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  • American Diabetes Association  (17)
  • 2015-2019  (17)
  • 1
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    A Type 1 Diabetes Genetic Risk Score Predicts Progression of Islet Autoimmunity and Development of Type 1 Diabetes in Individuals at Risk
    American Diabetes Association ; 2018
    In:  Diabetes Care Vol. 41, No. 9 ( 2018-09-01), p. 1887-1894
    Details
    In: Diabetes Care, American Diabetes Association, Vol. 41, No. 9 ( 2018-09-01), p. 1887-1894
    Abstract: We tested the ability of a type 1 diabetes (T1D) genetic risk score (GRS) to predict progression of islet autoimmunity and T1D in at-risk individuals. RESEARCH DESIGN AND METHODS We studied the 1,244 TrialNet Pathway to Prevention study participants (T1D patients’ relatives without diabetes and with one or more positive autoantibodies) who were genotyped with Illumina ImmunoChip (median [range] age at initial autoantibody determination 11.1 years [1.2–51.8], 48% male, 80.5% non-Hispanic white, median follow-up 5.4 years). Of 291 participants with a single positive autoantibody at screening, 157 converted to multiple autoantibody positivity and 55 developed diabetes. Of 953 participants with multiple positive autoantibodies at screening, 419 developed diabetes. We calculated the T1D GRS from 30 T1D-associated single nucleotide polymorphisms. We used multivariable Cox regression models, time-dependent receiver operating characteristic curves, and area under the curve (AUC) measures to evaluate prognostic utility of T1D GRS, age, sex, Diabetes Prevention Trial–Type 1 (DPT-1) Risk Score, positive autoantibody number or type, HLA DR3/DR4-DQ8 status, and race/ethnicity. We used recursive partitioning analyses to identify cut points in continuous variables. RESULTS Higher T1D GRS significantly increased the rate of progression to T1D adjusting for DPT-1 Risk Score, age, number of positive autoantibodies, sex, and ethnicity (hazard ratio [HR] 1.29 for a 0.05 increase, 95% CI 1.06–1.6; P = 0.011). Progression to T1D was best predicted by a combined model with GRS, number of positive autoantibodies, DPT-1 Risk Score, and age (7-year time-integrated AUC = 0.79, 5-year AUC = 0.73). Higher GRS was significantly associated with increased progression rate from single to multiple positive autoantibodies after adjusting for age, autoantibody type, ethnicity, and sex (HR 2.27 for GRS & gt;0.295, 95% CI 1.47–3.51; P = 0.0002). CONCLUSIONS The T1D GRS independently predicts progression to T1D and improves prediction along T1D stages in autoantibody-positive relatives.
    Type of Medium: Online Resource
    ISSN: 0149-5992 , 1935-5548
    URL: Article
    DOI: 10.2337/dc18-0087
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2018
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  • 2
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    Low-Dose Anti-Thymocyte Globulin Preserves C-Peptide, Reduces HbA1c, and Increases Regulatory to Conventional T-Cell Ratios in New-Onset Type 1 Diabetes: Two-Year Clinical Trial Data
    American Diabetes Association ; 2019
    In:  Diabetes Vol. 68, No. 6 ( 2019-06-01), p. 1267-1276
    Details
    In: Diabetes, American Diabetes Association, Vol. 68, No. 6 ( 2019-06-01), p. 1267-1276
