Persistence of β-Cell Responsiveness for Over Two Years in Autoantibody-Positive Children With Marked Metabolic Impairment at Screening

Emily K. Sims; David Cuthbertson; Jamie L. Felton; Heba M. Ismail; Brandon M. Nathan; Laura M. Jacobsen; Emily Paprocki; Alberto Pugliese; Jerry Palmer; Mark Atkinson; Carmella Evans-Molina; Jay S. Skyler; Maria J. Redondo; Kevan C. Herold; Jay M. Sosenko

doi:10.2337/dc22-1362

Persistence of β-Cell Responsiveness for Over Two Years in Autoantibody-Positive Children With Marked Metabolic Impairment at Screening

Emily K. Sims, David Cuthbertson, Jamie L. Felton, Heba M. Ismail, Brandon M. Nathan, Laura M. Jacobsen, Emily Paprocki, Alberto Pugliese, Jerry Palmer, Mark Atkinson, Carmella Evans-Molina, Jay S. Skyler, Maria J. Redondo, Kevan C. Herold, Jay M. Sosenko

Pediatric Endocrinology

Research output: Contribution to journal › Article › peer-review

Abstract

OBJECTIVE: We studied longitudinal differences between progressors and nonprogressors to type 1 diabetes with similar and substantial baseline risk.

RESEARCH DESIGN AND METHODS: Changes in 2-h oral glucose tolerance test indices were used to examine variability in diabetes progression in the Diabetes Prevention Trial-Type 1 (DPT-1) study (n = 246) and Type 1 Diabetes TrialNet Pathway to Prevention study (TNPTP) (n = 503) among autoantibody (Ab)+ children (aged <18.0 years) with similar baseline metabolic impairment (DPT-1 Risk Score [DPTRS] of 6.5-7.5), as well as in TNPTP Ab- children (n = 94).

RESULTS: Longitudinal analyses revealed annualized area under the curve (AUC) of C-peptide increases in nonprogressors versus decreases in progressors (P ≤ 0.026 for DPT-1 and TNPTP). Vector indices for AUC glucose and AUC C-peptide changes (on a two-dimensional grid) also differed significantly (P < 0.001). Despite marked baseline metabolic impairment of nonprogressors, changes in AUC C-peptide, AUC glucose, AUC C-peptide-to-AUC glucose ratio (AUC ratio), and Index60 did not differ from Ab- relatives during follow-up. Divergence between nonprogressors and progressors occurred by 6 months from baseline in both cohorts (AUC glucose, P ≤ 0.007; AUC ratio, P ≤ 0.034; Index60, P < 0.001; vector indices of change, P < 0.001). Differences in 6-month change were positively associated with greater diabetes risk (respectively, P < 0.001, P ≤ 0.019, P < 0.001, and P < 0.001) in DPT-1 and TNPTP, except AUC ratio, which was inversely associated with risk (P < 0.001).

CONCLUSIONS: Novel findings show that even with similarly abnormal baseline risk, progressors had appreciably more metabolic impairment than nonprogressors within 6 months and that the measures showing impairment were predictive of type 1 diabetes. Longitudinal metabolic patterns did not differ between nonprogressors and Ab- relatives, suggesting persistent β-cell responsiveness in nonprogressors.

Original language	English (US)
Pages (from-to)	2982-2990
Number of pages	9
Journal	Diabetes care
Volume	45
Issue number	12
DOIs	https://doi.org/10.2337/dc22-1362
State	Published - Dec 2022

Bibliographical note

Funding Information:
Acknowledgments. The authors acknowledge the support of the Type 1 Diabetes TrialNet Study Group, which identified study participants and provided samples and follow-up data for this study. Funding. The Type 1 Diabetes TrialNet Study Group is a clinical trials network funded by the National Institutes of Health (NIH) through the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Institute of Allergy and Infectious Diseases, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development, through cooperative agreements U01 DK061010, U01 DK061034, U01 DK061042, U01 DK061058, U01 DK085465, U01 DK085453, U01 DK085461, U01 DK085466, U01 DK085499, U01 DK085504, U01 DK085509, U01 DK103180, U01 DK103153, U01 DK085476, U01 DK103266, U01 DK103282, U01 DK106984, U01 DK106994, U01 DK107013, U01 DK107014, UC4 DK097835, and UC4 DK106993, and JDRF. E.K.S. receives support from NIH grants R01 DK121929, and U01DK127382-012. E.K.S. was also supported by the Doris Duke Charitable Foundation (grant 2021258) through the COVID-19 Fund to Retain Clinical Scientists collaborative grant program and supported by the John Templeton Foundation (grant 62288). M.J.R. was supported by NIH grants R01 DK121843 and R01 DK124395.

