Group members

The Zinc transporter 8 (Znt8) action group: The ZnT8 in type 1 and type 2 diabetes etiology and pathogenesis

Background

T1D is an immune-mediated disease of complex aetiology specifically targeted at the pancreatic islet β cells. Antibodies (Ab) directed against insulin, GAD65 and IA-2 have been demonstrated to be markers of the islet autoimmunity that precede clinical onset of T1D. These autoantibodies were able to predict T1D in most but not all of the patients. The recent description of zinc transporter 8 (ZnT8) as an islet autoantigen in T1D was therefore important since adding ZnT8 autoantibodies (ZnT8A) may improve the accuracy of prediction. The ZnT8 is located in the membrane of insulin vesicles were it facilitates transport of zinc ions from the cytoplasm into the vesicles. The major C allele of the nonsynonymous single nucleotide polymorphism (nsSNP), rs13266634 in the SLC30A8, was identified to confer risk of T2D. The SNP causes an amino acid substitution at residue 325, from an arginine encoded by the C allele to a tryptophan encoded by the minor T allele. Abs against both of the tow epitopes in ZnT8 was identified in diabetes patients. A third polymorphism at the same residue, resulting in ZnT8 Glutamine (Gln325), which is rare in all populations tested. Furthermore, it was demonstrated that Ab against the Znt8Arg variant was more prevalent in CC-homozygotes whereas Ab against the ZnT8Trp variant were more prevalent in TT-homozygotes.

The task of the ZnT8 action group is to:

1) provide a resource forum for projects elucidating the role of ZnT8 in beta cell function and its contribution to both T1D and T2D.
2) establish/coordinate collaborative efforts both within and outside LUDC.
3) review recent literature and available resources and to discuss research projects on a regular basis (monthly meetings).
4) prepare publications and grant applications once projects have been initiated.

The ZnT8 action group is relevant to all LUDC research projects aiming to elucidate the beta cell function but is particularly relevant to the research in type 1 and 2 diabetes including genomics in diabetes, human islet dysfunction, inflammation, defective signal transduction and novel therapies.
The action group will be able to use LUDC resources including human islets, beta cell sorting, microRNA as well as human biopsies and pathology samples. The study of this key beta cell protein is central to the mission of the LUDC in both beta cell physiology, type 1 and type 2 diabetes etiology and pathogenesis.
The novel islet autoantibodies are of particular interest to the prediction and prevention of type 1 diabetes.
Ongoing basic research on beta cell physiology will be close to translation in DIAPREV-IT, DiPiS, TEDDY, ANDIS and BOTNIA.

Achievements

  • Monthly meetings with several invited speakers: Fabrice Chimienti, Ahmed J. Delli, Åke Lernmark, Carina Törn, Cecilia Andersson, Helena Elding Larsson, Anastasia Papadopoulou, Jens Lagerstedt, Tarun Ahluwalia, Jalal Taneera, Albert Salehi, Corrado Cilio, Caroline Brorsson.
  • Investigation and development of a novel triple mix radio binding assay for the three ZnT8 (ZnT8-RWQ) autoantibody variants for screening studies as Better Diabetes Diagnosis.
  • Investigation and development of plans to screen samples from diabetes patients within ANDIS (All New Diabetics In Scania).

Publications 2010-2012

1. Delli AJ; Vaziri-Sani F, Lindblad B; Elding-Larsson H; Carlsson A; Forsander G; Ivarsson SA; Ludvigsson J; Kockum I; Marcus C; Samuelsson U; Örtqvist E; Groop L; Bondinas GP; Papadopoulos GK; and Lernmark Å; for the Better Diabetes Diagnosis (BDD) Study Group. ZnT8 autoantibodies and their association with SLC30A8 and HLA-DQ genes differ between immigrant and Swedish patients with newly diagnosed type 1 diabetes in the Better Diabetes Diagnosis (BDD) study. Diabetes, 2012. In press.

2. Andersen MLM*, Vaziri-Sani F*, Delli A, Pörksen S, Jacobssen E, Thomsen J, Svensson J, Petersen JS, Hansen L, Lernmark Å, Mortensen HB, and Nielsen LB. Association between autoantibodies to the Arginine variant of the Zinc transporter 8 (ZnT8) and stimulated C-peptide levels in Danish children and adolescents with newly diagnosed type 1 diabetes. Pediatric Diabetes, 2012. *The first two authors contributed equally to the manuscript). In press.

3. Sorensen JS, Vaziri-Sani F, Maziarz M, Kristensen K, Ellerman A, Breslow N, Lernmark A, Pociot F, Brorsson C, Birkebaek NH; on behalf of the Danish Study Group for Childhood Diabetes. Islet autoantibodies and residual beta cell function in type 1 diabetes children followed for 3-6 years.  Diabetes Res Clin Pract. Jan 15, 2012, In press.

4. Kjellerås J, Vaziri-Sani F, Agardh D. Improved efficacy by using the pTnT-rhtTG plasmid for the detection of celiac disease specific transglutaminase autoantibodies in radioligand binding assays. Scand J Clin Lab Invest, 71(8):701-4, 2011.

5. Vaziri-Sani F, Delli AJ, Elding-Larsson H, Lindblad B, Carlsson A, Forsander G, Ivarsson SA, Ludvigsson J, Marcus C, Lernmark Å. A novel triple mix radiobinding assay for the three ZnT8 (ZnT8-RWQ) autoantibody variants in children with newly diagnosed diabetes. J Immunol Methods, 31;371(1-2):25-37, 2011.

6. Nielsen LB, Vaziri-Sani F, Pörksen S, Andersen ML, Svensson J, Bergholdt R, Pociot F, Hougaard P, de Beaufort C, Castaño L, Mortensen HB, Lernmark Å, Hansen L. Relationship between ZnT8Ab, the SLC30A8 gene and disease progression in children with newly diagnosed type 1 diabetes. Autoimmunity, 44(8):616-23, 2011.

7. Andersson C, Larsson K, Vaziri-Sani F, Lynch K, Carlsson A, Cedervall E, Jönsson B, Neiderud J, Månsson M, Nilsson A, Lernmark Å, Elding Larsson H, Ivarsson SA. The three ZnT8 autoantibody variants togetherimprove the diagnostic sensitivity of childhood and adolescent type 1 diabetes. Autoimmunity. 44(5):394-405, 2011.

8. Brorsson C, Vaziri-Sani F, Bergholdt R, Eising S, Nilsson A, Svensson J, Lernmark Å, Pociot F; Danish Study Group of Childhood Diabetes. Correlations between islet autoantibody specificity and the SLC30A8 genotype with HLA-DQB1 and metabolic control in new onset type 1 diabetes. Autoimmunity. 44(2):107-14, 2011.

9. Vaziri-Sani F, Oak S, Radtke J, Lernmark Å, Lynch K, Agardh CD, Cilio CM, Lethagen AL, Ortqvist E, Landin-Olsson M, Törn C, Hampe CS. ZnT8 autoantibody titers in type 1 diabetes patients decline rapidly after clinical onset. Autoimmunity. 43(8):598-606, 2010.

Last updated: September 24, 2012
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