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Complications

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

  1. Saul Genuth1,
  2. Wanjie Sun2,
  3. Patricia Cleary2,
  4. David R. Sell3,
  5. William Dahms4,
  6. John Malone5,
  7. William Sivitz6,
  8. Vincent M. Monnier3,7 and
  9. for the DCCT Skin Collagen Ancillary Study Group*
  1. 1Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio
  2. 2Biostatistics Center, George Washington University, Rockville, Maryland
  3. 3Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio
  4. 4Department of Pediatrics, Rainbow Babies and Children’s Hospital and University Hospitals of Cleveland, Cleveland, Ohio
  5. 5Department of Pediatrics, University of South Florida, Tampa, Florida
  6. 6Department of Medicine, Veterans Administration Hospital, University of Iowa, Iowa City, Iowa
  7. 7Department of Biochemistry, Case Western Reserve University School of Medicine, Cleveland, Ohio
  1. Address correspondence and reprint requests to Saul Genuth, MD, Case Western Reserve University, Cleveland, OH 44106. E-mail: smg15{at}cwru.edu
Diabetes 2005 Nov; 54(11): 3103-3111. https://doi.org/10.2337/diabetes.54.11.3103
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  • FIG. 1.
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    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.
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    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.
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    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

  • Figures
  • TABLE 1

    DCCT baseline and close-out characteristics of participants versus nonparticipants active as of year 10 of the EDIC study

    DCCT baselineSkin biopsy study
    ParticipantsNonparticipantsP
    n2111,143—
    DCCT baseline
        Age (years)28 ± 727 ± 70.006
        Women48480.979
        Diabetes duration (years)5.0 ± 4.15.7 ± 4.10.013
        Stimulated C-peptide (pmol/ml)0.12 ± 0.110.11 ± 0.120.376
        Insulin dosage (units/kg)0.63 ± 0.230.67 ± 0.250.008
        A1C8.8 ± 1.78.9 ± 1.60.922
        Systolic blood pressure (mmHg)116 ± 11114 ± 120.011
        Diastolic blood pressure (mmHg)73 ± 972 ± 90.268
        Triglycerides (mmol) (now in mg/dl)81 ± 5280 ± 470.825
        HDL cholesterol (mmol) (now in mg/dl)51 ± 1250 ± 120.634
        LDL cholesterol (mmol) (now in mg/dl)111 ± 30109 ± 290.409
        No retinopathy (10/10)5749—
        Microaneurisms only <(20/20)2532—
        Mild nonproliferative diabetic retinopathy <(30/30)1010—
        Moderate nonproliferative diabetic retinopathy <(45/45)780.145
        Albuminuria (mg/24 h)15 ± 1416 ± 200.225
        Creatinine clearance (ml/min)131 ± 32128 ± 280.248
        AER >40 mg/day4.35.10.619
        Presence of clinical neuropathy8.15.80.201
    DCCT close out (EDIC baseline)
        DCCT mean A1C8.0 ± 1.68.2 ± 1.40.400
        Systolic blood pressure (mmHg)117 ± 11116 ± 120.670
        Diastolic blood pressure (mmHg)75 ± 974 ± 90.192
        Triglycerides (mmol) (now in mg/dl)79 ± 4287 ± 530.017
        HDL cholesterol (mmol) (now in mg/dl)51 ± 1351 ± 130.944
        LDL cholesterol (mmol) (now in mg/dl)111 ± 29114 ± 290.098
        Severe nonproliferative diabetic retinopathy or worse (53/<53+)1.95.50.032
        Laser (focal or scatter)2.85.50.105
        Albuminuria (mg/24 h)25 ± 10249 ± 3290.047
        AER >40 mg/dl9.59.80.877
    • Data are means ± SD or percent.