    Abstract: A three-arm, randomized, double-masked, placebo-controlled phase 2b trial performed by the Type 1 Diabetes TrialNet Study Group previously demonstrated that low-dose anti-thymocyte globulin (ATG) (2.5 mg/kg) preserved β-cell function and reduced HbA1c for 1 year in new-onset type 1 diabetes. Subjects (N = 89) were randomized to 1) ATG and pegylated granulocyte colony-stimulating factor (GCSF), 2) ATG alone, or 3) placebo. Herein, we report 2-year area under the curve (AUC) C-peptide and HbA1c, prespecified secondary end points, and potential immunologic correlates. The 2-year mean mixed-meal tolerance test–stimulated AUC C-peptide, analyzed by ANCOVA adjusting for baseline C-peptide, age, and sex (n = 82) with significance defined as one-sided P & lt; 0.025, was significantly higher in subjects treated with ATG versus placebo (P = 0.00005) but not ATG/GCSF versus placebo (P = 0.032). HbA1c was significantly reduced at 2 years in subjects treated with ATG (P = 0.011) and ATG/GCSF (P = 0.022) versus placebo. Flow cytometry analyses demonstrated reduced circulating CD4:CD8 ratio, increased regulatory T-cell:conventional CD4 T-cell ratios, and increased PD-1+CD4+ T cells following low-dose ATG and ATG/GCSF. Low-dose ATG partially preserved β-cell function and reduced HbA1c 2 years after therapy in new-onset type 1 diabetes. Future studies should determine whether low-dose ATG might prevent or delay the onset of type 1 diabetes.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db19-0057
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2019
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  • 3
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    Identical and Nonidentical Twins: Risk and Factors Involved in Development of Islet Autoimmunity and Type 1 Diabetes
    American Diabetes Association ; 2019
    In:  Diabetes Care Vol. 42, No. 2 ( 2019-02-01), p. 192-199
    Details
    In: Diabetes Care, American Diabetes Association, Vol. 42, No. 2 ( 2019-02-01), p. 192-199
    Abstract: There are variable reports of risk of concordance for progression to islet autoantibodies and type 1 diabetes in identical twins after one twin is diagnosed. We examined development of positive autoantibodies and type 1 diabetes and the effects of genetic factors and common environment on autoantibody positivity in identical twins, nonidentical twins, and full siblings. RESEARCH DESIGN AND METHODS Subjects from the TrialNet Pathway to Prevention Study (N = 48,026) were screened from 2004 to 2015 for islet autoantibodies (GAD antibody [GADA], insulinoma-associated antigen 2 [IA-2A] , and autoantibodies against insulin [IAA]). Of these subjects, 17,226 (157 identical twins, 283 nonidentical twins, and 16,786 full siblings) were followed for autoantibody positivity or type 1 diabetes for a median of 2.1 years. RESULTS At screening, identical twins were more likely to have positive GADA, IA-2A, and IAA than nonidentical twins or full siblings (all P & lt; 0.0001). Younger age, male sex, and genetic factors were significant factors for expression of IA-2A, IAA, one or more positive autoantibodies, and two or more positive autoantibodies (all P ≤ 0.03). Initially autoantibody-positive identical twins had a 69% risk of diabetes by 3 years compared with 1.5% for initially autoantibody-negative identical twins. In nonidentical twins, type 1 diabetes risk by 3 years was 72% for initially multiple autoantibody–positive, 13% for single autoantibody–positive, and 0% for initially autoantibody-negative nonidentical twins. Full siblings had a 3-year type 1 diabetes risk of 47% for multiple autoantibody–positive, 12% for single autoantibody–positive, and 0.5% for initially autoantibody-negative subjects. CONCLUSIONS Risk of type 1 diabetes at 3 years is high for initially multiple and single autoantibody–positive identical twins and multiple autoantibody–positive nonidentical twins. Genetic predisposition, age, and male sex are significant risk factors for development of positive autoantibodies in twins.
