Index60 Identifies Individuals at Appreciable Risk for Stage 3 Among an Autoantibody-Positive Population With Normal 2-Hour Glucose Levels: Implications for Current Staging Criteria of Type 1 Diabetes

Brandon M. Nathan; Maria J. Redondo; Heba Ismail; Laura Jacobsen; Emily K. Sims; Jerry Palmer; Jay Skyler; Laura Bocchino; Susan Geyer; Jay M. Sosenko

doi:10.2337/dc21-0944

Index60 Identifies Individuals at Appreciable Risk for Stage 3 Among an Autoantibody-Positive Population With Normal 2-Hour Glucose Levels: Implications for Current Staging Criteria of Type 1 Diabetes

Brandon M. Nathan, Maria J. Redondo, Heba Ismail, Laura Jacobsen, Emily K. Sims, Jerry Palmer, Jay Skyler, Laura Bocchino, Susan Geyer, Jay M. Sosenko

Pediatric Endocrinology

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

20 Scopus citations

Abstract

OBJECTIVE: We assessed whether Index60, a composite measure of fasting C-peptide, 60-min C-peptide, and 60-min glucose, could improve the metabolic staging of type 1 diabetes for progression to clinical disease (stage 3) among autoantibody-positive (Ab+) individuals with normal 2-h glucose values (<140 mg/dL).

RESEARCH DESIGN AND METHODS: We analyzed 3,058 Type 1 Diabetes TrialNet Pathway to Prevention participants with 2-h glucose <140 mg/dL and Index60 <1.00 values from baseline oral glucose tolerance tests. Characteristics associated with type 1 diabetes (younger age, greater Ab+, higher HLA DR3-DQ2/DR4-DQ8 prevalence, and lower C-peptide) were compared among four mutually exclusive groups: top 2-h glucose quartile only (HI-2HGLU), top Index60 quartile only (HI-IND60), both top quartiles (HI-BOTH), and neither top quartile (LO-BOTH). Additionally, within the 2-h glucose distribution of <140 mg/dL and separately within the Index60 <1.00 distribution, comparisons were made between those above or below the medians.

RESULTS: HI-IND60 and HI-BOTH were younger, with greater frequency of more than two Ab+, and lower C-peptide levels, than either HI-2HGLU or LO-BOTH (all P < 0.001). The cumulative incidence for stage 3 was greater for HI-IND60 and HI-BOTH than for either HI-2HGLU or LO-BOTH (all P < 0.001). Those with Index60 values above the median were younger and had higher frequency of two or more Ab+ (P < 0.001) and DR3-DQ2/DR4-DQ8 prevalence (P < 0.001) and lower area under the curve (AUC) C-peptide levels (P < 0.001) than those below. Those above the 2-h glucose median had higher AUC C-peptide levels (P < 0.001), but otherwise did not differ from those below.

CONCLUSIONS: Index60 identifies individuals with characteristics of type 1 diabetes at appreciable risk for progression who would otherwise be missed by 2-h glucose staging criteria.

Original language	English (US)
Pages (from-to)	311-318
Number of pages	8
Journal	Diabetes care
Volume	45
Issue number	2
DOIs	https://doi.org/10.2337/dc21-0944
State	Published - Feb 2022

Bibliographical note

Funding Information:
Funding. This trial was sponsored by the Type 1 Diabetes TrialNet Study Group, a clinical trials network funded by the National Institutes of Health through the National Institute of Diabetes and Digestive and Kidney Diseases, 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-DK-061010, U01-DK-061034, U01-DK-0 61042, U01-DK-061058, U01-DK-085465, U01-DK-0 85453, U01-DK-0854 61, U01-DK-085466, U01-D K-085499, U01-DK-085504, U01-DK-085509, U01-DK-103180, U01-DK-103153, U01-DK-085476, U01-DK-103266, U01-DK-103282, U01-DK-106984, U01-DK-106994, U01-DK-107013, U01-DK-107014, and UC4-DK-106993, JDRF, the Victorian State Government Operational Infrastructure Support Program, and the National Health and Medical Research Council Research Institute Infrastructure Support Scheme. Duality of Interest. No potential conflicts of interest relevant to this article were reported. Author Contributions. B.M.N. conceived the study design, wrote the manuscript, and researched data. M.J.R. contributed to the discussion and reviewed/edited the manuscript. H.I., L.J., E.K.S., J.P., and J.S. reviewed/edited the manuscript. L.B. researched data, performed statistical analysis, and reviewed/edited the manuscript. S.G. researched data, performed statistical analyses, contributed to the discussion, and reviewed/edited the manuscript. J.M.S. conceived the study design, researched data, performed statistical analyses, and wrote the manuscript. All authors reviewed and approved the final submission. B.M.N. and J.M.S. are the guarantors of this work and, as such, had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

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© The Authors.