  • TABLE 2

    Univariate analysis of risk factors versus retinopathy and nephropathy outcome

    CharacteristicsThree or more–step ETDRS progression or scatter laser therapy from DCCT close out through EDIC study year 10Development of microalbuminuria or worse from DCCT close out through EDIC study year 9–10
    EventNoneventP valueEventNoneventP value
    n67117—34151—
    Demographics
        Age at EDIC study baseline34.4 ± 6.834.0 ± 6.50.777734.1 ± 6.334.6 ± 6.60.5883
        Women (%)55.245.30.195055.947.70.3875
    Diabetes duration at EDIC study baseline (years)11.3 ± 4.411.0 ± 5.00.367910.5 ± 4.011.0 ± 4.80.7269
    DCCT treatment group
        Intensive (%)41.865.00.002352.958.30.5698
    Glycemic control
        DCCT mean A1C (%)9.0 ± 1.77.6 ± 1.2<0.00018.8 ± 1.67.8 ± 1.40.0005
        EDIC study mean A1C up to EDIC study year 10 (%)8.8 ± 1.47.7 ± 0.9<0.0001———
        EDIC study mean A1C up to EDIC study year 9–10 (%)———9.2 ± 1.37.8 ± 1.1<0.0001
    Medical at EDIC baseline
        Mean blood pressure (mmHg)90.7 ± 9.388.1 ± 8.00.117492.6 ± 8.488.0 ± 8.20.0089
        Hypertension ever (%)14.97.70.120825.37.30.0048
        Triglycerides (mmol) (now in mg/dl)81.0 ± 44.076.6 ± 43.30.688286.6 ± 45.473.9 ± 39.10.1165
        HDL cholesterol (mmol) (now in mg/dl)53.0 ± 14.251.2 ± 12.20.467051.8 ± 12.451.6 ± 12.90.9218
        LDL cholesterol (mmol) (now in mg/dl)112 ± 29108 ± 290.3577116 ± 30108 ± 280.0856
        Overweight (%)35.835.00.915438.237.10.9004
        Smoker at DCCT close out (%)26.915.40.058923.517.20.3907
    Retinopathy at EDIC study baseline
        No retinopathy (10/10) (%)25.430.8—17.733.1—
        Microaneurisms only <(20/20) (%)29.941.0—38.239.1—
        Mild to moderate nonproliferative diabetic retinopathy or worse (35/<35+) (%)44.828.20.071144.127.80.1007
    Renal at EDIC baseline
        Albuminuria (mg/24 h)44.7 ± 16611.7 ± 21.10.000213.6 ± 9.48.3 ± 5.10.0014
        AER ≥40 (%)17.94.30.0023———
    Neuropathy at EDIC baseline (%)16.44.30.005214.78.70.2845
    Skin collagens at EDIC study baseline (pmol/mg collagen)
        Furosine924 ± 253669 ± 172<0.0001878 ± 242717 ± 2050.0001
        CML607 ± 134501 (120)<0.0001596 ± 126514 ± 1290.0007
        Pentosidine29.0 ± 8.224.3 ± 6.9<0.00018.624.7 ± 6.80.0003
        Fluorescence197 ± 40176 ± 370.0002201 ± 45181 ± 500.0033
        Acid-soluble collagen (%)0.6 ± 0.40.5 ± 0.30.13250.6 ± 0.40.6 ± 0.30.1599
        Pepsin-soluble collagen (%)5.9 ± 3.97.3 ± 3.0<0.00016.0 ± 2.87.1 ± 3.40.0187
    • 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 modelsdfχ2P valueR2
    Unadjusted effect
        DCCT mean A1C134.3<0.00010.142
        EDIC study mean A1C140.5<0.00010.168
        Furosine, CML, pentosidine, fluorescence, acid/pepsin soluble662.2<0.00010.258
        Pentosidine, fluorescence, acid/pepsin soluble421.80.00020.090
        Furosine, CML259.4<0.00010.246
        Furosine152.2<0.00010.216
        CML127.7<0.00010.115
    Adjusted effect
        DCCT mean A1C effect adjusted for
    Furosine, CML10.00.98740.000
    Furosine10.40.54300.001
    CML117.4<0.00010.072
        EDIC study mean A1C effect adjusted for
    Furosine, CML126.0<0.00010.108
    Furosine124.6<0.00010.102
    CML143.4<0.00010.180
        Furosine, CML effect adjusted for
    Pentosidine, fluorescence, acid/pepsin soluble246.3<0.00010.192
        DCCT mean A1C232.7<0.00010.136
        EDIC study mean A1C245.9<0.00010.190
        Pentosidine, fluorescence, acid/pepsin soluble effect adjusted for
    Furosine, CML44.80.30340.020
        Furosine effect adjusted for
    DCCT mean A1C122.2<0.00010.092
    EDIC study mean A1C133.5<0.00010.139
        CML effect adjusted for
    DCCT mean A1C114.4<0.00010.061
    EDIC study mean A1C127.6<0.00010.114
    • 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 modelsdfχ2P valueR2
    Unadjusted effect
        DCCT mean A1C110.40.00120.062
        EDIC study mean A1C132.0<0.00010.189
        Log DCCT close-out AER113.60.00020.081
        Furosine, CML, pentosidine, fluorescence, acid/pepsin soluble619.30.00360.114
        Pentosidine, fluorescence, acid/pepsin soluble412.60.01350.075
        Furosine, CML218.20.00010.108
        Furosine113.40.00020.080
        CML110.20.00140.060
    Adjusted effect
        DCCT mean A1C effect adjusted for
    Furosine, CML10.00.96430.000
    Furosine10.20.64130.001
    CML14.80.02780.029
        DCCT mean A1C, log AER effect adjusted for
    Furosine, CML210.80.00460.064
        EDIC study mean A1C effect adjusted for
    Furosine, CML123.1<0.00010.137
    Furosine121.8<0.00010.129
    CML126.0<0.00010.154
        Furosine, CML effect adjusted for
    Pentosidine, fluorescence, acid/pepsin soluble211.00.00410.065
    DCCT mean A1C, log AER213.10.00140.078
    DCCT mean A1C212.80.00160.076
    EDIC study mean A1C214.40.00080.085
        Pentosidine, fluorescence, acid/pepsin soluble effect adjusted for
    Furosine, CML44.50.33940.027
        Furosine effect adjusted for
    DCCT mean A1C17.10.00790.042
    EDIC study mean A1C17.10.00760.042
        CML effect adjusted for
    DCCT mean A1C16.30.01230.037
    EDIC study mean A1C110.70.00110.064
    • 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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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
Saul Genuth, Wanjie Sun, Patricia Cleary, David R. Sell, William Dahms, John Malone, William Sivitz, Vincent M. Monnier, for the DCCT Skin Collagen Ancillary Study Group*
Diabetes Nov 2005, 54 (11) 3103-3111; DOI: 10.2337/diabetes.54.11.3103

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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
Saul Genuth, Wanjie Sun, Patricia Cleary, David R. Sell, William Dahms, John Malone, William Sivitz, Vincent M. Monnier, for the DCCT Skin Collagen Ancillary Study Group*
Diabetes Nov 2005, 54 (11) 3103-3111; DOI: 10.2337/diabetes.54.11.3103
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Keywords

AER, albumin excretion rate
AGE, advanced glycation end product
CML, Nε-(carboxymethyl)-lysine
DCCT, Diabetes Control and Complications Trial
EDIC, Epidemiology of Diabetes Interventions and Complications

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