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  • American Diabetes Association  (68)
  • 2020-2024  (68)
  • 1
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    Time to Peak Glucose and Peak C-Peptide During the Progression to Type 1 Diabetes in the Diabetes Prevention Trial and TrialNet Cohorts
    American Diabetes Association ; 2021
    In:  Diabetes Care Vol. 44, No. 10 ( 2021-10-01), p. 2329-2336
    Details
    In: Diabetes Care, American Diabetes Association, Vol. 44, No. 10 ( 2021-10-01), p. 2329-2336
    Abstract: To assess the progression of type 1 diabetes using time to peak glucose or C-peptide during oral glucose tolerance tests (OGTTs) in autoantibody-positive relatives of people with type 1 diabetes. RESEARCH DESIGN AND METHODS We examined 2-h OGTTs of participants in the Diabetes Prevention Trial Type 1 (DPT-1) and TrialNet Pathway to Prevention (PTP) studies. We included 706 DPT-1 participants (mean ± SD age, 13.84 ± 9.53 years; BMI Z-score, 0.33 ± 1.07; 56.1% male) and 3,720 PTP participants (age, 16.01 ± 12.33 years; BMI Z-score, 0.66 ± 1.3; 49.7% male). Log-rank testing and Cox regression analyses with adjustments (age, sex, race, BMI Z-score, HOMA-insulin resistance, and peak glucose/C-peptide levels, respectively) were performed. RESULTS In each of DPT-1 and PTP, higher 5-year diabetes progression risk was seen in those with time to peak glucose & gt;30 min and time to peak C-peptide & gt;60 min (P & lt; 0.001 for all groups), before and after adjustments. In models examining strength of association with diabetes development, associations were greater for time to peak C-peptide versus peak C-peptide value (DPT-1: χ2 = 25.76 vs. χ2 = 8.62; PTP: χ2 = 149.19 vs. χ2 = 79.98; all P & lt; 0.001). Changes in the percentage of individuals with delayed glucose and/or C-peptide peaks were noted over time. CONCLUSIONS In two independent at-risk populations, we show that those with delayed OGTT peak times for glucose or C-peptide are at higher risk of diabetes development within 5 years, independent of peak levels. Moreover, time to peak C-peptide appears more predictive than the peak level, suggesting its potential use as a specific biomarker for diabetes progression.
    Type of Medium: Online Resource
    ISSN: 0149-5992 , 1935-5548
    URL: Article
    DOI: 10.2337/dc21-0226
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2021
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  • 2
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    300-OR: Stage Transitions in Preclinical Type 1 Diabetes—Protective Effect of IA2 Variant Autoantibody Positivity
    American Diabetes Association ; 2023
    In:  Diabetes Vol. 72, No. Supplement_1 ( 2023-06-20)
    Details
    In: Diabetes, American Diabetes Association, Vol. 72, No. Supplement_1 ( 2023-06-20)
    Abstract: We previously demonstrated that the IA2 variant (IA2var) autoantibody (AA) is associated with enhanced prediction of type 1 diabetes (T1D) in at-risk individuals but its effect on progression through preclinical T1D stages is unknown. We aimed to assess the influence of IA2var AA on rates and risks of transitions from Stage 1 (multiple AA positive, no dysglycemia) to Stage 2 (multiple AA positive, dysglycemia) and to Stage 3 (clinical T1D). Participants in the Diabetes Prevention Trial (DPT-1) with Stage 1 or Stage 2 T1D at baseline and having ≥2 glucose tolerance tests during follow-up were selected (N=175). Standard AA (GAD65, ICA, ICA512 and insulin AA) were considered as biomarkers in addition to IA2var. Data analysis used Markov transition models. The estimated 12-month probability of transition from Stage 1 to 3 (N=89) was 13.8% (95% CI: 9.7%, 18.8%) and from Stage 2 to 3 (N=86) it was 41.3% (30.6%, 52.6%). IA2var AA, sex, age and were statistically significant risk factors for the Stage 2 to 3 transition (Table 1, B). Importantly, IA2var AA (the only significantly influential AA) was associated with a reduction in the risk of transition from Stage 2 to 3. In sum, male sex, older age and positive IA2var AA significantly decreased the risk of transition from Stage 2 to Stage 3 T1D. This information has important implications for the selection of candidates for T1D prevention in clinical and research practices. Disclosure C.Beam: None. S.Pietropaolo: None. M.J.Acevedo-calado: None. M.A.Herman: Research Support; Eli Lilly and Company. M.J.Redondo: None. M.Pietropaolo: None. Funding National Institutes of Health (2R01DK053456-19A1); Robert and Janice McNair Foundation