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

UN SDGs

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

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10.2337/dc21-0944

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Nathan, B. M., Redondo, M. J., Ismail, H., Jacobsen, L., Sims, E. K., Palmer, J., Skyler, J., Bocchino, L., Geyer, S., & Sosenko, J. M. (2022). Index60 Identifies Individuals at Appreciable Risk for Stage 3 Among an Autoantibody-Positive Population With Normal 2-Hour Glucose Levels: Implications for Current Staging Criteria of Type 1 Diabetes. Diabetes care, 45(2), 311-318. https://doi.org/10.2337/dc21-0944

Index60 Identifies Individuals at Appreciable Risk for Stage 3 Among an Autoantibody-Positive Population With Normal 2-Hour Glucose Levels: Implications for Current Staging Criteria of Type 1 Diabetes. / Nathan, Brandon M.; Redondo, Maria J.; Ismail, Heba et al.
In: Diabetes care, Vol. 45, No. 2, 02.2022, p. 311-318.

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

Nathan, BM, Redondo, MJ, Ismail, H, Jacobsen, L, Sims, EK, Palmer, J, Skyler, J, Bocchino, L, Geyer, S & Sosenko, JM 2022, 'Index60 Identifies Individuals at Appreciable Risk for Stage 3 Among an Autoantibody-Positive Population With Normal 2-Hour Glucose Levels: Implications for Current Staging Criteria of Type 1 Diabetes', Diabetes care, vol. 45, no. 2, pp. 311-318. https://doi.org/10.2337/dc21-0944

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title = "Index60 Identifies Individuals at Appreciable Risk for Stage 3 Among an Autoantibody-Positive Population With Normal 2-Hour Glucose Levels: Implications for Current Staging Criteria of Type 1 Diabetes",

abstract = "OBJECTIVE: We assessed whether Index60, a composite measure of fasting C-peptide, 60-min C-peptide, and 60-min glucose, could improve the metabolic staging of type 1 diabetes for progression to clinical disease (stage 3) among autoantibody-positive (Ab+) individuals with normal 2-h glucose values (<140 mg/dL).RESEARCH DESIGN AND METHODS: We analyzed 3,058 Type 1 Diabetes TrialNet Pathway to Prevention participants with 2-h glucose <140 mg/dL and Index60 <1.00 values from baseline oral glucose tolerance tests. Characteristics associated with type 1 diabetes (younger age, greater Ab+, higher HLA DR3-DQ2/DR4-DQ8 prevalence, and lower C-peptide) were compared among four mutually exclusive groups: top 2-h glucose quartile only (HI-2HGLU), top Index60 quartile only (HI-IND60), both top quartiles (HI-BOTH), and neither top quartile (LO-BOTH). Additionally, within the 2-h glucose distribution of <140 mg/dL and separately within the Index60 <1.00 distribution, comparisons were made between those above or below the medians.RESULTS: HI-IND60 and HI-BOTH were younger, with greater frequency of more than two Ab+, and lower C-peptide levels, than either HI-2HGLU or LO-BOTH (all P < 0.001). The cumulative incidence for stage 3 was greater for HI-IND60 and HI-BOTH than for either HI-2HGLU or LO-BOTH (all P < 0.001). Those with Index60 values above the median were younger and had higher frequency of two or more Ab+ (P < 0.001) and DR3-DQ2/DR4-DQ8 prevalence (P < 0.001) and lower area under the curve (AUC) C-peptide levels (P < 0.001) than those below. Those above the 2-h glucose median had higher AUC C-peptide levels (P < 0.001), but otherwise did not differ from those below.CONCLUSIONS: Index60 identifies individuals with characteristics of type 1 diabetes at appreciable risk for progression who would otherwise be missed by 2-h glucose staging criteria.",

