Glycation and Carboxymethyllysine Levels in Skin Collagen Predict the Risk of Future 10-Year Progression of Diabetic Retinopathy and Nephropathy in the Diabetes Control and Complications Trial and Epidemiology of Diabetes Interventions and Complications Participants With Type 1 Diabetes
Article Figures & Tables
Figures
- FIG. 1.
Distribution of skin collagens by retinopathy progression status. The mean and SD of each skin collagen parameter are compared in those participants whose retinopathy progressed (red bars) three or more steps on the Early Treatment of Diabetic Retinopathy Scale scale and/or required retinal photocoagulation between the end of the DCCT and year 10 of EDIC versus those whose retinopathy did not progress (▒). All values are adjusted for age and diabetes duration at the time of the biopsy.
- FIG. 2.
Risk of retinopathy progression by DCCT mean A1C and furosine. Shown is the risk of progression of retinopathy in the upper quartile of skin collagen furosine (>Q3) (blue bars) compared with the progression in the lower three quartiles of furosine (<Q3) (yellow bars). The comparison is made in the upper (>Q3) and lower three (<Q3) quartiles of A1C separately. *P value is from a between-group furosine (>Q3 vs. <Q3) comparison within each A1C (HBA1c) strata using the χ2 test. The greatest risk of progression occurs when both furosine and A1C are >Q3, but the dominance of furosine over A1C as a risk factor is evident.
- FIG. 3.
Distribution of skin collagens by nephropathy progression status. The mean and SD of each skin collagen parameter are compared in those participants who developed microalbuminuria or worse (red bars) between the end of the DCCT and EDIC year 9–10 versus those who did not develop microalbuminuria (▒). All values are adjusted for age and diabetes duration at the time of the biopsy.
Tables
- TABLE 1
DCCT baseline and close-out characteristics of participants versus nonparticipants active as of year 10 of the EDIC study
DCCT baseline Skin biopsy study Participants Nonparticipants P n 211 1,143 — DCCT baseline Age (years) 28 ± 7 27 ± 7 0.006 Women 48 48 0.979 Diabetes duration (years) 5.0 ± 4.1 5.7 ± 4.1 0.013 Stimulated C-peptide (pmol/ml) 0.12 ± 0.11 0.11 ± 0.12 0.376 Insulin dosage (units/kg) 0.63 ± 0.23 0.67 ± 0.25 0.008 A1C 8.8 ± 1.7 8.9 ± 1.6 0.922 Systolic blood pressure (mmHg) 116 ± 11 114 ± 12 0.011 Diastolic blood pressure (mmHg) 73 ± 9 72 ± 9 0.268 Triglycerides (mmol) (now in mg/dl) 81 ± 52 80 ± 47 0.825 HDL cholesterol (mmol) (now in mg/dl) 51 ± 12 50 ± 12 0.634 LDL cholesterol (mmol) (now in mg/dl) 111 ± 30 109 ± 29 0.409 No retinopathy (10/10) 57 49 — Microaneurisms only <(20/20) 25 32 — Mild nonproliferative diabetic retinopathy <(30/30) 10 10 — Moderate nonproliferative diabetic retinopathy <(45/45) 7 8 0.145 Albuminuria (mg/24 h) 15 ± 14 16 ± 20 0.225 Creatinine clearance (ml/min) 131 ± 32 128 ± 28 0.248 AER >40 mg/day 4.3 5.1 0.619 Presence of clinical neuropathy 8.1 5.8 0.201 DCCT close out (EDIC baseline) DCCT mean A1C 8.0 ± 1.6 8.2 ± 1.4 0.400 Systolic blood pressure (mmHg) 117 ± 11 116 ± 12 0.670 Diastolic blood pressure (mmHg) 75 ± 9 74 ± 9 0.192 Triglycerides (mmol) (now in mg/dl) 79 ± 42 87 ± 53 0.017 HDL cholesterol (mmol) (now in mg/dl) 51 ± 13 51 ± 13 0.944 LDL cholesterol (mmol) (now in mg/dl) 111 ± 29 114 ± 29 0.098 Severe nonproliferative diabetic retinopathy or worse (53/<53+) 1.9 5.5 0.032 Laser (focal or scatter) 2.8 5.5 0.105 Albuminuria (mg/24 h) 25 ± 102 49 ± 329 0.047 AER >40 mg/dl 9.5 9.8 0.877 Data are means ± SD or percent.