    Type of Medium: Online Resource
    ISSN: 0012-1797
    URL: Article
    DOI: 10.2337/db23-300-OR
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2023
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  • 3
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    The Rare and Atypical Diabetes Network (RADIANT) Study: Design and Early Results
    American Diabetes Association ; 2023
    In:  Diabetes Care Vol. 46, No. 6 ( 2023-06-01), p. 1265-1270
    Details
    In: Diabetes Care, American Diabetes Association, Vol. 46, No. 6 ( 2023-06-01), p. 1265-1270
    Abstract: The Rare and Atypical Diabetes Network (RADIANT) will perform a study of individuals and, if deemed informative, a study of their family members with uncharacterized forms of diabetes. RESEARCH DESIGN AND METHODS The protocol includes genomic (whole-genome [WGS], RNA, and mitochondrial sequencing), phenotypic (vital signs, biometric measurements, questionnaires, and photography), metabolomics, and metabolic assessments. RESULTS Among 122 with WGS results of 878 enrolled individuals, a likely pathogenic variant in a known diabetes monogenic gene was found in 3 (2.5%), and six new monogenic variants have been identified in the SMAD5, PTPMT1, INS, NFKB1, IGF1R, and PAX6 genes. Frequent phenotypic clusters are lean type 2 diabetes, autoantibody-negative and insulin-deficient diabetes, lipodystrophic diabetes, and new forms of possible monogenic or oligogenic diabetes. CONCLUSIONS The analyses will lead to improved means of atypical diabetes identification. Genetic sequencing can identify new variants, and metabolomics and transcriptomics analysis can identify novel mechanisms and biomarkers for atypical disease.
    Type of Medium: Online Resource
    ISSN: 0149-5992 , 1935-5548
    URL: Article
    DOI: 10.2337/dc22-2440
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2023
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  • 4
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    Introducing the Endotype Concept to Address the Challenge of Disease Heterogeneity in Type 1 Diabetes
    American Diabetes Association ; 2020
    In:  Diabetes Care Vol. 43, No. 1 ( 2020-01-01), p. 5-12
    Details
    In: Diabetes Care, American Diabetes Association, Vol. 43, No. 1 ( 2020-01-01), p. 5-12
    Abstract: The clinical diagnosis of new-onset type 1 diabetes has, for many years, been considered relatively straightforward. Recently, however, there is increasing awareness that within this single clinical phenotype exists considerable heterogeneity: disease onset spans the complete age range; genetic susceptibility is complex; rates of progression differ markedly, as does insulin secretory capacity; and complication rates, glycemic control, and therapeutic intervention efficacy vary widely. Mechanistic and immunopathological studies typically show considerable patchiness across subjects, undermining conclusions regarding disease pathways. Without better understanding, type 1 diabetes heterogeneity represents a major barrier both to deciphering pathogenesis and to the translational effort of designing, conducting, and interpreting clinical trials of disease-modifying agents. This realization comes during a period of unprecedented change in clinical medicine, with increasing emphasis on greater individualization and precision. For complex disorders such as type 1 diabetes, the option of maintaining the “single disease” approach appears untenable, as does the notion of individualizing each single patient’s care, obliging us to conceptualize type 1 diabetes less in terms of phenotypes (observable characteristics) and more in terms of disease endotypes (underlying biological mechanisms). Here, we provide our view on an approach to dissect heterogeneity in type 1 diabetes. Using lessons from other diseases and the data gathered to date, we aim to delineate a roadmap through which the field can incorporate the endotype concept into laboratory and clinical practice. We predict that such an effort will accelerate the implementation of precision medicine and has the potential for impact on our approach to translational research, trial design, and clinical management.
