Zinc

Taken directly from a recent review by Fukada and Kambe [1], "(Zinc) plays indispensable roles in multifarious cellular processes, affecting the expression and activity of a variety of molecules, including transcription factors, enzymes, adapters, channels, growth factors, and their receptors."

The newest autoantibody determination to enter the clinical realm of type 1 diabetes testing is the detection of autoantibodies against the type 8 zinc transporter (ZnT8) [2]. This transporter moves zinc into insulin containing granules in the beta cells of the islets of Langerhans.

Autoantibodies to ZnT8 (termed "ZnT8A") are frequently found at the onset of type 1 diabetes [2]. However, the question arises, "What is the value of ZnT8A testing when autoantibodies can be detected against the islet cell cytoplasm (ICA), glutamic acid decarboxylase (GADA), insulin (IAA) and the insulinoma-2 autoantigen (IA-2A)?"

The answer to this question is 3 fold:

(1) New-onset patients with clinically suspected type 1 diabetes who are negative for GADA, IA-2A and IAA can be positive for ZnT8A affirming an autoimmune etiology for a patient's diabetes. In a recent study, 14% of new-onset patients negative for GADA, IA-2A and IAA were positive for ZnT8A [3].

(2) In the detection of latent autoimmune diabetes of adulthood (LADA), ZnT8A are nearly as common as GADA. In a 2012 study from Trabucchi et al. [4], the frequencies of GADA and ZnT8A in patients with adult-onset diabetes were, respectively, 7.7% and 7.0%. However, more meaningful is that many patients were positive for ZnT8A were negative for GADA. Adding ZnT8A testing to GADA testing will increase the yield of detection of LADA by ~60%. In other words the frequency of LADA defined by the presence of GADA alone is 12.5% in adult-onset subjects with diabetes; however, the frequency of LADA rises to 20% when ZnT8A testing is added to GADA testing.

(3) Finally, in type 1 diabetes patients who have received a pancreas transplant, the presence of ZnT8A (as well as GADA and IA-2A), predict graft failure [5]. This is not good news for the patient or the transplant team; however, the recognition of such autoantibodies may allow the transplant team to identify patients who may require more vigorous immunosuppression to prevent a re-occurrence of beta-cell autoimmunity with subsequent destruction of the transplanted beta cells.

References

1. Fukada T, Kambe T. Molecular and genetic features of zinc transporters in physiology and pathogenesis. Metallomics. 2011 Jul;3(7):662-74.
2. Wenzlau JM, Juhl K, Yu L, Moua O, Sarkar SA, Gottlieb P, Rewers M, Eisenbarth GS, Jensen J, Davidson HW, Hutton JC. The cation efflux transporter ZnT8 (Slc30A8) is a major autoantigen in human type 1 diabetes. Proc Natl Acad Sci U S A. 2007 Oct 23;104(43):17040-5.
3. Vermeulen I, Weets I, Asanghanwa M, Ruige J, Van Gaal L, Mathieu C, Keymeulen B, Lampasona V, Wenzlau JM, Hutton JC, Pipeleers DG, Gorus FK; Belgian Diabetes Registry. Contribution of antibodies against IA-2β and zinc transporter 8 to classification of diabetes diagnosed under 40 years of age. Diabetes Care. 2011 Aug;34(8):1760-5.
4. Trabucchi A, Faccinetti NI, Guerra LL, Puchulu FM, Frechtel GD, Poskus E, Valdez SN. Detection and characterization of ZnT8 autoantibodies could help to screen latent autoimmune diabetes in adult-onset patients with type 2 phenotype. Autoimmunity. 2012 Mar;45(2):137-42.
5. Occhipinti M, Lampasona V, Vistoli F, Bazzigaluppi E, Scavini M, Boggi U, Marchetti P, Bosi E. Zinc transporter 8 autoantibodies increase the predictive value of islet autoantibodies for function loss of technically successful solitary pancreas transplant. Transplantation. 2011 Sep 27;92(6):674-7.