08 (−3.16 to 2.37) < 0.001
      BMI 25.8 (23.4–28.5) 28.0 (25.2–31.4) 29.6 (26.8–33.7) 31.4 (28.1–36.0) 30.4 (27.5–33.7) 0.000
      Hypertension history < 0.001
      No 6,634 (36.8%) 665 (19.5%) 123 (11.8%) 24 (8.48%) 39 (12.9%)
      Yes 11,385 (63.2%) 2,750 (80.5%) 920 (88.2%) 259 (91.5%) 263 (87.1%)
      Hyperlipidemia history < 0.001
      No 12,107 (67.2%) 1,569 (45.9%) 351 (33.7%) 65 (23.0%) 25 (8.28%)
      Yes 5,912 (32.8%) 1,846 (54.1%) 692 (66.3%) 218 (77.0%) 277 (91.7%)
      Calcium 2.38 (2.33–2.44) 2.39 (2.33–2.45) 2.40 (2.34–2.46) 2.39 (2.34–2.48) 2.39 (2.33–2.46) < 0.001
      Urate 289 (240–344) 317 (267–372) 322 (267–376) 351 (301–412) 331 (286–390) < 0.001
      Data are the mean ± standard deviation, or numbers (%). Analysis of variance was used to test the difference of continuous variables across subgroups of T2D and χ2 for categorical variables.

      Table 1. 

      Baseline characteristics of participants according to the progression of T2D.

    • Model 1 Model 2
      OR 95% CI p-Value FDR-adjusted p-Value OR 95% CI p-Value FDR-adjusted p-Value
      RNFL (μm) 0.967 0.960–0.974 < 0.001 0.001 0.982 0.973–0.992 < 0.001 0.003
      GCL-IPL (μm) 0.986 0.980–0.991 < 0.001 0.001 0.992 0.985–1.000 0.041 0.082
      INL (μm) 0.985 0.971–1.000 0.044 0.044 0.984 0.967–1.002 0.089 0.133
      ISOS-RPE (μm) 0.960 0.952–0.968 < 0.001 0.001 0.980 0.969–0.990 < 0.001 0.003
      ELM-ISOS (μm) 0.917 0.896–0.939 < 0.001 0.001 0.976 0.948–1.005 0.1 0.133
      RPE (μm) 1.021 1.010–1.034 < 0.001 0.001 1.005 0.990–1.020 0.51 0.510
      Overall macular thickness (μm) 0.983 0.981–0.986 < 0.001 0.001 0.992 0.989–0.995 < 0.001 0.003
      Macular volume (mm3) 0.682 0.585–0.795 < 0.001 0.001 0.889 0.738–1.071 0.216 0.247
      Model 1 was adjusted for age and gender. Model 2 was adjusted for age, gender, education level, ethnicity, smoking status, drinking status, health status, physical activity level, Townsend index, BMI, hypertension, hyperlipidemia, blood calcium, and blood uric acid. FDR-adjusted p-value: False discovery rate-adjusted p-value calculated using the Benjamini–Hochberg procedure. Bold values indicate statistical significance (p < 0.05).

      Table 2. 

      Changes in retinal sublayer thickness with T2D progression.