    Type of Medium: Online Resource
    ISSN: 0149-5992 , 1935-5548
    URL: Article
    DOI: 10.2337/dc19-0880
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2020
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  • 5
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    1229-P: Participation of Hispanic (Hisp) and African-American (AA) Youth in an Observational Study in Diabetes
    American Diabetes Association ; 2022
    In:  Diabetes Vol. 71, No. Supplement_1 ( 2022-06-01)
    Details
    In: Diabetes, American Diabetes Association, Vol. 71, No. Supplement_1 ( 2022-06-01)
    Abstract: Background and Aim: Suboptimal representation of race/ethnic minorities in clinical research contributes to critical gaps in our knowledge of diabetes in these populations. We aimed to evaluate the participation of AA and Hisp youth in an observational study in diabetes to assess factors impacting participation. Methods: We studied 92 participants in the Diabetes Study in Children of Diverse Ethnicity and Race (DISCOVER) that is currently enrolling youth (age 0-yrs) with non-secondary diabetes for collection of data and blood samples. We compared racial/ethnic distribution of actual vs. target enrollment and refusal rates by race/ethnicity. We analyzed qualitative data on reasons for study refusal. Results: The racial/ethnic distribution of participants was 60.9% Hisp, 27.2% AA, 12.0% non-Hispanic white [NHW] and 0% other, vs. enrollment targets of 35.3% Hisp, 31.8% AA, 29.9% NHW and 3% other (p=0.001) . In the population of eligible candidates, 31.1% of the children were Hisp, 18.8% AA, 42.2% NHW and 7.9% other. Refusal rates were 20.0%, 16.7%, 38.9% and 100%, respectively, for Hisp, AA, NHW and other (p=0.072) . Among those who refused, the reasons noted were no interest in research (44.4% overall, 80% in AA youth) , blood draw (29.6% overall, 42.6% in Hisp youth) , no direct benefit to the participant (11.1%) , and being too busy (18.5%) or overwhelmed by the recent diabetes diagnosis (11.1%) . NHW youth cited the first 3 reasons, with similar frequency, for refusal. Conclusions: Refusal rates were not elevated in AA and Hisp children compared with NHW. Actual enrollment was statistically different from the target, with over-representation of Hisp youth and underrepresentation of NHW youth. Facilitators of racial/ethnic minority participation in research studies may include diverse racial/ethnic distribution in the population where the study is conducted, a trusted environment, race/ethnicity concordance with research team members, and a minimally invasive study protocol. Disclosure M.J. Redondo: Advisory Panel; Provention Bio, Inc. M. Tosur: Advisory Panel; Provention Bio, Inc. A.B. Muir: None. S. Iftekhar: None. S. Deen: None. D.J. Perry: None. D.H. Glueck: None. K. Vehik: None. R.A. Oram: Consultant; Janssen Research & Development, LLC. Research Support; Randox R & D. W. Hagopian: Research Support; Janssen Research & Development, LLC. D. Dabelea: None. M.A. Atkinson: None. Funding NIH NIDDK RDK124395
    Type of Medium: Online Resource
    ISSN: 0012-1797
    URL: Article
    DOI: 10.2337/db22-1229-P
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2022
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  • 6
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    110-OR: Type 2 Diabetes (T2D)–Associated TCF7L2 Genetic Variants and Indices of Insulin Secretion and Sensitivity in Individuals at Risk for Type 1 Diabetes (T1D)
    American Diabetes Association ; 2020
    In:  Diabetes Vol. 69, No. Supplement_1 ( 2020-06-01)
    Details
    In: Diabetes, American Diabetes Association, Vol. 69, No. Supplement_1 ( 2020-06-01)
