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Baseline heterogeneity in glucose metabolism marks the risk for type 1 diabetes and complicates secondary prevention

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Abstract

Aims

Non-diabetic children with multiple islet autoantibodies were recruited to a secondary prevention trial. The objective was to determine the predictive value of baseline (1) HbA1c and metabolic variables derived from intravenous (IvGTT) and oral glucose tolerance tests (OGTT), (2) insulin resistance and (3) number, type and levels of islet autoantibodies, for progression to type 1 diabetes.

Methods

Children [n = 50, median 5.1 (4–17.9) years] with autoantibodies to glutamate decarboxylase (GAD65A) and at least one of insulinoma-associated protein 2 (IA-2A), insulin or ZnT8 transporter (ZnT8RA, ZnT8WA, ZnT8QA) were screened with IvGTT and OGTT and followed for a minimum of 2 years.

Results

Baseline first phase insulin response (sum of serum-insulin at 1 and 3 min during IvGTT; FPIR) ≤3 μU/mL [HR 4.42 (CI 1.40–14.0) p = 0.011] and maximal plasma glucose ≥11.1 mmol/L measured at 30, 60 and/or 90 min during OGTT [HR 6.13 (CI 1.79–21.0) p = 0.0039] were predictors for progression to diabetes. The combination of FPIR from IvGTT and maximal plasma glucose during OGTT predicted diabetes in 10/12 children [HR 9.17 (CI 2.0–42.0) p = 0.0043]. High-level IA-2A, but not number of autoantibodies, correlated to dysglycemia during OGTT (p = 0.008) and to progression to type 1 diabetes [HR 4.98 (CI 1.09–22.0) p = 0.039].

Conclusions

Baseline FPIR, maximal plasma glucose ≥11.1 at 30, 60 or 90 min during OGTT and high-level IA-2A need to be taken into account when randomizing islet autoantibody positive non-diabetic children to secondary prevention.

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Acknowledgments

We thank all the participating families and Diamyd Medical AB for donating the GAD-Alum. Our research is supported in part by the Swedish Research Council (Grant 14064), Swedish Childhood Diabetes Foundation, Swedish Diabetes Association, National Institutes of Health (DK26190), UMAS Fund, the Knut and Alice Wallenberg Foundation, and the Skåne County Council for Research and Development and the Juvenile Diabetes Research Foundation (17-2011-576).

Conflict of interest

Helena Elding Larsson, Christer Larsson and Åke Lernmark declare that they have no conflict of interests.

Ethical standard

The study was approved by the Regional Ethical Board in Lund, Sweden.

Human and animal rights disclosure

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1976, as revised in 2008.

Informed consent disclosure

Informed consent was obtained from all participants or their legal representatives prior to inclusion in the study.

Author information

Authors and Affiliations

  1. Department of Clinical Sciences Malmö/Pediatric Endocrinology, Skåne University Hospital SUS, Lund University, Jan Waldenströms gata 35, CRC 60:11, 20502, Malmö, Sweden

    Helena Elding Larsson & Åke Lernmark

  2. Department of Laboratory Medicine, Lund University, Lund, Sweden

    Christer Larsson

Authors
  1. Helena Elding Larsson
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  2. Christer Larsson
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  3. Åke Lernmark
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the DiAPREV-IT study group

Corresponding author

Correspondence to Helena Elding Larsson.

Additional information

Managed by Antonio Secchi.

EuCT 2008-007484-16, NCT01122446.

Appendix

Appendix

Members of the DiAPREV-IT study group are

PI: Helena Elding Larsson (Malmö), Co-PI: Åke Lernmark (Malmö), Study nurses: Caroline Nilsson, Gertie Hansson.

Lab personnel

Jeanette Arvastsson, Rasmus Bennet, Charlotte Brundin, Ida Jönsson, Zeliha Mestan, Anita Ramelius, and Ingrid Wigheden.

Physicians

Cecilia Andersson (Malmö), Susanne Bach Meineche (Malmö), Annelie Carlsson (Lund), Elisabeth Cederwall (Ängelholm), Corrado Cilio (Malmö), Sten Ivarsson (Malmö), Berglind Jonsdottir (Malmö), Björn Jönsson (Ystad), Karin Larsson (Kristianstad), Bengt Lindberg (Malmö), Markus Lundgren (Kristianstad), Jan Neiderud (Helsingborg), Ann Olsson (Trollhättan), Lars Åke Persson (Uppsala), Eva Örtqvist (Stockholm).

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Elding Larsson, H., Larsson, C., Lernmark, Å. et al. Baseline heterogeneity in glucose metabolism marks the risk for type 1 diabetes and complicates secondary prevention. Acta Diabetol 52, 473–481 (2015). https://doi.org/10.1007/s00592-014-0680-1

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