Publisher Copyright:
© 2022 by the American Diabetes Association.

Keywords

Child
Humans
C-Peptide/metabolism
Diabetes Mellitus, Type 1/diagnosis
Blood Glucose/metabolism
Glucose Tolerance Test
Autoantibodies
Glucose
Disease Progression

PubMed: MeSH publication types

Research Support, Non-U.S. Gov't
Journal Article
Research Support, N.I.H., Extramural

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.2337/dc22-1362

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Sims, E. K., Cuthbertson, D., Felton, J. L., Ismail, H. M., Nathan, B. M., Jacobsen, L. M., Paprocki, E., Pugliese, A., Palmer, J., Atkinson, M., Evans-Molina, C., Skyler, J. S., Redondo, M. J., Herold, K. C., & Sosenko, J. M. (2022). Persistence of β-Cell Responsiveness for Over Two Years in Autoantibody-Positive Children With Marked Metabolic Impairment at Screening. Diabetes care, 45(12), 2982-2990. https://doi.org/10.2337/dc22-1362

Sims, EK, Cuthbertson, D, Felton, JL, Ismail, HM, Nathan, BM, Jacobsen, LM, Paprocki, E, Pugliese, A, Palmer, J, Atkinson, M, Evans-Molina, C, Skyler, JS, Redondo, MJ, Herold, KC & Sosenko, JM 2022, 'Persistence of β-Cell Responsiveness for Over Two Years in Autoantibody-Positive Children With Marked Metabolic Impairment at Screening', Diabetes care, vol. 45, no. 12, pp. 2982-2990. https://doi.org/10.2337/dc22-1362

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title = "Persistence of β-Cell Responsiveness for Over Two Years in Autoantibody-Positive Children With Marked Metabolic Impairment at Screening",

abstract = "OBJECTIVE: We studied longitudinal differences between progressors and nonprogressors to type 1 diabetes with similar and substantial baseline risk.RESEARCH DESIGN AND METHODS: Changes in 2-h oral glucose tolerance test indices were used to examine variability in diabetes progression in the Diabetes Prevention Trial-Type 1 (DPT-1) study (n = 246) and Type 1 Diabetes TrialNet Pathway to Prevention study (TNPTP) (n = 503) among autoantibody (Ab)+ children (aged <18.0 years) with similar baseline metabolic impairment (DPT-1 Risk Score [DPTRS] of 6.5-7.5), as well as in TNPTP Ab- children (n = 94).RESULTS: Longitudinal analyses revealed annualized area under the curve (AUC) of C-peptide increases in nonprogressors versus decreases in progressors (P ≤ 0.026 for DPT-1 and TNPTP). Vector indices for AUC glucose and AUC C-peptide changes (on a two-dimensional grid) also differed significantly (P < 0.001). Despite marked baseline metabolic impairment of nonprogressors, changes in AUC C-peptide, AUC glucose, AUC C-peptide-to-AUC glucose ratio (AUC ratio), and Index60 did not differ from Ab- relatives during follow-up. Divergence between nonprogressors and progressors occurred by 6 months from baseline in both cohorts (AUC glucose, P ≤ 0.007; AUC ratio, P ≤ 0.034; Index60, P < 0.001; vector indices of change, P < 0.001). Differences in 6-month change were positively associated with greater diabetes risk (respectively, P < 0.001, P ≤ 0.019, P < 0.001, and P < 0.001) in DPT-1 and TNPTP, except AUC ratio, which was inversely associated with risk (P < 0.001).CONCLUSIONS: Novel findings show that even with similarly abnormal baseline risk, progressors had appreciably more metabolic impairment than nonprogressors within 6 months and that the measures showing impairment were predictive of type 1 diabetes. Longitudinal metabolic patterns did not differ between nonprogressors and Ab- relatives, suggesting persistent β-cell responsiveness in nonprogressors.",

keywords = "Child, Humans, C-Peptide/metabolism, Diabetes Mellitus, Type 1/diagnosis, Blood Glucose/metabolism, Glucose Tolerance Test, Autoantibodies, Glucose, Disease Progression",

