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The insulin gene is transcribed in the human thymus and transcription levels correlate with allelic variation at the INS VNTR-IDDM2 susceptibility locus for type 1 diabetes

Nature Genetics volume 15, pages 293–297 (1997)Cite this article

Abstract

Type 1, or insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease associated with loss of tolerance to several pancreatic islet cell molecules, including insulin, glutamic acid decarboxylase (GAD), ICA69 and the tyrosine phosphatase IA-2 (refs 1–3). Among several predisposing loci, IDDM2 maps to the insulin gene (INS) VNTR (variable number of tandem repeats) minisatellite on chromosome 11p15 (refs 4–9). Allelic variation at this VNTR locus correlates with steady-state levels of INS mRNA in pancreas8,10–11 and transfected rodent cell lines12,14, but it is difficult to reconcile the association of lower INS mRNA levels in the pancreas with class III VNTRs that are dominantly protective from IDDM8,15. We show that during fetal development and childhood, mRNAs for insulin and other islet cell autoantigens (GAD, ICA69, IA-2) are expressed at low levels in the human thymus. Critically, we also detect proinsulin and insulin protein. VNTR alleles correlate with differential INS mRNA expression in the thymus where, in contrast to the pancreas, protective class III VNTRs are associated with higher steady-state levels of INS mRNA expression. This finding provides a plausible explanation for the dominant protective effect of class III VNTRs, and suggests that diabetes susceptibility and resistance associated with IDDM2 may derive from the VNTR influence on INS transcription in the thymus. Higher levels of (pro)insulin in the thymus may promote negative selection (deletion) of insulin-specific T-lymphocytes which play a critical role in the pathogenesis of type-1 diabetes.

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Authors and Affiliations

  1. Diabetes Research Institute, University of Miami School of Medicine, Miami, Florida, USA

    Alberto Pugliese, Markus Zeller, Alarico Fernandez Jr., Laura J. Zalcberg, Richard J. Bartlett & Camillo Ricordi

  2. Division of Immunogenetics, Children's Hospital, University of Pittsburgh, Pittsburgh, Pennsylvania, USA

    Massimo Pietropaolo

  3. Barbara Davis Center for Childhood Diabetes, University of Colorado Health Sciences Center, Denver, Colorado, USA

    George S. Eisenbarth

  4. The Wellcome Trust Centre for Human Genetics, Nuffield Department of Surgery, University of Oxford, Oxford, UK

    Simon T. Bennett

  5. Department of Medicine and Immunology, Duke University Medical Center, Durham, North Carolina, USA

    Dhavalkumar D. Patel

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  1. Alberto Pugliese
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Correspondence to Alberto Pugliese.

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Pugliese, A., Zeller, M., Fernandez, A. et al. The insulin gene is transcribed in the human thymus and transcription levels correlate with allelic variation at the INS VNTR-IDDM2 susceptibility locus for type 1 diabetes. Nat Genet 15, 293–297 (1997). https://doi.org/10.1038/ng0397-293

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