- TABLE 2
Univariate analysis of risk factors versus retinopathy and nephropathy outcome
Characteristics Three or more–step ETDRS progression or scatter laser therapy from DCCT close out through EDIC study year 10 Development of microalbuminuria or worse from DCCT close out through EDIC study year 9–10 Event Nonevent P value Event Nonevent P value n 67 117 — 34 151 — Demographics Age at EDIC study baseline 34.4 ± 6.8 34.0 ± 6.5 0.7777 34.1 ± 6.3 34.6 ± 6.6 0.5883 Women (%) 55.2 45.3 0.1950 55.9 47.7 0.3875 Diabetes duration at EDIC study baseline (years) 11.3 ± 4.4 11.0 ± 5.0 0.3679 10.5 ± 4.0 11.0 ± 4.8 0.7269 DCCT treatment group Intensive (%) 41.8 65.0 0.0023 52.9 58.3 0.5698 Glycemic control DCCT mean A1C (%) 9.0 ± 1.7 7.6 ± 1.2 <0.0001 8.8 ± 1.6 7.8 ± 1.4 0.0005 EDIC study mean A1C up to EDIC study year 10 (%) 8.8 ± 1.4 7.7 ± 0.9 <0.0001 — — — EDIC study mean A1C up to EDIC study year 9–10 (%) — — — 9.2 ± 1.3 7.8 ± 1.1 <0.0001 Medical at EDIC baseline Mean blood pressure (mmHg) 90.7 ± 9.3 88.1 ± 8.0 0.1174 92.6 ± 8.4 88.0 ± 8.2 0.0089 Hypertension ever (%) 14.9 7.7 0.1208 25.3 7.3 0.0048 Triglycerides (mmol) (now in mg/dl) 81.0 ± 44.0 76.6 ± 43.3 0.6882 86.6 ± 45.4 73.9 ± 39.1 0.1165 HDL cholesterol (mmol) (now in mg/dl) 53.0 ± 14.2 51.2 ± 12.2 0.4670 51.8 ± 12.4 51.6 ± 12.9 0.9218 LDL cholesterol (mmol) (now in mg/dl) 112 ± 29 108 ± 29 0.3577 116 ± 30 108 ± 28 0.0856 Overweight (%) 35.8 35.0 0.9154 38.2 37.1 0.9004 Smoker at DCCT close out (%) 26.9 15.4 0.0589 23.5 17.2 0.3907 Retinopathy at EDIC study baseline No retinopathy (10/10) (%) 25.4 30.8 — 17.7 33.1 — Microaneurisms only <(20/20) (%) 29.9 41.0 — 38.2 39.1 — Mild to moderate nonproliferative diabetic retinopathy or worse (35/<35+) (%) 44.8 28.2 0.0711 44.1 27.8 0.1007 Renal at EDIC baseline Albuminuria (mg/24 h) 44.7 ± 166 11.7 ± 21.1 0.0002 13.6 ± 9.4 8.3 ± 5.1 0.0014 AER ≥40 (%) 17.9 4.3 0.0023 — — — Neuropathy at EDIC baseline (%) 16.4 4.3 0.0052 14.7 8.7 0.2845 Skin collagens at EDIC study baseline (pmol/mg collagen) Furosine 924 ± 253 669 ± 172 <0.0001 878 ± 242 717 ± 205 0.0001 CML 607 ± 134 501 (120) <0.0001 596 ± 126 514 ± 129 0.0007 Pentosidine 29.0 ± 8.2 24.3 ± 6.9 <0.0001 8.6 24.7 ± 6.8 0.0003 Fluorescence 197 ± 40 176 ± 37 0.0002 201 ± 45 181 ± 50 0.0033 Acid-soluble collagen (%) 0.6 ± 0.4 0.5 ± 0.3 0.1325 0.6 ± 0.4 0.6 ± 0.3 0.1599 Pepsin-soluble collagen (%) 5.9 ± 3.9 7.3 ± 3.0 <0.0001 6.0 ± 2.8 7.1 ± 3.4 0.0187 Data are means ± SD or percent, unless otherwise indicated. ETDRS, Early Treatment of Diabetic Retinopathy Scale. Values in bold indicate P < 0.05.