    Abstract: In individuals with new onset T1D, T2D-associated TCF7L2 genetic variants are associated with lower area-under-the curve (AUC) glucose and higher AUC C-peptide responses to a mixed meal. We aimed to test whether TCF7L2 variants affect glucose metabolism in nondiabetic islet autoantibody-positive (AbPos) individuals. We studied 1065 TrialNet Pathway to Prevention Study participants (AbPos relatives of persons with T1D) with TCF7L2 SNPs who underwent oral glucose tolerance tests (OGTT) (mean age 16.3 yrs, 63% & lt;18 years old, 91.1% non-Hispanic, 47.7% male; T2D-associated TCF7L2 SNP: 48.1% 0 alleles, 43.9% 1 allele, 8% 2 alleles). We assessed the contribution of TCF7L2 SNP variants on Fasting (FIIS) and OGTT Index of Insulin Sensitivity (OIIS), Insulin Secretion (OIISec), and Disposition Index (ODI) with univariate and multivariate analyses. Then we studied the interaction between TCF7L2 SNP and BMI. With Bonferroni correction for multiple comparisons, p-values & lt;0.0086 were considered statistically significant. Insulin sensitivity and secretion indices were significantly associated with age (FIIS, OIIS, OIISec), BMI Z-score (FIIS, OIIS, OIISec, ODI) and Hispanic ethnicity (FIIS, OIIS) but not sex in univariate analyses. TCF7L2 SNP was not significantly associated with these indices in univariate or multivariate analyses adjusting for BMI, age, sex and race-ethnicity. There was a significant interaction between BMI and presence of 2 (vs. 0) TCF7L2 SNP alleles on insulin sensitivity (OIIS) in children (p=0.0079) but not adults (p=0.94). After adjusting for age, ethnicity and sex, the difference did not reach statistical significance (p=0.0135). Restricting to non-obese participants, the results were similar. In sum, in nondiabetic AbPos individuals, the TCF7L2 variant does not appear to impact insulin sensitivity or secretion indices after accounting for BMI, age, sex and race-ethnicity. Disclosure M.J. Redondo: None. M.V. Warnock: None. L.E. Bocchino: None. S. Geyer: None. A. Pugliese: None. A. Steck: None. I. Libman: Consultant; Self; Novo Nordisk A/S. C. Evans-Molina: Consultant; Self; Bristol-Myers Squibb. D.J. Becker: None. J. Sosenko: None. F. Bacha: Research Support; Self; AstraZeneca, Takeda Development Center Americas, Inc. Funding National Institute of Diabetes and Digestive and Kidney Diseases
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db20-110-OR
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2020
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  • 7
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    1463-P: Heterozygous Variant in NFKB1 Presenting with Autoantibody-Negative (AbNeg) Insulin-Dependent Diabetes (IDDM)
    American Diabetes Association ; 2023
    In:  Diabetes Vol. 72, No. Supplement_1 ( 2023-06-20)
    Details
    In: Diabetes, American Diabetes Association, Vol. 72, No. Supplement_1 ( 2023-06-20)
    Abstract: Due to its uncertain etiology and clinical management, AbNeg IDDM is a phenotype of interest for the NIH-funded Rare and Atypical Diabetes Network (RADIANT), which aims to identify and characterize people with unknown forms of diabetes (DM). We report a case of childhood-onset AbNeg IDDM found to have a likely pathogenic variant in NFKB1. A 17-year-old female presented with DM at age 7 with A1c 10.8%; random C-peptide 0.21 ng/ml; no diabetic ketoacidosis; negative GAD65, insulin, IA-2 and ZnT8 Ab; normal BMI%ile; no signs of insulin resistance; and negative genetic testing for monogenic DM. She has required continuous insulin therapy. Past medical history: IgA deficiency, vitamin D deficiency, orthostatic intolerance, neurocardiogenic pre-syncope and chronic