The cation efflux transporter ZnT8 (Slc30A8) is a major autoantigen in human type 1 diabetes.

Barbara Davis Center for Childhood Diabetes, University of Colorado at Denver and Health Sciences Center, 1775 North Ursula Street, Aurora, CO 80045, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 11/2007; 104(43):17040-5. DOI: 10.1073/pnas.0705894104
Source: PubMed

ABSTRACT Type 1 diabetes (T1D) results from progressive loss of pancreatic islet mass through autoimmunity targeted at a diverse, yet limited, series of molecules that are expressed in the pancreatic beta cell. Identification of these molecular targets provides insight into the pathogenic process, diagnostic assays, and potential therapeutic agents. Autoantigen candidates were identified from microarray expression profiling of human and rodent pancreas and islet cells and screened with radioimmunoprecipitation assays using new-onset T1D and prediabetic sera. A high-ranking candidate, the zinc transporter ZnT8 (Slc30A8), was targeted by autoantibodies in 60-80% of new-onset T1D compared with <2% of controls and <3% type 2 diabetic and in up to 30% of patients with other autoimmune disorders with a T1D association. ZnT8 antibodies (ZnTA) were found in 26% of T1D subjects classified as autoantibody-negative on the basis of existing markers [glutamate decarboxylase (GADA), protein tyrosine phosphatase IA2 (IA2A), antibodies to insulin (IAA), and islet cytoplasmic autoantibodies (ICA)]. Individuals followed from birth to T1D showed ZnT8A as early as 2 years of age and increasing levels and prevalence persisting to disease onset. ZnT8A generally emerged later than GADA and IAA in prediabetes, although not in a strict order. The combined measurement of ZnT8A, GADA, IA2A, and IAA raised autoimmunity detection rates to 98% at disease onset, a level that approaches that needed to detect prediabetes in a general pediatric population. The combination of bioinformatics and molecular engineering used here will potentially generate other diabetes autoimmunity markers and is also broadly applicable to other autoimmune disorders.

  • Human Molecular Genetics 07/2013; 22(16):3347-3362. DOI:10.1093/hmg/ddt183 · 6.68 Impact Factor
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    ABSTRACT: Type 1 diabetes (T1D) is an autoimmune disorder caused by inflammatory destruction of the pancreatic tissue. The etiopathogenesis and characteristics of the pathologic process of pancreatic destruction are well described. In addition, the putative susceptibility genes for T1D as a monoglandular disease and the relation to polyglandular autoimmune syndrome (PAS) have also been well explored. The incidence of T1D has steadily increased in most parts of the world, especially in industrialized nations. T1D is frequently associated with autoimmune endocrine and non-endocrine diseases and patients with T1D are at a higher risk for developing several glandular autoimmune diseases. Familial clustering is observed, which suggests that there is a genetic predisposition. Various hypotheses pertaining to viral- and bacterial-induced pancreatic autoimmunity have been proposed, however a definitive delineation of the autoimmune pathomechanism is still lacking. In patients with PAS, pancreatic and endocrine autoantigens either colocalize on one antigen-presenting cell or are expressed on two/various target cells sharing a common amino acid, which facilitates binding to and activation of T cells. The most prevalent PAS phenotype is the adult type 3 variant or PAS type III, which encompasses T1D and autoimmune thyroid disease. This review discusses the findings of recent studies showing noticeable differences in the genetic background and clinical phenotype of T1D either as an isolated autoimmune endocrinopathy or within the scope of polyglandular autoimmune syndrome.
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    ABSTRACT: Metabolic disturbances of trace elements may be implicated in the complications of type 2 diabetes mellitus (T2DM). The aim of the study was to determine the level of Zinc (Zn), Selenium (Se), Copper (Cu) and the metal binding protein Metallothionein-1 (MT-1) in T2DM. Fifty-five (55) T2DM subjects and 30 Controls (C) were studied for, Se, Zn, Cu and MT-1. Zn, Se and Cu were analyzed using Flame Atomic Absorption Spectroscopy. Mean FBG in the T2DM and C groups were 183 ± 5 mg/dl and 88 ± 5 mg/dl, respectively. Mean Se, Zn and Cu levels in the T2DM group were 204 ± 91 μg/l, 407 ± 117 μg/l and 1,337 ± 527 μg/l, respectively. The control group had Se, Zn and Cu levels of 123 ± 25 μg/l, 750 ± 190 μg/l and 989 ± 197 μg/l, respectively. While Zn levels in T2DM were half that of the C, Se levels were ≈ 2-fold. Se, Zn and Cu differences between the two groups were statistically significant (P = 0.000; P = 0.000, P = 0.000, respectively). The metabolic derailment of MT-1 in the T2DM group showed a wide variation with the T2DM having significantly lower MT-1 values (P = 0.000). A negative correlation was seen between Cu and Zn in the T2DM group (P = 0.022). A standardized canonical discriminant function was obtained as D = 0.823*FBG−0.149*MT−0.457*Zn + 0.172*Cu + 0.362*Se with contributions of FBG > Zn > Se > Cu > MT-1. In conclusion, alterations in the levels of Zn, Se and Cu were observed in Ghanaian T2DM patients.
    International Journal of Diabetes in Developing Countries 06/2013; 33(2):86-95. DOI:10.1007/s13410-013-0111-9 · 0.37 Impact Factor

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