- TABLE 3
Summary of multiple multivariate logistic regressions for retinopathy
Covariate effects from multiple models df χ2 P value R2 Unadjusted effect DCCT mean A1C 1 34.3 <0.0001 0.142 EDIC study mean A1C 1 40.5 <0.0001 0.168 Furosine, CML, pentosidine, fluorescence, acid/pepsin soluble 6 62.2 <0.0001 0.258 Pentosidine, fluorescence, acid/pepsin soluble 4 21.8 0.0002 0.090 Furosine, CML 2 59.4 <0.0001 0.246 Furosine 1 52.2 <0.0001 0.216 CML 1 27.7 <0.0001 0.115 Adjusted effect DCCT mean A1C effect adjusted for Furosine, CML 1 0.0 0.9874 0.000 Furosine 1 0.4 0.5430 0.001 CML 1 17.4 <0.0001 0.072 EDIC study mean A1C effect adjusted for Furosine, CML 1 26.0 <0.0001 0.108 Furosine 1 24.6 <0.0001 0.102 CML 1 43.4 <0.0001 0.180 Furosine, CML effect adjusted for Pentosidine, fluorescence, acid/pepsin soluble 2 46.3 <0.0001 0.192 DCCT mean A1C 2 32.7 <0.0001 0.136 EDIC study mean A1C 2 45.9 <0.0001 0.190 Pentosidine, fluorescence, acid/pepsin soluble effect adjusted for Furosine, CML 4 4.8 0.3034 0.020 Furosine effect adjusted for DCCT mean A1C 1 22.2 <0.0001 0.092 EDIC study mean A1C 1 33.5 <0.0001 0.139 CML effect adjusted for DCCT mean A1C 1 14.4 <0.0001 0.061 EDIC study mean A1C 1 27.6 <0.0001 0.114 Dependent variable: three or more–step progression of retinopathy on the Early Treatment of Diabetic Retinopathy Scale or scatter laser therapy from DCCT close out through EDIC study year 10. As defined in the statistical methods section, χ2 and P values are from likelihood ratio test, and R2 is entropy R2.
- TABLE 4
Summary of multiple multivariate logistic regressions for nephropathy
Covariate effects from multiple models df χ2 P value R2 Unadjusted effect DCCT mean A1C 1 10.4 0.0012 0.062 EDIC study mean A1C 1 32.0 <0.0001 0.189 Log DCCT close-out AER 1 13.6 0.0002 0.081 Furosine, CML, pentosidine, fluorescence, acid/pepsin soluble 6 19.3 0.0036 0.114 Pentosidine, fluorescence, acid/pepsin soluble 4 12.6 0.0135 0.075 Furosine, CML 2 18.2 0.0001 0.108 Furosine 1 13.4 0.0002 0.080 CML 1 10.2 0.0014 0.060 Adjusted effect DCCT mean A1C effect adjusted for Furosine, CML 1 0.0 0.9643 0.000 Furosine 1 0.2 0.6413 0.001 CML 1 4.8 0.0278 0.029 DCCT mean A1C, log AER effect adjusted for Furosine, CML 2 10.8 0.0046 0.064 EDIC study mean A1C effect adjusted for Furosine, CML 1 23.1 <0.0001 0.137 Furosine 1 21.8 <0.0001 0.129 CML 1 26.0 <0.0001 0.154 Furosine, CML effect adjusted for Pentosidine, fluorescence, acid/pepsin soluble 2 11.0 0.0041 0.065 DCCT mean A1C, log AER 2 13.1 0.0014 0.078 DCCT mean A1C 2 12.8 0.0016 0.076 EDIC study mean A1C 2 14.4 0.0008 0.085 Pentosidine, fluorescence, acid/pepsin soluble effect adjusted for Furosine, CML 4 4.5 0.3394 0.027 Furosine effect adjusted for DCCT mean A1C 1 7.1 0.0079 0.042 EDIC study mean A1C 1 7.1 0.0076 0.042 CML effect adjusted for DCCT mean A1C 1 6.3 0.0123 0.037 EDIC study mean A1C 1 10.7 0.0011 0.064 Dependent variable: development of microalbuminuria or worse from DCCT close out through EDIC study year 10. As defined in the statistical methods section, χ2 and P values are from likelihood ratio test, and R2 is entropy R2.
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