    Type of Medium: Online Resource
    ISSN: 0149-5992 , 1935-5548
    URL: Article
    DOI: 10.2337/dc18-0288
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2019
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  • 4
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    Low-Dose Anti-Thymocyte Globulin (ATG) Preserves β-Cell Function and Improves HbA1c in New-Onset Type 1 Diabetes
    American Diabetes Association ; 2018
    In:  Diabetes Care Vol. 41, No. 9 ( 2018-09-01), p. 1917-1925
    Details
    In: Diabetes Care, American Diabetes Association, Vol. 41, No. 9 ( 2018-09-01), p. 1917-1925
    Abstract: A pilot study suggested that combination therapy with low-dose anti-thymocyte globulin (ATG) and pegylated granulocyte colony-stimulating factor (GCSF) preserves C-peptide in established type 1 diabetes (T1D) (duration 4 months to 2 years). We hypothesized that 1) low-dose ATG/GCSF or 2) low-dose ATG alone would slow the decline of β-cell function in patients with new-onset T1D (duration & lt;100 days). RESEARCH DESIGN AND METHODS A three-arm, randomized, double-masked, placebo-controlled trial was performed by the Type 1 Diabetes TrialNet Study Group in 89 subjects: 29 subjects randomized to ATG (2.5 mg/kg intravenously) followed by pegylated GCSF (6 mg subcutaneously every 2 weeks for 6 doses), 29 to ATG alone (2.5 mg/kg), and 31 to placebo. The primary end point was mean area under the curve (AUC) C-peptide during a 2-h mixed-meal tolerance test 1 year after initiation of therapy. Significance was defined as one-sided P value & lt; 0.025. RESULTS The 1-year mean AUC C-peptide was significantly higher in subjects treated with ATG (0.646 nmol/L) versus placebo (0.406 nmol/L) (P = 0.0003) but not in those treated with ATG/GCSF (0.528 nmol/L) versus placebo (P = 0.031). HbA1c was significantly reduced at 1 year in subjects treated with ATG and ATG/GCSF, P = 0.002 and 0.011, respectively. CONCLUSIONS Low-dose ATG slowed decline of C-peptide and reduced HbA1c in new-onset T1D. Addition of GCSF did not enhance C-peptide preservation afforded by low-dose ATG. Future studies should be considered to determine whether low-dose ATG alone or in combination with other agents may prevent or delay the onset of the disease.
    Type of Medium: Online Resource
    ISSN: 0149-5992 , 1935-5548
    URL: Article
    DOI: 10.2337/dc18-0494
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2018
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  • 5
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    The Influence of Parental Type 1 Diabetes (T1D) on the Progression to T1D in Autoantibody-Positive Offspring
    American Diabetes Association ; 2018
    In:  Diabetes Vol. 67, No. Supplement_1 ( 2018-07-01)
    Details
    In: Diabetes, American Diabetes Association, Vol. 67, No. Supplement_1 ( 2018-07-01)
    Abstract: Studies have suggested that autoantibody positivity (Ab+) and T1D occur less commonly in maternal offspring (MO) than paternal offspring (PO) of T1D patients. However, there is little information on the impact of parental T1D on progression to T1D once Ab+ occurs in the offspring. We have thus compared MO vs. PO for progression to T1D in the Ab+ cohort of the TrialNet Pathway to Prevention study using data from 33,382 screened subjects whose parents had T1D. Cox regression with adjustments for age, sex, ethnicity, Abs, and Index60 (a composite measure of C-peptide and glucose) was used to compare T1D progression. The prevalence of Ab+ was lower for MO than for PO [3.1% (549/17,652) vs. 4.5% (726/16,027), p & lt;0.001]. However, among those Ab+ participants, progression to T1D was greater in MO [HR=1.46 (95% CI: 1.13-1.90), p=0.004] . Although progression from single Ab+ to multiple (M)Ab+ did not differ significantly between MO (n=208) and PO (n=267) [HR=0.76 (0.48-1.19), p=0.23], progression from MAb+ to T1D was significantly higher in MO (n=341) than PO (n=459) [HR=1.45 (1.10-1.90), p & lt;0.01]. We assessed whether in utero exposure might explain the greater risk for progression from MAb+ to T1D in MO. In a comparison of mothers and fathers diagnosed with T1D before the birth of offspring, MO (n=224) were at more risk for T1D than PO (n=357) [HR=1.40 ( 1.02-1.93), p=0.035]. However, among parents diagnosed with T1D after the birth of offspring, the risk for T1D among MO (n=75) and PO (n=69) was similar [HR=1.15 (0.60-2.22), p=0.67] . The risk for MO of mothers who were diagnosed before their birth vs. MO of mothers who were diagnosed after their birth was not significantly different [HR=1.37 (0.75-2.5), p=0.31]. In conclusion, as observed previously, MO had a lower prevalence of Ab+ than PO. However, when Ab+ was present, MO were at higher risk for T1D. Moreover, the overall findings suggest that in utero exposure could possibly contribute to the increased risk from MAb+ to T1D in MO. Disclosure H.M. Ismail: None. E.K. Sims: None. S. Geyer: None. M.J. Redondo: None. C. Evans-Molina: None. I. Libman: Consultant; Self; Novo Nordisk A/S. L. DiMeglio: Advisory Panel; Self; Eli Lilly and Company. Research Support; Self; Dexcom, Inc., Medtronic, Sanofi, Caladrius Biosciences, Inc., Janssen Research & Development, Xeris Pharmaceuticals, Inc., Sanofi. D.J. Becker: None. J.P. Palmer: None. J.S. Skyler: Advisory Panel; Self; ADOCIA, Abvance. Consultant; Self; AstraZeneca, Becton, Dickinson and Company, Boehringer Ingelheim GmbH. Advisory Panel; Self; Dance Biopharm. Consultant; Self; Diavacs, Inc., Elcelyx Therapeutics, Inc., Eli Lilly and Company, Ideal Life Inc., ImmunoMolecular Therapeutics, Intrexon, Merck & Co., Inc.. Advisory Panel; Self; Orgenesis Inc.. Consultant; Self; Sanofi, Servier, VTV Therapeutics, Valeritas, Inc., Viacyte, Inc.. Board Member; Self; Dexcom, Inc.. Stock/Shareholder; Self; Dexcom, Inc.. Board Member; Self; Intarcia Therapeutics, Inc.. Stock/Shareholder; Self; Intarcia Therapeutics, Inc.. Board Member; Self; Moerae Matrix. Stock/Shareholder; Self; Moerae Matrix, Dance Biopharm, Ideal Life Inc., Intrexon, VasoPrep Surgical. J. Krischer: None. D. Schatz: None. A. Pugliese: None. J. Sosenko: None.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db18-1693-P
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2018
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  • 6
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    Individuals with Single Islet Autoantibody Positivity (SA+) at Type 1 Diabetes (T1D) Diagnosis Have Distinct Characteristics
    American Diabetes Association ; 2018
    In:  Diabetes Vol. 67, No. Supplement_1 ( 2018-07-01)
    Details
    In: Diabetes, American Diabetes Association, Vol. 67, No. Supplement_1 ( 2018-07-01)
    Abstract: Multiple autoantibody positivity (MA+) usually precedes clinical T1D. However, a subset of patients who develop T1D have SA+. We hypothesized that individuals who at T1D diagnosis express SA+ compared with MA+ have different demographic, metabolic, immunologic and genetic characteristics. We studied 620 TrialNet participants who developed clinical T1D (median age=12.3 years [range=1.4-58.6], 47.5% male, 88% white). Using multivariable modeling and adjusting for potential confounders, we investigated differences between participants with SA+ vs. MA+ (of autoantibodies to GAD65 [GADA] , insulin [mIAA], IA2, ZnT8 and ICA) at T1D diagnosis. We found 95 participants who had SA+ (70% GADA+) and 525 participants with MA+. In univariate analyses, individuals with SA+ vs. MA+ were older at T1D diagnosis (median 16.4 vs. 11.7 years, p & lt;0.0001) and had higher