TRANSLATIONAL AND CLINICAL MEDICINE - Georgian Medical Journal

Diabetes is one of the most challenging chronic and heterogeneous diseases all over the world. For now it is already established, that in most of the cases Diabetes Type 1 results from autoimmune destruction of the insulin-producing beta cells in the islets of Langerhans. The combined measurement of zinc transporter 8 antibodies (ZnT8A), glutamic acid decarboxylase antibodies (GADA), insulinoma associated autoantigen 2  antibodies (IA2A), and insulin antibodies (IAA)  raised autoimmunity detection rates at disease onset. Zinc (Zn) plays essential roles in cellular metabolism of mammals. The pancreatic islet β-cell is among the cells which contain high levels of zinc. It is concentrated in the insulin secretory granules and is essential for the proper storage, secretion, and the action of insulin. Zinc transport in mammalians is regulated by the family of Zn transporters.  ZnT8 is expressed in pancreatic islet β-cells. The essential role of this protein is to transports zinc ions from the cytosol into the vesicles of β-cells for insulin secration and storage. ZnT8 is one of main antigens in the etiology of type 1 diabetes mellitus and it can be used as diagnostic and predictive tool for Type 1 Diabetes Mellitus. Though the onset of type 1 diabetes  cannot be prevented, it is still very important to reveal the different risk groups as the knowledge  of the increased risk can help to prevent acute onset of the disease with ketoacidosis and concomitant morbidities.

Diabetes; Autoimmunity; ZnT8; Antibodies

Cho NH, Whiting D, Guariguata L, Montoya PA, Forouhi N, Hambleton I. IDF diabetes atlas. Brussels, Belgium: International Diabetes Federation. 2013.

Onkamo P, Väänänen S, Karvonen M, Tuomilehto J. Worldwide increase in incidence of Type I diabetes–the analysis of the data on published incidence trends. Diabetologia. 1999 Dec 1;42(12):1395-403.

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. Proceedings of the National Academy of Sciences. 2007 Oct 23;104(43):17040-5.

Lemaire K, Ravier MA, Schraenen A, Creemers JW, Van de Plas R, Granvik M, Van Lommel L, Waelkens E, Chimienti F, Rutter GA, Gilon P. Insulin crystallization depends on zinc transporter ZnT8 expression, but is not required for normal glucose homeostasis in mice. Proceedings of the National Academy of Sciences. 2009 Sep 1;106(35):14872-7.

Garg VK, Gupta R, Goyal RK. Hypozincemia in diabetes mellitus. The Journal of the Association of Physicians of India. 1994 Sep;42(9):720-1.

Roussel AM, Kerkeni A, Zouari N, Mahjoub S, Matheau JM, Anderson RA. Antioxidant effects of zinc supplementation in Tunisians with type 2 diabetes mellitus. Journal of the American College of Nutrition. 2003 Aug 1;22(4):316-21.

Ho E, Quan N, Tsai YH, Lai W, Bray TM. Dietary zinc supplementation inhibits NF κB activation and protects against chemically induced diabetes in CD1 mice. Experimental biology and medicine. 2001 Feb 1;226(2):103-11.

Edmin SO, Dodson GG, Cutfield SM. Role of zinc in insulin biosynthesis: Some possible zinc insulin interactions in the pancreatic beta cells. Diabetologia. 1980;19:174-82.

Kawasaki E. ZnT8 and type 1 diabetes [Review]. Endocrine journal. 2012;59(7):531-7.

Lichten LA, Cousins RJ. Mammalian zinc transporters: nutritional and physiologic regulation. Annual review of nutrition. 2009 Aug 21;29:153-76.

Chimienti F, Favier A, Seve M. ZnT-8, a pancreatic beta-cell-specific zinc transporter. Biometals. 2005 Aug 1;18(4):313-7.

Chimienti F, Devergnas S, Favier A, Seve M. Identification and cloning of a β-cell–specific zinc transporter, ZnT-8, localized into insulin secretory granules. Diabetes. 2004 Sep 1;53(9):2330-7.

Lampasona V, Petrone A, Tiberti C, Capizzi M, Spoletini M, Di Pietro S, Songini M, Bonicchio S, Giorgino F, Bonifacio E, Bosi E. Zinc transporter 8 antibodies complement GAD and IA-2 antibodies in the identification and characterization of adult-onset autoimmune diabetes non insulin requiring autoimmune diabetes (NIRAD) 4. Diabetes care. 2010 Jan 1;33(1):104-8.

Achenbach P, Lampasona V, Landherr U, Koczwara K, Krause S, Grallert H, Winkler C, Pflüger M, Illig T, Bonifacio E, Ziegler AG. Autoantibodies to zinc transporter 8 and SLC30A8 genotype stratify type 1 diabetes risk. Diabetologia. 2009 Sep 1;52(9):1881-8.

Ziegler AG, Nepom GT. Prediction and pathogenesis in type 1 diabetes. Immunity. 2010 Apr 23;32(4):468-78.

Gorus FK, Balti EV, Vermeulen I, Demeester S, Van Dalem A, Costa O, Dorchy H, Tenoutasse S, Mouraux T, De Block C, Gillard P. Screening for insulinoma antigen 2 and zinc transporter 8 autoantibodies: a cost‐effective and age‐independent strategy to identify rapid progressors to clinical onset among relatives of type 1 diabetic patients. Clinical & Experimental Immunology. 2013 Jan 1;171(1):82-90.

Yu L, Boulware DC, Beam CA, Hutton JC, Wenzlau JM, Greenbaum CJ, Bingley PJ, Krischer JP, Sosenko JM, Skyler JS, Eisenbarth GS. Zinc transporter-8 autoantibodies improve prediction of type 1 diabetes in relatives positive for the standard biochemical autoantibodies. Diabetes Care. 2012 Jun 1;35(6):1213-8.

De Grijse J, Asanghanwa M, Nouthe B, Albrecher N, Goubert P, Vermeulen I, Van Der Meeren S, Decochez K, Weets I, Keymeulen B, Lampasona V. Predictive power of screening for antibodies against insulinoma-associated protein 2 beta (IA-2β) and zinc transporter-8 to select first-degree relatives of type 1 diabetic patients with risk of rapid progression to clinical onset of the disease: implications for prevention trials. Diabetologia. 2010 Mar 1;53(3):517-24.

Vermeulen I, Weets I, Asanghanwa M, Ruige J, Van Gaal L, Mathieu C, Keymeulen B, Lampasona V, Wenzlau JM, Hutton JC, Pipeleers DG. Contribution of antibodies against IA-2β and zinc transporter 8 to classification of diabetes diagnosed under 40 years of age. Diabetes Care. 2011 Aug 1;34(8):1760-5.