author = "Nathan, {Brandon M.} and Redondo, {Maria J.} and Heba Ismail and Laura Jacobsen and Sims, {Emily K.} and Jerry Palmer and Jay Skyler and Laura Bocchino and Susan Geyer and Sosenko, {Jay M.}",

note = "Funding Information: Funding. This trial was sponsored by the Type 1 Diabetes TrialNet Study Group, a clinical trials network funded by the National Institutes of Health through the National Institute of Diabetes and Digestive and Kidney Diseases, 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-DK-061010, U01-DK-061034, U01-DK-0 61042, U01-DK-061058, U01-DK-085465, U01-DK-0 85453, U01-DK-0854 61, U01-DK-085466, U01-D K-085499, U01-DK-085504, U01-DK-085509, U01-DK-103180, U01-DK-103153, U01-DK-085476, U01-DK-103266, U01-DK-103282, U01-DK-106984, U01-DK-106994, U01-DK-107013, U01-DK-107014, and UC4-DK-106993, JDRF, the Victorian State Government Operational Infrastructure Support Program, and the National Health and Medical Research Council Research Institute Infrastructure Support Scheme. Duality of Interest. No potential conflicts of interest relevant to this article were reported. Author Contributions. B.M.N. conceived the study design, wrote the manuscript, and researched data. M.J.R. contributed to the discussion and reviewed/edited the manuscript. H.I., L.J., E.K.S., J.P., and J.S. reviewed/edited the manuscript. L.B. researched data, performed statistical analysis, and reviewed/edited the manuscript. S.G. researched data, performed statistical analyses, contributed to the discussion, and reviewed/edited the manuscript. J.M.S. conceived the study design, researched data, performed statistical analyses, and wrote the manuscript. All authors reviewed and approved the final submission. B.M.N. and J.M.S. are the guarantors of this work and, as such, had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Publisher Copyright: {\textcopyright} The Authors.",

year = "2022",

month = feb,

doi = "10.2337/dc21-0944",

language = "English (US)",

volume = "45",

pages = "311--318",

journal = "Diabetes care",

issn = "0149-5992",

publisher = "American Diabetes Association Inc.",

number = "2",

}

TY - JOUR

T1 - Index60 Identifies Individuals at Appreciable Risk for Stage 3 Among an Autoantibody-Positive Population With Normal 2-Hour Glucose Levels

T2 - Implications for Current Staging Criteria of Type 1 Diabetes

AU - Nathan, Brandon M.

AU - Redondo, Maria J.

AU - Ismail, Heba

AU - Jacobsen, Laura

AU - Sims, Emily K.

AU - Palmer, Jerry

AU - Skyler, Jay

AU - Bocchino, Laura

AU - Geyer, Susan

AU - Sosenko, Jay M.

N1 - Funding Information: Funding. This trial was sponsored by the Type 1 Diabetes TrialNet Study Group, a clinical trials network funded by the National Institutes of Health through the National Institute of Diabetes and Digestive and Kidney Diseases, 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-DK-061010, U01-DK-061034, U01-DK-0 61042, U01-DK-061058, U01-DK-085465, U01-DK-0 85453, U01-DK-0854 61, U01-DK-085466, U01-D K-085499, U01-DK-085504, U01-DK-085509, U01-DK-103180, U01-DK-103153, U01-DK-085476, U01-DK-103266, U01-DK-103282, U01-DK-106984, U01-DK-106994, U01-DK-107013, U01-DK-107014, and UC4-DK-106993, JDRF, the Victorian State Government Operational Infrastructure Support Program, and the National Health and Medical Research Council Research Institute Infrastructure Support Scheme. Duality of Interest. No potential conflicts of interest relevant to this article were reported. Author Contributions. B.M.N. conceived the study design, wrote the manuscript, and researched data. M.J.R. contributed to the discussion and reviewed/edited the manuscript. H.I., L.J., E.K.S., J.P., and J.S. reviewed/edited the manuscript. L.B. researched data, performed statistical analysis, and reviewed/edited the manuscript. S.G. researched data, performed statistical analyses, contributed to the discussion, and reviewed/edited the manuscript. J.M.S. conceived the study design, researched data, performed statistical analyses, and wrote the manuscript. All authors reviewed and approved the final submission. B.M.N. and J.M.S. are the guarantors of this work and, as such, had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Publisher Copyright: © The Authors.