author = "Sims, {Emily K.} and David Cuthbertson and Felton, {Jamie L.} and Ismail, {Heba M.} and Nathan, {Brandon M.} and Jacobsen, {Laura M.} and Emily Paprocki and Alberto Pugliese and Jerry Palmer and Mark Atkinson and Carmella Evans-Molina and Skyler, {Jay S.} and Redondo, {Maria J.} and Herold, {Kevan C.} and Sosenko, {Jay M.}",

note = "Funding Information: Acknowledgments. The authors acknowledge the support of the Type 1 Diabetes TrialNet Study Group, which identified study participants and provided samples and follow-up data for this study. Funding. The Type 1 Diabetes TrialNet Study Group is a clinical trials network funded by the National Institutes of Health (NIH) through the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Institute of Allergy and Infectious Diseases, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development, through cooperative agreements U01 DK061010, U01 DK061034, U01 DK061042, U01 DK061058, U01 DK085465, U01 DK085453, U01 DK085461, U01 DK085466, U01 DK085499, U01 DK085504, U01 DK085509, U01 DK103180, U01 DK103153, U01 DK085476, U01 DK103266, U01 DK103282, U01 DK106984, U01 DK106994, U01 DK107013, U01 DK107014, UC4 DK097835, and UC4 DK106993, and JDRF. E.K.S. receives support from NIH grants R01 DK121929, and U01DK127382-012. E.K.S. was also supported by the Doris Duke Charitable Foundation (grant 2021258) through the COVID-19 Fund to Retain Clinical Scientists collaborative grant program and supported by the John Templeton Foundation (grant 62288). M.J.R. was supported by NIH grants R01 DK121843 and R01 DK124395. Publisher Copyright: {\textcopyright} 2022 by the American Diabetes Association.",

year = "2022",

month = dec,

doi = "10.2337/dc22-1362",

language = "English (US)",

volume = "45",

pages = "2982--2990",

journal = "Diabetes Care",

issn = "1935-5548",

publisher = "American Diabetes Association Inc.",

number = "12",

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TY - JOUR

T1 - Persistence of β-Cell Responsiveness for Over Two Years in Autoantibody-Positive Children With Marked Metabolic Impairment at Screening

AU - Sims, Emily K.

AU - Cuthbertson, David

AU - Felton, Jamie L.

AU - Ismail, Heba M.

AU - Nathan, Brandon M.

AU - Jacobsen, Laura M.

AU - Paprocki, Emily

AU - Pugliese, Alberto

AU - Palmer, Jerry

AU - Atkinson, Mark

AU - Evans-Molina, Carmella

AU - Skyler, Jay S.

AU - Redondo, Maria J.

AU - Herold, Kevan C.

AU - Sosenko, Jay M.

N1 - Funding Information: Acknowledgments. The authors acknowledge the support of the Type 1 Diabetes TrialNet Study Group, which identified study participants and provided samples and follow-up data for this study. Funding. The Type 1 Diabetes TrialNet Study Group is a clinical trials network funded by the National Institutes of Health (NIH) through the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Institute of Allergy and Infectious Diseases, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development, through cooperative agreements U01 DK061010, U01 DK061034, U01 DK061042, U01 DK061058, U01 DK085465, U01 DK085453, U01 DK085461, U01 DK085466, U01 DK085499, U01 DK085504, U01 DK085509, U01 DK103180, U01 DK103153, U01 DK085476, U01 DK103266, U01 DK103282, U01 DK106984, U01 DK106994, U01 DK107013, U01 DK107014, UC4 DK097835, and UC4 DK106993, and JDRF. E.K.S. receives support from NIH grants R01 DK121929, and U01DK127382-012. E.K.S. was also supported by the Doris Duke Charitable Foundation (grant 2021258) through the COVID-19 Fund to Retain Clinical Scientists collaborative grant program and supported by the John Templeton Foundation (grant 62288). M.J.R. was supported by NIH grants R01 DK121843 and R01 DK124395. Publisher Copyright: © 2022 by the American Diabetes Association.