migraine. Family history: Autoimmune adult-onset DM and hypothyroidism in mother, frequent upper respiratory infections in sisters, Addison’s disease in maternal grandfather, hemochromatosis in paternal grandmother and pericarditis at age 30 in paternal grandfather. Physical exam: Unremarkable. RADIANT Labs: Undetectable serum C-peptide. Negative Ab. Whole genome sequencing: Heterozygous likely pathogenic variant in NFKB1 impacting the canonical splice acceptor sequence (NM_003998.4:c.1753-1G & gt;C). This is a case of youth-onset AbNeg IDDM found to have a likely pathogenic variant in NFKB1. Heterozygous loss-of-function variants in NFKB1 are associated with Common Variable Immunodeficiency (CVID) type 12 (OMIM #616576), characterized by incomplete penetrance and variable expressivity of immunodeficiency and autoimmunity, including features of IDDM. Immune dysregulation may explain lack of classic Ab. There are no prior reports of CVID first ascertained through a DM phenotype. Thus, this case represents a phenotype expansion of NFKB1-associated disease, and contributes to our understanding of the heterogeneity of AbNeg IDDM. Genetic testing of first-degree relatives is underway. Disclosure M.J.Redondo: None. A.Balasubramanyam: None. P.Liu: Other Relationship; Baylor Genetics. A.N.Alkanaq: None. M.Tosur: Advisory Panel; Provention Bio, Inc. N.Ram: None. R.J.Kreienkamp: None. E.A.Oral: Advisory Panel; Amryt Pharma Plc, Regeneron, Rejuvenate Bio, Third Rock Ventures, Consultant; Amryt Pharma Plc, Ionis Pharmaceuticals, Regeneron, Other Relationship; Amryt Pharma Plc, Research Support; Amryt Pharma Plc, Novo Nordisk, Fractyl Health, Inc., Ionis Pharmaceuticals, Regeneron, GI Dynamics, Rejuvenate Bio. C.Pihoker: None. J.Posey: None. Funding National Institutes of Health (U54DK118638)
    Type of Medium: Online Resource
    ISSN: 0012-1797
    URL: Article
    DOI: 10.2337/db23-1463-P
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2023
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  • 8
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    1318-P: Postprandial C-Peptide (pCP) in Provider-Diagnosed Pediatric Type 1 Diabetes (T1D) and Type 2 Diabetes (T2D)
    American Diabetes Association ; 2024
    In:  Diabetes Vol. 73, No. Supplement_1 ( 2024-06-14)
    Details
    In: Diabetes, American Diabetes Association, Vol. 73, No. Supplement_1 ( 2024-06-14)
    Abstract: Introduction & Objective: Classification of diabetes (DM) type (T1D vs T2D) is often challenging in adolescence, especially among non-White ethnic groups. We hypothesized that pCP differentiates between provider-diagnosed T1D and T2D in ethnically diverse youth with DM. Methods: We studied 410 youth in the Diabetes Study in Children of Diverse Ethnicity and Race (DISCOVER) Study. Low C-peptide, pre-defined as pCP & lt; 1.8 ng/ml (0.6 nmol/L) was compared between youth diagnosed with T1D and T2D using Fisher’s exact tests. Differences in the distribution of log pCP were assessed visually with histograms. Results: There were 356 youth diagnosed with T1D (age 8.4 ± 3.1 yrs; 55% female; 36% Hispanic, 19% non-Hispanic Black) and 54 (13%) with T2D (age 11.7 ±1.7 yrs; 71% female; 70% Hispanic, 21.4% non-Hispanic Black). Low pCP was observed in 97.8% of T1D vs 27.1% of T2D youth (p & lt;0.0001); 99.6% (T1D) vs 24.0% (T2D) (p & lt;0.0001) in those with DM duration & gt;4 yrs; 97.2% (T1D) vs 22.2% (T2D) (p & lt;0.0001) in those with simultaneous glucose & gt;115 mg/dl (6.4 mmol/L); and 99.5% (T1D) vs 11.1% (T2D) ( & lt;0.0001) in those with DM for & gt;4 yrs and glucose & gt;115 mg/dl (Figure). Conclusion: In ethnically diverse youth, pCP & lt;1.8 ng/ml can reliably identify