fasting C-peptide (1.87 vs. 1.47 nmol/L, p=0.007), higher 30-0 minute C-peptide difference (1.42 vs. 1.18, p=0.009) and lower Index60 (composite measure of fasting C-peptide, 60-min glucose and 60-min C-peptide) (2.31 vs. 2.68, p=0.0005). Gender, race, ethnicity, BMI-Z-score, presence of HLA DR3-DQ2 and/or DR4-DQ8, fasting glucose, AUC glucose and AUC C-peptide were not significantly different. By multivariable analyses, SA+ at onset corresponded with older age (OR=1.05, p & lt;0.0001), lower Index60 (OR=0.77, p=0.008), and lower likelihood of mIAA+ (OR=0.27, p & lt;0.0001) and GADA+ (OR=0.25, p & lt;0.0001); gender, HLA, BMI-Z-score and other autoantibody types were not significantly different. Independent factors of being SA+ differed between DR3/DR4-DQ8 heterozygous participants (older age and not having mIAA+ or GADA+) (p & lt;0.01) and those not DR3/DR4-DQ8 (lower Index60 and not having GADA+) (p & lt;0.01). In conclusion, the number of islet autoantibodies at T1D diagnosis is associated with distinct characteristics, which may suggest heterogeneous pathogenesis with relevance for T1D prevention and treatment. Disclosure M.J. Redondo: None. J. Sosenko: None. I. Libman: Consultant; Self; Novo Nordisk A/S. J.J. McVean: Speaker's Bureau; Self; Medtronic MiniMed, Inc. M.A. Atkinson: Other Relationship; Self; Patent Issued. D.J. Becker: None. S. Geyer: None.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db18-1691-P
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2018
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  • 7
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    Dysglycemia and Index60 as Prediagnostic End Points for Type 1 Diabetes Prevention Trials
    American Diabetes Association ; 2017
    In:  Diabetes Care Vol. 40, No. 11 ( 2017-11-01), p. 1494-1499
    Details
    In: Diabetes Care, American Diabetes Association, Vol. 40, No. 11 ( 2017-11-01), p. 1494-1499
    Abstract: We assessed dysglycemia and a T1D Diagnostic Index60 (Index60) ≥1.00 (on the basis of fasting C-peptide, 60-min glucose, and 60-min C-peptide levels) as prediagnostic end points for type 1 diabetes among Type 1 Diabetes TrialNet Pathway to Prevention Study participants. RESEARCH DESIGN AND METHODS Two cohorts were analyzed: 1) baseline normoglycemic oral glucose tolerance tests (OGTTs) with an incident dysglycemic OGTT and 2) baseline Index60 & lt;1.00 OGTTs with an incident Index60 ≥1.00 OGTT. Incident dysglycemic OGTTs were divided into those with (DYS/IND+) and without (DYS/IND−) concomitant Index60 ≥1.00. Incident Index60 ≥1.00 OGTTs were divided into those with (IND/DYS+) and without (IND/DYS−) concomitant dysglycemia. RESULTS The cumulative incidence for type 1 diabetes was greater after IND/DYS− than after DYS/IND− (P & lt; 0.01). Within the normoglycemic cohort, the cumulative incidence of type 1 diabetes was higher after DYS/IND+ than after DYS/IND− (P & lt; 0.001), whereas within the Index60 & lt;1.00 cohort, the cumulative incidence after IND/DYS+ and after IND/DYS− did not differ significantly. Among nonprogressors, type 1 diabetes risk at the last OGTT was greater for IND/DYS− than for DYS/IND− (P & lt; 0.001). Hazard ratios (HRs) of DYS/IND− with age and 30- to 0-min C-peptide were positive (P & lt; 0.001 for both), whereas HRs of type 1 diabetes with these variables were inverse (P & lt; 0.001 for both). In contrast, HRs of IND/DYS− and type 1 diabetes with age and 30- to 0-min C-peptide were consistent (all inverse [P & lt; 0.01 for all]). CONCLUSIONS The findings suggest that incident dysglycemia without Index60 ≥1.00 is a suboptimal prediagnostic end point for type 1 diabetes. Measures that include both glucose and C-peptide levels, such as Index60 ≥1.00, appear better suited as prediagnostic end points.