    • Model 1 Model 2
      OR 95% CI p-Value FDR-adjusted p-Value OR 95% CI p-Value FDR-adjusted p-Value
      Healthy vs. Pre-T2D
      RNFL (μm) 0.980 0.997–0.990 < 0.001 0.001 0.990 0.980–0.998 0.045 0.120
      GCL-IPL (μm) 0.996 0.990–1.003 0.266 0.266 1.001 0.993–1.010 0.782 0.791
      INL (μm) 0.993 0.980–1.010 0.432 0.432 0.997 0.976–1.018 0.791 0.791
      ISOS-RPE (μm) 0.970 0.966–0.983 < 0.001 0.001 0.991 0.979–1.003 0.134 0.268
      ELM-ISOS (μm) 0.917 0.891–0.943 < 0.001 0.001 0.961 0.930–0.994 0.020 0.080
      RPE (μm) 1.026 1.012–1.040 < 0.001 0.001 1.009 0.992–1.026 0.28 0.448
      Overall macular thickness (μm) 0.989 0.986–0.992 < 0.001 0.001 0.996 0.992–0.999 0.016 0.080
      Macular volume (mm3) 0.721 0.616–0.844 < 0.001 0.001 0.916 0.756–1.110 0.37 0.493
      Pre-T2D vs. T2D without any complications
      RNFL (μm) 0.955 0.941–0.970 < 0.001 0.001 0.972 0.952–0.992 0.005 0.019
      GCL-IPL (μm) 0.973 0.963–0.985 < 0.001 0.001 0.979 0.965–0.994 0.007 0.019
      INL (μm) 0.970 0.944–0.998 0.036 0.048 0.955 0.920–0.991 0.015 0.024
      ISOS-RPE (μm) 0.951 0.938–0.965 < 0.001 0.001 0.975 0.955–0.995 0.013 0.024
      ELM-ISOS (μm) 0.918 0.875–0.962 < 0.001 0.001 0.960 0.906–1.018 0.173 0.198
      RPE (μm) 1.024 1.001–1.048 0.038 0.048 1.008 0.978–1.039 0.588 0.588
      Overall macular thickness (μm) 0.976 0.972–0.981 < 0.001 0.001 0.984 0.978–0.990 < 0.001 0.008
      Macular volume (mm3) 0.358 0.197–0.651 0.001 0.002 0.451 0.219–0.931 0.031 0.041
      T2D without any complications vs. T2D with microvascular complications
      RNFL (μm) 0.949 0.922–0.977 < 0.001 0.001 0.963 0.938–1.051 0.057 0.080
      GCL-IPL (μm) 0.962 0.942–0.983 < 0.001 0.001 0.961 0.960–0.963 0.007 0.016
      INL (μm) 0.969 0.919–1.022 0.255 0.340 0.992 0.928–1.137 0.031 0.054
      ISOS-RPE (μm) 0.928 0.907–0.949 < 0.001 0.001 0.929 0.899–0.985 < 0.001 0.004
      ELM-ISOS (μm) 0.915 0.837–0.999 0.048 0.096 1.004 0.799–1.085 0.936 0.936
      RPE (μm) 1.012 0.968–1.058 0.599 0.599 0.997 0.868–1.038 0.919 0.936
      Overall macular thickness (μm) 0.969 0.960–0.977 < 0.001 0.001 0.970 0.956–0.990 < 0.001 0.004
      Macular volume (mm3) 0.145 0.021–1.025 0.053 0.096 NA – – –
      T2D with microvascular complications vs. T2D with microvascular and macrovascular complications
      RNFL (μm) 0.932 0.907–0.959 < 0.001 0.001 0.970 0.933–1.009 0.128 0.205
      GCL-IPL (μm) 0.966 0.946–0.985 0.001 0.002 0.970 0.943–0.998 0.035 0.093
      INL (μm) 0.982 0.933–1.034 0.480 0.48 0.943 0.878–1.012 0.104 0.205
      ISOS-RPE (μm) 0.946 0.923–0.970 < 0.001 0.001 0.955 0.918–0.994 0.025 0.093
      ELM-ISOS (μm) 0.901 0.826–0.982 0.017 0.023 0.976 0.872–1.093 0.676 0.676
      RPE (μm) 0.969 0.926–1.013 0.19 0.217 0.982 0.922–1.047 0.585 0.669
      overall macular thickness (μm) 0.973 0.965–0.982 < 0.001 0.001 0.982 0.970–0.995 0.005 0.040
      Macular volume (mm3)l 0.592 0.179–1.953 0.389 0.389 0.654 0.150–2.841 0.571 0.669
      Model 1 was adjusted for age and gender. Model 2 was adjusted for age, gender, education level, ethnicity, smoking status, drinking status, health status, physical activity level, townsend index, BMI, hypertension, hyperlipidemia, blood calcium, and blood uric acid. FDR-adjusted p-value: False discovery rate-adjusted p-value calculated using the Benjamini–Hochberg procedure. Bold values indicate statistical significance (p < 0.05).

      Table 3. 

      Comparison of retinal sublayer thickness results between different T2D stages.

    • Outcome cutoff
      Stage threshold      		 Model 1 (baseline) Model 2 (+ glucose) Model 3 (+ glucose + retinal sublayer thickness metrics including RNFL, ISOS-RPE, and overall macular thickness)
      AUC (95% CI) AUC (95% CI) p-Value (vs. Model 1) AUC (95% CI) p-Value (vs. Model 2)
      Stage ≥ 1 0.739 (0.731–0.748) 0.771 (0.763–0.779) < 0.001 0.776 (0.768–0.784) < 0.001
      Stage ≥ 2 0.783 (0.770–0.796) 0.853 (0.840–0.866) < 0.001 0.859 (0.847–0.871) < 0.001
      Stage ≥ 3 0.831 (0.815–0.847) 0.866 (0.851–0.881) < 0.001 0.872 (0.858–0.887) 0.006
      Stage ≥ 4 0.835 (0.814–0.856) 0.860 (0.840–0.880) < 0.001 0.864 (0.844–0.884) 0.105
      Model 1 (baseline): Adjusted for age, sex, and BMI. Model 2 (clinical): Model 1 + blood glucose levels. Model 3 (combined): Model 2 + OCT-derived retinal sublayer thickness metrics (RNFL, ISOS-RPE, and overall macular thickness) Outcome definitions: The outcome cutoffs represent binary classification tasks at progressively severe thresholds: Stage ≥ 1 distinguishes individuals with any glucose abnormality (Stages 1–4) from healthy controls (Stage 0). Stage ≥ 2 distinguishes individuals with diagnosed T2D (Stages 2–4) from nondiabetic individuals (Stages 0–1). Stage ≥ 3 distinguishes T2D patients with complications (Stages 3–4) from those without complications or diabetes (Stages 0–2). Stage ≥ 4 distinguishes T2D patients with macrovascular events (Stage 4) from all other groups (Stages 0–3). p-values compare the predictive performance between models using the DeLong test for correlated ROC curves. p-values (vs. Model 1) indicate the improvement achieved by adding glucose to the base model; p-values (vs. Model 2) indicates the incremental value of adding OCT metrics to the clinical model. Bold values indicate statistical significance (p < 0.05).

      Table 4. 

      Incremental predictive value of retinal sublayer thickness added to clinical models for discriminating the progression of T2D stages.