those with provider-diagnosed T1D. Performance further improves in youth with DM duration & gt;4 yrs and a simultaneous glucose & gt;115 mg/dl. A sizeable subset of youth with T2D have lower pCP. Disclosure M.J. Redondo: None. K.K. Harrall: None. S.M. Bird: None. M. Tosur: None. S. Uysal: None. A.F. Siller: None. H.J. Velasquez: None. A. Muir: None. K. Vehik: None. T.M. Brusko: None. M.A. Atkinson: None. D. Dabelea: None. W. Hagopian: Research Support; Janssen Pharmaceuticals, Inc., Provention Bio, Inc. Consultant; Sanofi-Aventis U.S., Randox R & D. R.A. Oram: Research Support; Randox R & D. Consultant; Provention Bio, Inc., Sanofi. Funding National Institutes of Health (NIDDK R01DK124395)
    Type of Medium: Online Resource
    ISSN: 0012-1797
    URL: Article
    DOI: 10.2337/db24-1318-P
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2024
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  • 9
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    348-OR: Metabolic Phenotype of Autoantibody Positive (AbPos) Long-Term Nonprogressors (LTNPs) to Type 1 Diabetes (T1D)
    American Diabetes Association ; 2020
    In:  Diabetes Vol. 69, No. Supplement_1 ( 2020-06-01)
    Details
    In: Diabetes, American Diabetes Association, Vol. 69, No. Supplement_1 ( 2020-06-01)
    Abstract: Few studies have described the metabolic phenotype of AbPos individuals who remain T1D free for an extended period of time. We aimed to compare C-peptide and glucose (Glu) data from oral glucose tolerance tests (OGTTs) performed longitudinally in 646 AbPos TrialNet Pathway to Prevention (PTP) participants who remained T1D free for ≥5.0 yrs (LTNPs; mean follow-up: 7.8±2.3 yrs) versus 405 Rapid Progressor (RP) PTP participants who progressed to T1D within & lt;2 yrs of study entry (mean follow-up 0.97±0.54 yrs) and 150 Ab negative (AbNeg) controls. At study entry, 48% of LTNPs were single AbPos and 52% were multiple AbPos; 45.8% of single AbPos LTNPs became multiple AbPos during follow-up. LTNPs were older (mean age 18.8 ± 14.1 yrs) compared to RPs (11.8 ± 9.3 yrs) and AbNeg individuals (16 ± 10 yrs) (p & lt;0.001). LTNPS exhibited an intermediate metabolic phenotype, with age and BMIZ-adjusted C-peptide area under the curve (AUC) and 30-0 min C-peptide values that were lower than AbNegs but higher than RPs (p & lt;0.001), and Index60 levels (a composite of glucose and C-peptide values from OGTTs) that were higher than AbNegs but lower than RPs (p & lt;0.001). Longitudinal trends in LTNPs were analyzed using fitted linear mixed models. Multiple AbPos LTNPs had higher Glu AUC (p=0.01) and Index60 values (p=0.032) compared to single AbPos LTNPs. However within both AbPos groups, metabolic patterns were remarkably stable over extended follow-up. When measures were evaluated for non-linear interactions using a regression tree analysis, the combination of Index60 & lt;1.06 + Glu AUC & lt;137.7 at baseline was associated with an odds ratio of 8.55 (p & lt;0.001) of being a LTNP. These data suggest that, while β cell function is reduced in LTNPs at the time of AbPos identification, longitudinal Glu and C-peptide patterns are largely stable without evidence of a relapsing or remitting course. Baseline OGTT measures (here, Index 60 and Glu AUC) may be able to predict AbPos individuals with lower risk of progression to T1D. Disclosure C. Evans-Molina: Consultant; Self; Bristol-Myers Squibb. Z.I. Saeed: None. J. Sosenko: None. M.A. Atkinson: None. K.C. Herold: Consultant; Self; Provention Bio, Inc. H.M. Ismail: None. H. Elding Larsson: None. M. Lundgren: None. A. Moran: Research Support; Self; Abbott, Intrexon, JDRF, Medtronic, National Institute of Diabetes and Digestive and Kidney Diseases, Provention Bio, Inc. Other Relationship; Self; Novo Nordisk Inc. D.J. Moore: None. B.M. Nathan: None. J.P. Palmer: None. E.K. Sims: None. A. Steck: None. D.K. Wherrett: None. M.J. Redondo: None. Funding National Institutes of Health (U01107014, U01DK106993)