    Type of Medium: Online Resource
    ISSN: 0149-5992 , 1935-5548
    URL: Article
    DOI: 10.2337/dc17-0916
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2017
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  • 8
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    1684-P: Using Index60 to Detect Heterogeneity and Identify Subpopulations with Characteristic Type 1 Diabetes (T1D) Profiles among Individuals with Normal Two-Hour Glucose Levels
    American Diabetes Association ; 2019
    In:  Diabetes Vol. 68, No. Supplement_1 ( 2019-06-01)
    Details
    In: Diabetes, American Diabetes Association, Vol. 68, No. Supplement_1 ( 2019-06-01)
    Abstract: We assessed whether Index60 could identify subpopulations with heterogeneous T1D features among autoantibody positive (Ab+) individuals with a normal 2-hour glucose. Index60 is a composite measure of fasting C-peptide, 60-minute C-peptide, and 60-minute glucose that has potential utility as a prediabetes endpoint when values are ≥1.00. Baseline 2-hour OGTTs of Ab+ TrialNet Pathway to Prevention participants in the normal 2-hour glucose ( & lt;140 mg/dl) range and low Index60 range ( & lt;1.00) were studied. The top 2-hour glucose & lt;140 mg/dl quartile was compared with the top Index60 & lt;1.00 quartile for characteristic T1D features (groups mutually exclusive). Those in the top Index60 quartile (Group B) or in both top quartiles (Group C) had profiles more typical of T1D than those in the top 2-hour glucose quartile (Group A), who had higher C-peptide levels, lower Ab+ frequencies, and were older (Table). Also, as indicated by within group odds ratios, Group A had less association of DR3-DQ2/DR4-DQ8 with the top quartile (Group A: 1.19, ns; Group B: 1.49, p & lt;0.01; Group C: 1.63, p & lt;0.01). In summary, Index60 can detect heterogeneity among those with normal 2-hour glucose levels, and identify subpopulations with appreciably more characteristic T1D features. The atypia of Group A demonstrates the importance of this Index60 utility. Disclosure B.M. Nathan: None. S. Geyer: None. L.E. Bocchino: None. J.P. Palmer: None. L.M. Jacobsen: None. M.J. Redondo: None. E.K. Sims: None. J.S. Skyler: Advisory Panel; Self; ADOCIA, Applied Therapeutics, Dance Biopharm Holdings Inc., Orgenesis Ltd., Tolerion, Inc., Viacyte, Inc. Board Member; Self; Dexcom, Inc., Intarcia Therapeutics, Inc., Moerae Matrix, Inc. Consultant; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Dalcor, Dialogics, Elcelyx Therapeutics, Inc., Esperion, GeNeuro Innovation, Ideal Life, Immunomolecular Therapeutics, Intrexon, Kamada, Nestlé, Sanofi, Valeritas, Inc., Zafgen, Inc. Stock/Shareholder; Self; Dexcom, Inc., Ideal Life, Intarcia Therapeutics, Inc., Intrexon, Moerae Matrix, Inc. J.M. Sosenko: None. Funding National Institutes of Health; JDRF
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db19-1684-P
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2019
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  • 9
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    84-OR: Index60 and 2-Hour Glucose Diagnostic Thresholds: Comparison of Type 1 Diabetes (T1D) Marker Profiles
    American Diabetes Association ; 2019
    In:  Diabetes Vol. 68, No. Supplement_1 ( 2019-06-01)
    Details
    In: Diabetes, American Diabetes Association, Vol. 68, No. Supplement_1 ( 2019-06-01)
    Abstract: Since T1D is increasingly recognized as a heterogeneous disorder, we sought to determine whether different diagnostic criteria could identify individuals with a distinct profile of markers typical for T1D. We studied autoantibody positive (Ab+) TrialNet Pathway to Prevention participants. Markers that typically cluster in individuals diagnosed with T1D were compared between groups defined by oral glucose tolerance test (OGTT) 2-hour glucose ≥200 mg/dl (2hrglu≥200), which is an ADA standard diagnostic criterion, and Index60≥2.00 (Ind60≥2.00; based on fasting C-peptide [C-pep] and OGTT 60-minute C-pep and 60-minute glucose), which has previously shown potential utility as a diagnostic criterion for T1D. Three groups were compared: (A) 2hrglu≥200 Only (Ind60 & lt;2.00), (B) Ind60≥2.00 Only (2hrglu & lt;200), and (C) Both