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Diabetes Care. 2017 Apr;40(4):561-568. doi: 10.2337/dc16-1527. Epub 2017 Feb 7.

Identification of Unique Antigenic Determinants in the Amino Terminus of IA-2 (ICA512) in Childhood and Adult Autoimmune Diabetes: New Biomarker Development.

Author information

1
Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Baylor College of Medicine, Houston, TX.
2
Benaroya Research Institute, University of Washington, Seattle, WA.
3
Department of Medicinal Chemistry, College of Pharmacy, University of Toledo, Toledo, OH.
4
Diabetes Clinic, Department of Internal Medicine, and Laboratory of Microbiology & Immunology, Azienda Ospedaliera G. Brotzu, Cagliari, Italy.
5
Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione, Palermo, Italy.
6
Division of Metabolism, Endocrinology & Diabetes, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI.
7
Department of Industrial and Systems Engineering, University of Washington, Seattle, WA.
8
Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO.
9
Rocky Vista University College of Osteopathic Medicine, Parker, CO.
10
Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Baylor College of Medicine, Houston, TX massimo.pietropaolo@bcm.edu.

Abstract

OBJECTIVE:

The characterization of diverse subtypes of diabetes is a dynamic field of clinical research and an active area of discussion. The objective of this study was to identify new antigenic determinants in the neuroendocrine autoantigen IA-2 (ICA512) and assess whether circulating autoantibodies directed to new IA-2 epitopes identify autoimmune diabetes in young and adult populations with diabetes.

RESEARCH DESIGN AND METHODS:

Clinically diagnosed patients with type 2 diabetes (n = 258; diabetes duration: 0.01-31 years) were evaluated using a new biomarker detecting autoantibodies directed to the extracellular domain of the neuroendocrine autoantigen IA-2 (IA-2ec). The proportion of IA-2ec autoantibodies was also evaluated in newly diagnosed patients with type 1 diabetes (n = 150; diabetes duration: 0.04-0.49 years). In addition, IA-2 (intracellular domain), GAD65, and zinc transporter 8 autoantibodies were assayed.

RESULTS:

IA-2ec autoantibodies were detected in patients with type 1 diabetes and, surprisingly, in 5% of patients with type 2 diabetes without serologic responses to other IA-2 antigenic epitopes or other islet autoantigens. We also assessed the ability of IA-2ec-derived peptides to elicit CD4+ T-cell responses by stimulating peripheral blood mononuclear cells from patients with type 1 diabetes (n = 18) and HLA-matched healthy subjects (n = 13) with peptides and staining with the peptide/DQ8-specific tetramers, observing disease-associated responses to previously unreported epitopes within IA-2ec.

CONCLUSIONS:

We developed a new antibody biomarker identifying novel antigenic determinants within the N terminus of IA-2. IA-2ec autoantibodies can be detected in patients with type 1 diabetes and in a subgroup of adult autoimmune patients with type 2 diabetes phenotype negative for conventional islet autoantibody testing. These observations suggest that islet autoimmunity may be more common in clinically diagnosed type 2 diabetes than previously observed.

PMID:
28174261
PMCID:
PMC5360285
DOI:
10.2337/dc16-1527
[Indexed for MEDLINE]
Free PMC Article

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