Insulin Resistance and Progression to Type 1 Diabetes in the European Nicotinamide Diabetes Intervention Trial (ENDIT)

  1. Polly J. Bingley, MD1,
  2. Jeffrey L Mahon, MD2,
  3. Edwin A.M. Gale, MD1 and
  4. for the European Nicotinamide Diabetes Intervention Trial (ENDIT) Group*
  1. 1Clinical Science at North Bristol, University of Bristol, U.K
  2. 2Endocrinology and Metabolism, University of Western Ontario, London, Ontario, Canada
  1. Address correspondence and reprint requests to Professor Polly Bingley, Diabetes and Metabolism, Medical School Unit, Southmead Hospital, Bristol BS10 5NB, U.K. E-mail: polly.bingley{at}bristol.ac.uk

Abstract

OBJECTIVE—Insulin resistance can modulate progression to type 1 diabetes in individuals with ongoing islet autoimmunity. We wanted to see whether measures of insulin resistance improved risk assessment in islet cell antibody (ICA)-positive relatives when added to other immune and metabolic markers.

RESEARCH DESIGN AND METHODS—The retrospective cohort analysis included 213 family members participating in the European Nicotinamide Diabetes Intervention Trial. All were aged <25 years, with at least one islet antibody in addition to ICA ≥20 Juvenile Diabetes Foundation units. Median length of follow-up was 4.21 years, and 105 individuals developed diabetes. Oral and intravenous glucose tolerance tests were performed at baseline; antibodies to GAD, IA-2, and insulin were determined by radioimmunoassay; and insulin resistance was estimated by homeostasis model assessment. Risk was assessed by Cox regression analysis

RESULTS—The overall cumulative risk of diabetes within 5 years was 54.1% (95% CI 46.0–62.3). Multivariate analysis confirmed that baseline first-phase insulin response (FPIR) quartile (P < 0.0001), number of additional antibody markers (P < 0.0001), and 120-min glucose in the oral glucose tolerance test (P < 0.0001) were independent determinants of risk of progression, whereas addition of homeostasis model assessment of insulin resistance (HOMA2-IR) achieved only borderline significance (P = 0.06). HOMA2-IR was an independent determinant in participants with loss of FPIR (P = 0.025) but not in those with preserved FPIR (P = 0.3).

CONCLUSIONS—These data suggest that insulin resistance accelerates progression to type 1 diabetes in antibody-positive relatives in whom insulin secretion is markedly reduced but does not affect progression when insulin secretion is relatively well preserved.

Footnotes

  • Published ahead of print at http://care.diabetesjournals.org on 24 October 2007. DOI: 10.2337/dc07-0103.

    A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.

    The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

  • *

    ↵* A complete listing of the members of the European Nicotinamide Diabetes Intervention Trial Group can be found in the appendix.

    • Accepted October 15, 2007.
    • Received January 17, 2007.
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  1. Published online before print October 24, 2007, doi: 10.2337/dc07-0103 Diabetes Care January 2008 vol. 31 no. 1 146-150
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