Ind60≥200 and 2hrglu≥2.00. Participants in the Ind60≥2.00-Only or Ind60≥2.00 and 2hrglu≥200 groups were younger, had lower 30-0 minute C-pep and AUC C-pep, and had higher percentages of mIAA and multiple Ab+ compared with those in the 2-hrglu≥200 Only group (Table). In sum, individuals with Ind60≥2.00 had more characteristic T1D features than those with 2-hrglu≥200 but Ind60 & lt;2.00, who were atypical. It thus appears that the use of T1D-specific diagnostic measures, such as Ind60≥2.00, may help identify more homogeneous groups of individuals with T1D. Disclosure M.J. Redondo: None. B.M. Nathan: None. L.E. Bocchino: None. S. Geyer: None. L.M. Jacobsen: None. E.K. Sims: None. A. Pugliese: None. J.S. Skyler: Advisory Panel; Self; ADOCIA, Applied Therapeutics, Dance Biopharm Holdings Inc., Orgenesis Ltd., Tolerion, Inc., Viacyte, Inc. Board Member; Self; Dexcom, Inc., Intarcia Therapeutics, Inc., Moerae Matrix, Inc. Consultant; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Dalcor, Dialogics, Elcelyx Therapeutics, Inc., Esperion, GeNeuro Innovation, Ideal Life, Immunomolecular Therapeutics, Intrexon, Kamada, Nestlé, Sanofi, Valeritas, Inc., Zafgen, Inc. Stock/Shareholder; Self; Dexcom, Inc., Ideal Life, Intarcia Therapeutics, Inc., Intrexon, Moerae Matrix, Inc. J.P. Palmer: None. J. Sosenko: None. Funding National Institutes of Health
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db19-84-OR
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2019
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  • 10
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    Transcription Factor 7-Like 2 ( TCF7L2 ) Gene Polymorphism and Progression From Single to Multiple Autoantibody Positivity in Individuals at Risk for Type 1 Diabetes
    American Diabetes Association ; 2018
    In:  Diabetes Care Vol. 41, No. 12 ( 2018-12-01), p. 2480-2486
    Details
    In: Diabetes Care, American Diabetes Association, Vol. 41, No. 12 ( 2018-12-01), p. 2480-2486
    Abstract: The type 2 diabetes–associated alleles at the TCF7L2 locus mark a type 1 diabetes phenotype characterized by single islet autoantibody positivity as well as lower glucose and higher C-peptide measures. Here, we studied whether the TCF7L2 locus influences progression of islet autoimmunity, from single to multiple (≥2) autoantibody positivity, in relatives of patients with type 1 diabetes. RESEARCH DESIGN AND METHODS We evaluated 244 participants in the Type 1 Diabetes TrialNet Pathway to Prevention study with confirmed single autoantibody positivity at screening and Immunochip single nucleotide polymorphism data (47.5% male; median age 12.8 years, range 1.2–45.9; 90.2% white). We analyzed risk allele frequency at TCF7L2 rs4506565 (in linkage disequilibrium with rs7903146). Altogether, 62.6% participants carried ≥1 risk allele. Univariate and multivariable Cox proportional hazards models and Kaplan-Meier statistical methods were used. RESULTS During follow-up (median 5.2 years, range 0.2–12.6), 62% of the single autoantibody–positive participants developed multiple autoantibody positivity. In the overall cohort, the TCF7L2 locus did not significantly predict progression to multiple autoantibody positivity. However, among single GAD65 autoantibody–positive participants (n = 158), those who carried ≥1 risk allele had a lower rate of progression to multiple autoantibody positivity (hazard ratio [HR] 0.65, P = 0.033) than those who did not, after adjustment for HLA risk haplotypes and age. Among subjects who were either IA-2 or insulin autoantibody positive only, carrying ≥1 TCF7L2 risk allele was not a significant factor overall, but in overweight or obese participants, it increased the risk of progression to multiple autoantibody positivity (HR 3.02, P = 0.016) even with adjustment for age. CONCLUSIONS The type 2 diabetes–associated TCF7L2 locus influences progression of islet autoimmunity, with differential effects by autoantibody specificity and interaction by obesity/overweight.
    Type of Medium: Online Resource
    ISSN: 0149-5992 , 1935-5548
    URL: Article
    DOI: 10.2337/dc18-0861
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2018
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