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db20-348-OR
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2020
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  • 10
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    1618-P: Insulin Secretion Variability According to the Specific Type 1 Diabetes (T1D) Risk Predictor
    American Diabetes Association ; 2020
    In:  Diabetes Vol. 69, No. Supplement_1 ( 2020-06-01)
    Details
    In: Diabetes, American Diabetes Association, Vol. 69, No. Supplement_1 ( 2020-06-01)
    Abstract: The risk for T1D, a major criterion for entry into disease prevention trials, can be assessed in various ways, but usually includes autoantibody (Ab) and/or metabolic measures. Given inherent variations in these biomarkers, it is possible that informative characteristics differ between populations selected by different risk measures. Thus, we assessed whether indices of insulin secretion [C-pep; first phase insulin response (FPIR)] vary between groups defined by distinctive risk measures. We used data from Diabetes Prevention Trial-Type 1 (DPT-1) participants, all being ICA positive subjects with or without biochemical Ab (bAb) positivity (GADA, IA-2A, mIAA). C-pep and FPIR values from baseline oral and intravenous glucose tolerance tests were compared between those who had 2-3 bAbs (≥2bAb) and those who had 0-1 bAb plus Index60≥0.40 (≤1bAb+Ind60). Index60 is a composite C-pep and glucose measure. These groups were chosen so that T1D risk would be similar (50% 5-year risk for both, log rank p=0.95). Ages (mean±SD) for ≥2bAb (n=289) and ≤1bAb+Ind60 (n=175) were 12.8±8.2 and 13.3±9.6 yrs, respectively (p=0.53). BMI Z-score was greater for ≥2bAb (0.42±1.12 vs. 0.15±1.09, p=0.01). C-pep levels were consistently higher for ≥2bAb than ≤1bAb+Ind60 [30-0 minute C-pep: 2.73±1.58 vs. 2.04±1.12 ng/mL, p & lt;0.0001; area under the curve (AUC) C-pep: 3.70±1.55 vs. 3.27±1.12 ng/ml, p=0.013; AUC C-pep/AUC glucose: 0.030±0.013 vs. 0.025±0.007 (ng/ml)/(mg/dl), p & lt;0.001]. FPIR was also higher for ≥2bAb (122.0±87.3 vs. 96.2±47.1 µU/ml, p & lt;0.01). All comparisons remained significant with adjustments for age and BMI Z-score. Of those with ≤1bAb+Ind60, 0 bAb did not differ from 1 bAb for C-pep indices or FPIR. In conclusion, C-pep and FPIR values can differ appreciably according to the measure that defines risk. This should be considered in choosing risk measures for prevention trials. Disclosure L.M. Jacobsen: None. B.M. Nathan: None. H.M. Ismail: None. M.J. Redondo: None. D. Schatz: None. M.J. Haller: Advisory Panel; Self; SAB Biotherapeutics, Inc. E.K. Sims: None. J.S. Skyler: Advisory Panel; Self; Abvance Therapeutics, ADOCIA, Avotres, Boehringer Ingelheim Pharmaceuticals, Inc., Dance Biopharm Holdings, Inc., Immunomolecular Therapeutics, Intrexon, Oramed Pharmaceuticals, Orgenesis Inc., Sanofi, Tolerion, Inc., Viacyte, Inc. Board Member; Self; Applied Therapeutics, Dexcom, Inc., Intarcia Therapeutics. Consultant; Self; Novo Nordisk A/S. Research Support; Self; Tolerion, Inc. Stock/Shareholder; Self; Applied Therapeutics, Dexcom, Inc., Intarcia Therapeutics. J.P. Palmer: None. K.C. Herold: Consultant; Self; Provention Bio, Inc. J. Sosenko: None.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db20-1618-P
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2020
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