Index60 as an additional diagnostic criterion for type 1 diabetes

Abstract

Aims/hypothesis

We aimed to compare characteristics of individuals identified in the peri-diagnostic range by Index60 (composite glucose and C-peptide measure) ≥2.00, 2 h OGTT glucose ≥11.1 mmol/l, or both.

Methods

We studied autoantibody-positive participants in the Type 1 Diabetes TrialNet Pathway to Prevention study who, at their baseline OGTT, had 2 h blood glucose ≥11.1 mmol/l and/or Index60 ≥2.00 (n = 354, median age = 11.2 years, age range = 1.7–46.6; 49% male, 83% non-Hispanic White). Type 1 diabetes-relevant characteristics (e.g., age, C-peptide, autoantibodies, BMI) were compared among three mutually exclusive groups: 2 h glucose ≥11.1 mmol/l and Index60 <2.00 [Glu(+), n = 76], 2 h glucose <11.1 mmol/l and Index60 ≥2.00 [Ind(+), n = 113], or both 2 h glucose ≥11.1 mmol/l and Index60 ≥2.00 [Glu(+)/Ind(+), n = 165].

Results

Participants in Glu(+), vs those in Ind(+) or Glu(+)/Ind(+), were older (mean ages = 22.9, 11.8 and 14.7 years, respectively), had higher early (30–0 min) C-peptide response (1.0, 0.50 and 0.43 nmol/l), higher AUC C-peptide (2.33, 1.13 and 1.10 nmol/l), higher percentage of overweight/obesity (58%, 16% and 30%) (all comparisons, p < 0.0001), and a lower percentage of multiple autoantibody positivity (72%, 92% and 93%) (p < 0.001). OGTT-stimulated C-peptide and glucose patterns of Glu(+) differed appreciably from Ind(+) and Glu(+)/Ind(+). Progression to diabetes occurred in 61% (46/76) of Glu(+) and 63% (71/113) of Ind(+). Even though Index60 ≥2.00 was not a Pathway to Prevention diagnostic criterion, Ind(+) had a 4 year cumulative diabetes incidence of 95% (95% CI 86%, 98%).

Conclusions/interpretation

Participants in the Ind(+) group had more typical characteristics of type 1 diabetes than participants in the Glu(+) did and were as likely to be diagnosed. However, unlike Glu(+) participants, Ind(+) participants were not identified at the baseline OGTT.

Graphical abstract

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Data availability

TrialNet data can be requested from the NIDDK public repository. The datasets generated and analysed during the current study will be made available by request from the NIDDK Central Repository at https://repository.niddk.nih.gov/studies/trialnet

Abbreviations

GCRC:

Glucose and C-peptide response curve

Glu(+):

2 h glucose ≥11.1 mmol/l and Index60 <2.00

Glu(+)/Ind(+):

2 h glucose ≥11.1 mmol/l and Index60 ≥2.00

IA-2A:

Insulinoma-associated antigen-2 autoantibody

ICA:

Islet cell antibodies

Ind(+):

2 h glucose <11.1 mmol/l and Index60 ≥2.00

mIAA:

Microinsulin autoantibody assay

PTP:

Pathway to Prevention

ZnT8A:

Zinc transporter eight autoantibodies

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Acknowledgements

Parts of the content of this manuscript were communicated as an oral presentation at the ADA 79th Scientific Meeting in San Francisco, CA, in June 2019.

Authors’ relationships and activities

The authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work.

All authors are members of the Type 1 diabetes TrialNet Study Group (list of study group members in provided as electronic supplementary material [ESM]). MJR and JS are the guarantors of this article and take full responsibility for the work as a whole, including the study design, access to data and the decision to submit and publish the manuscript.

Contribution statement

MJR contributed to study design as well as data analysis and interpretation, and wrote the first draft of the manuscript. BMN, LMJ, ES, AP, DAS, MAA, JS and JP contributed to data interpretation and revised the manuscript. SG and LEB conducted data analysis and contributed to data interpretation and manuscript revisions. JMS conceptualised and designed the study, and contributed to data analysis and interpretation, and manuscript revisions. All authors have approved the version of the manuscript to be published.

Funding

The sponsor of the trial was the Type 1 diabetes TrialNet Study Group. 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, the National Institute of Allergy and Infectious Diseases, and The Eunice Kennedy Shriver National Institute of Child Health and Human Development, through the 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 DK106993 and the JDRF. The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the NIH or the JDRF.

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Correspondence to Maria J. Redondo.

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Complete listing of Type 1 Diabetes TrialNet Study Group members is included in the electronic supplementary material (ESM)

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Redondo, M.J., Nathan, B.M., Jacobsen, L.M. et al. Index60 as an additional diagnostic criterion for type 1 diabetes. Diabetologia (2021). https://doi.org/10.1007/s00125-020-05365-4

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Keywords

  • C-peptide
  • Diagnosis
  • Glucose
  • Heterogeneity
  • Index60
  • Insulin resistance
  • Prediction
  • TrialNet
  • Type 1 diabetes
  • Type 2 diabetes