PY - 2022/2

Y1 - 2022/2

N2 - OBJECTIVE: We assessed whether Index60, a composite measure of fasting C-peptide, 60-min C-peptide, and 60-min glucose, could improve the metabolic staging of type 1 diabetes for progression to clinical disease (stage 3) among autoantibody-positive (Ab+) individuals with normal 2-h glucose values (<140 mg/dL).RESEARCH DESIGN AND METHODS: We analyzed 3,058 Type 1 Diabetes TrialNet Pathway to Prevention participants with 2-h glucose <140 mg/dL and Index60 <1.00 values from baseline oral glucose tolerance tests. Characteristics associated with type 1 diabetes (younger age, greater Ab+, higher HLA DR3-DQ2/DR4-DQ8 prevalence, and lower C-peptide) were compared among four mutually exclusive groups: top 2-h glucose quartile only (HI-2HGLU), top Index60 quartile only (HI-IND60), both top quartiles (HI-BOTH), and neither top quartile (LO-BOTH). Additionally, within the 2-h glucose distribution of <140 mg/dL and separately within the Index60 <1.00 distribution, comparisons were made between those above or below the medians.RESULTS: HI-IND60 and HI-BOTH were younger, with greater frequency of more than two Ab+, and lower C-peptide levels, than either HI-2HGLU or LO-BOTH (all P < 0.001). The cumulative incidence for stage 3 was greater for HI-IND60 and HI-BOTH than for either HI-2HGLU or LO-BOTH (all P < 0.001). Those with Index60 values above the median were younger and had higher frequency of two or more Ab+ (P < 0.001) and DR3-DQ2/DR4-DQ8 prevalence (P < 0.001) and lower area under the curve (AUC) C-peptide levels (P < 0.001) than those below. Those above the 2-h glucose median had higher AUC C-peptide levels (P < 0.001), but otherwise did not differ from those below.CONCLUSIONS: Index60 identifies individuals with characteristics of type 1 diabetes at appreciable risk for progression who would otherwise be missed by 2-h glucose staging criteria.

AB - OBJECTIVE: We assessed whether Index60, a composite measure of fasting C-peptide, 60-min C-peptide, and 60-min glucose, could improve the metabolic staging of type 1 diabetes for progression to clinical disease (stage 3) among autoantibody-positive (Ab+) individuals with normal 2-h glucose values (<140 mg/dL).RESEARCH DESIGN AND METHODS: We analyzed 3,058 Type 1 Diabetes TrialNet Pathway to Prevention participants with 2-h glucose <140 mg/dL and Index60 <1.00 values from baseline oral glucose tolerance tests. Characteristics associated with type 1 diabetes (younger age, greater Ab+, higher HLA DR3-DQ2/DR4-DQ8 prevalence, and lower C-peptide) were compared among four mutually exclusive groups: top 2-h glucose quartile only (HI-2HGLU), top Index60 quartile only (HI-IND60), both top quartiles (HI-BOTH), and neither top quartile (LO-BOTH). Additionally, within the 2-h glucose distribution of <140 mg/dL and separately within the Index60 <1.00 distribution, comparisons were made between those above or below the medians.RESULTS: HI-IND60 and HI-BOTH were younger, with greater frequency of more than two Ab+, and lower C-peptide levels, than either HI-2HGLU or LO-BOTH (all P < 0.001). The cumulative incidence for stage 3 was greater for HI-IND60 and HI-BOTH than for either HI-2HGLU or LO-BOTH (all P < 0.001). Those with Index60 values above the median were younger and had higher frequency of two or more Ab+ (P < 0.001) and DR3-DQ2/DR4-DQ8 prevalence (P < 0.001) and lower area under the curve (AUC) C-peptide levels (P < 0.001) than those below. Those above the 2-h glucose median had higher AUC C-peptide levels (P < 0.001), but otherwise did not differ from those below.CONCLUSIONS: Index60 identifies individuals with characteristics of type 1 diabetes at appreciable risk for progression who would otherwise be missed by 2-h glucose staging criteria.

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Index60 Identifies Individuals at Appreciable Risk for Stage 3 Among an Autoantibody-Positive Population With Normal 2-Hour Glucose Levels: Implications for Current Staging Criteria of Type 1 Diabetes

Abstract

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