Cited by 945Diabetes and associated disordersT-cell and B-cell ImmunologyGenetic Associations and Epidemiology

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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

Pugliese, Alberto, Zeller, Markus, Fernandez, Alarico, Zalcberg, Laura J., Bartlett, Richard J., Ricordi, Camillo, Pietropaolo, Massimo, Eisenbarth, George S., Bennett, Simon T., Patel, Dhavalkumar D.·1997·Nature Genetics

DOI 10.1038/ng0397-293

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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 pancreas and transfected rodent cell lines, 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 IDDM. 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-specif…

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Authors: Pugliese, A., Zeller, M., Fernandez, A., Zalcberg, L. J., Bartlett, R. J., Ricordi, C., Pietropaolo, M., Eisenbarth, G. S., Bennett, S. T., & Patel, D. D.
Affiliations: University of Miami (US)
University of Pittsburgh (US)
Centre for Human Genetics (GB)
Duke Medical Center (US)
Corresponding author: Pugliese, Alberto
ORCID: Pugliese, Alberto
Ricordi, Camillo
Pietropaolo, Massimo
Bennett, Simon T.
Patel, Dhavalkumar D.
Venue: Nature Genetics
Publisher: Springer Science and Business Media LLC
Published: 1997-03
Volume: 15
Issue: 3
Pages: 293-297
ISSN: 1061-4036 (ISSN-L)
1546-1718
DOI: 10.1038/ng0397-293
OpenAlex: W2026468137
Cited by: 945
References: 33
Citations by year: 2026: 5 · 2025: 21 · 2024: 18 · 2023: 14 · 2022: 21 · 2021: 28 · 2020: 10 · 2019: 29 · 2018: 19 · 2017: 22 · 2016: 25 · 2015: 31 · 2014: 31 · 2013: 23 · 2012: 50
FWCI: 18.26
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Nature Genetics (publishedVersion)
PubMed (publishedVersion)
Funders: Wellcome Trust
Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD-33199)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
Keywords: insulin gene, type 1 diabetes, INS VNTR, variable number tandem repeats, thymus, insulin mRNA expression, proinsulin, glutamic acid decarboxylase, IA-2, negative selection, T cells, diabetes susceptibility, chromosome 11p15
MeSH terms: Aging, Alleles, Child, Child, Preschool, Chromosome Mapping, Chromosomes, Human, Pair 11, Diabetes Mellitus, Type 1, Disease Susceptibility, Embryonic and Fetal Development, Humans, Infant, Infant, Newborn, Insulin, Organ Specificity, Proinsulin, RNA, Messenger, Thymus Gland, Transcription, Genetic, Genetic Variation, Polymerase Chain Reaction, DNA Primers, Gene Expression Regulation, Developmental, Minisatellite Repeats

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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

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