PY - 2022/12

Y1 - 2022/12

N2 - OBJECTIVE: We studied longitudinal differences between progressors and nonprogressors to type 1 diabetes with similar and substantial baseline risk.RESEARCH DESIGN AND METHODS: Changes in 2-h oral glucose tolerance test indices were used to examine variability in diabetes progression in the Diabetes Prevention Trial-Type 1 (DPT-1) study (n = 246) and Type 1 Diabetes TrialNet Pathway to Prevention study (TNPTP) (n = 503) among autoantibody (Ab)+ children (aged <18.0 years) with similar baseline metabolic impairment (DPT-1 Risk Score [DPTRS] of 6.5-7.5), as well as in TNPTP Ab- children (n = 94).RESULTS: Longitudinal analyses revealed annualized area under the curve (AUC) of C-peptide increases in nonprogressors versus decreases in progressors (P ≤ 0.026 for DPT-1 and TNPTP). Vector indices for AUC glucose and AUC C-peptide changes (on a two-dimensional grid) also differed significantly (P < 0.001). Despite marked baseline metabolic impairment of nonprogressors, changes in AUC C-peptide, AUC glucose, AUC C-peptide-to-AUC glucose ratio (AUC ratio), and Index60 did not differ from Ab- relatives during follow-up. Divergence between nonprogressors and progressors occurred by 6 months from baseline in both cohorts (AUC glucose, P ≤ 0.007; AUC ratio, P ≤ 0.034; Index60, P < 0.001; vector indices of change, P < 0.001). Differences in 6-month change were positively associated with greater diabetes risk (respectively, P < 0.001, P ≤ 0.019, P < 0.001, and P < 0.001) in DPT-1 and TNPTP, except AUC ratio, which was inversely associated with risk (P < 0.001).CONCLUSIONS: Novel findings show that even with similarly abnormal baseline risk, progressors had appreciably more metabolic impairment than nonprogressors within 6 months and that the measures showing impairment were predictive of type 1 diabetes. Longitudinal metabolic patterns did not differ between nonprogressors and Ab- relatives, suggesting persistent β-cell responsiveness in nonprogressors.

AB - OBJECTIVE: We studied longitudinal differences between progressors and nonprogressors to type 1 diabetes with similar and substantial baseline risk.RESEARCH DESIGN AND METHODS: Changes in 2-h oral glucose tolerance test indices were used to examine variability in diabetes progression in the Diabetes Prevention Trial-Type 1 (DPT-1) study (n = 246) and Type 1 Diabetes TrialNet Pathway to Prevention study (TNPTP) (n = 503) among autoantibody (Ab)+ children (aged <18.0 years) with similar baseline metabolic impairment (DPT-1 Risk Score [DPTRS] of 6.5-7.5), as well as in TNPTP Ab- children (n = 94).RESULTS: Longitudinal analyses revealed annualized area under the curve (AUC) of C-peptide increases in nonprogressors versus decreases in progressors (P ≤ 0.026 for DPT-1 and TNPTP). Vector indices for AUC glucose and AUC C-peptide changes (on a two-dimensional grid) also differed significantly (P < 0.001). Despite marked baseline metabolic impairment of nonprogressors, changes in AUC C-peptide, AUC glucose, AUC C-peptide-to-AUC glucose ratio (AUC ratio), and Index60 did not differ from Ab- relatives during follow-up. Divergence between nonprogressors and progressors occurred by 6 months from baseline in both cohorts (AUC glucose, P ≤ 0.007; AUC ratio, P ≤ 0.034; Index60, P < 0.001; vector indices of change, P < 0.001). Differences in 6-month change were positively associated with greater diabetes risk (respectively, P < 0.001, P ≤ 0.019, P < 0.001, and P < 0.001) in DPT-1 and TNPTP, except AUC ratio, which was inversely associated with risk (P < 0.001).CONCLUSIONS: Novel findings show that even with similarly abnormal baseline risk, progressors had appreciably more metabolic impairment than nonprogressors within 6 months and that the measures showing impairment were predictive of type 1 diabetes. Longitudinal metabolic patterns did not differ between nonprogressors and Ab- relatives, suggesting persistent β-cell responsiveness in nonprogressors.

KW - Child

KW - Humans

KW - C-Peptide/metabolism

KW - Diabetes Mellitus, Type 1/diagnosis

KW - Blood Glucose/metabolism

KW - Glucose Tolerance Test

KW - Autoantibodies

KW - Glucose

KW - Disease Progression

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U2 - 10.2337/dc22-1362

DO - 10.2337/dc22-1362

M3 - Article

C2 - 36326757

AN - SCOPUS:85143198302

SN - 1935-5548

VL - 45

SP - 2982

EP - 2990

JO - Diabetes Care

JF - Diabetes Care

IS - 12

ER -

Persistence of β-Cell Responsiveness for Over Two Years in Autoantibody-Positive Children With Marked Metabolic Impairment at Screening

Abstract

Bibliographical note

Keywords

PubMed: MeSH publication types

UN SDGs

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