The solute carrier (SLC) group of membrane transport proteins include over 300 members organized into 52 families. Most members of the SLC group are located in the cell membrane.
Solutes that are transported by the various SLC group members are extraordinarily diverse and include both charged and uncharged organic molecules as well as inorganic ions and the gas ammonia.
As is typical of integral membrane proteins, SLCs contain a number of hydrophobic transmembrane alpha helices connected to each other by hydrophilic intra- and extra-cellular loops. Depending on the SLC, these transporters are functional as either monomers or obligate homo- or hetero-oligomers. Wikipedia
Solute carrier family 30 (zinc transporter), member 8, also known as SLC30A8, is a human gene that codes for a zinc transporter related to insulin secretion in humans. Certain alleles of this gene may increase the risk for developing type 2 diabetes, but a loss-of-function mutation appears to greatly reduce the risk of diabetes. (Wikipedia)
CHEMICAL STRUCTURE AND IMAGES
Protein Aminoacids Percentage (Width 700 px)
SYNTHESIS AND TURNOVER
The ZnT8 protein is encoded by the SLC30A8 gene, which is convincingly associated with type 2 diabetes risk at the single nucleotide polymorphism (SNP) rs13266634C>T, an amino acid substitution R325W. Although this amino acid variant determines the epitope specificity of ZnT8A in type 1 diabetes, either ZnT8RA or ZnT8WA, its association with risk of the disease itself is less clear. (Genetic association of zinc transporter 8 (ZnT8) autoantibodies in type 1 diabetes cases, 2012.)
(Genetic association of zinc transporter 8 (ZnT8) autoantibodies in type 1 diabetes cases, 2005.)
(ZnT8 and type 1 diabetes, 2012.)
Evidence suggests that TCF7L2 and PDX-1 (themselves both linked to normal versus pathological β-cell function) each contribute to regulation of ZnT8 expression and db/db mice down-regulate β-cell ZnT8 protein.
(Islet autoantigens: structure, function, localization, and regulation, 2012. )
Zinc modulates the expression of more than a hundred genes within the immune cells and it is an essential
trace element for immune function. Zinc has been shown to be required for the innate and the adaptive
immune reactions, and it is especially important for the generation of proinflammatory cytokines such as interleukin (IL-6) , tumor necrosis factor-α after lipopolysaccharide or other antigen stimulations and the development of T cells. Thus zinc deficiency induces thymic atrophy, lymphopenia, and suppression of cytolytic T cell responses, natural killer cell activity, and delayed-type hypersensitivity reactions. Zinc
also protects pancreatic β-cells from cytokine-induced destruction, which is observed in patients with type 1 diabetes, but also in type 2 diabetes. IL-1 β is a cytokine mainly derived from macrophage that participates in the regulation of inflammatory/ immune responses and is involved in the inhibition of glucose-stimulated insulin release as well as in islet cell destruction in both type 1 and type 2 diabetes.
ZnT8 is a major zinc transporter to move cytoplasmic zinc ions into secretory vesicles/granules in the b-cell.
(Identification and cloning of a beta-cell-specific zinc transporter, ZnT-8, localized into insulin secretory granules, 2004.)
Growing evidence has accumulated regarding the association between the zinc homeostasis and the
development of diabetes. Type 1 diabetes is characterized by a destruction of pancreatic β-cells, resulting
in absolute insulin deficiency causing hyperglycemia. The etiology of type 1 diabetes is not fully clarified, but it is well-recognized that major form of disease is associated with autoimmune-mechanisms (type 1A) and both genetic and environmental factors affect the onset of the disease. Evidence for the autoimmune basis of type 1 diabetes includes:
1) lymphocytic infiltration around and into the islets (insulitis),
2) the appearance of autoantibodies to multiple islet autoantigens,
3) the presence of both MHC-linked and non-MHC-linked disease susceptibility genes,
4) the increased propensity to develop multiple organ-specific autoimmune diseases.
Recently, zinc transporter 8 (ZnT8) was identified as a novel autoantigen based on a bioinformatics analysis focused on discovery of β-cell-specific proteins associated with the regulatory pathway of secretion.
ZnT8 is localized to insulin containing secretory granule membrane and transports zinc ion from the cytosol into the vesicles. (ZnT8 and type 1 diabetes, 2012 )
ZnT8 is also found to be a major autoantigen in development of autoimmunity in type 1 diabetes (T1D). Noteworthy, ZnT8 autoantibodies are highly prevalent in the beginning phase of T1D. With disease progression, titers are decreased dramatically. Approximately 80% of ZnT8 autoantibodies react with the epitopes that reside in the C-terminal 102 amino acids of the ZnT8 protein. Epitope mapping indicates that more than one epitope in the C-terminal end of ZnT8 is involved in autoimmunity, but the epitope containing R325 is the major determinant for ZnT8 autoimmunity. (The SLC30 family of zinc transporters - a review of current understanding of their biological and pathophysiological roles, 2013. )
In addition, ZnT8 is reported to be associated with β-cell survival. The overexpression of ZnT8 in β-cells increases the zinc content and protects β-cells from apoptosis related to zinc depletion. (ZnT8 and type 1 diabetes, 2012.)
Zinc ions are essential for the formation of insulin crystals in pancreatic b cells, thereby contributing to packaging efficiency of stored insulin. (Regulation and functional effects of ZNT8 in human pancreatic islets, 2012.)
Autoantibodies to glutamic acid decarboxylase (GADA), insulinoma-associated antigen-2 (IA-2A) and insulin (IAA) and islet cell autoantibodies (ICA) have long been established as associated with the development of type 1 diabetes, with over 90% of newly diagnosed cases positive for at least one of these autoantibodies. Most recently, autoantibodies to the pancreatic beta cell-specific protein, zinc transporter 8 (ZnT8A), have also been shown to be associated with type 1 diabetes. Over 60% of newly diagnosed cases are positive for ZnT8A, and 4% of cases are positive for ZnT8A only, thus suggesting their utility as a predictive and diagnostic marker in type 1 diabetes. The percentage of newly diagnosed cases positive for ZnT8A (as well as the magnitude of the ZnT8A titre) has been positively correlated with an older age at diagnosis of type 1 diabetes in children and has been shown to decline following diagnosis of type 1 diabetes. The same correlations have also been found with IA-2A and GADA.
The ZnT8 protein is encoded by the SLC30A8 gene, which is convincingly associated with type 2 diabetes risk at the single nucleotide polymorphism (SNP) rs13266634C>T, an amino acid substitution R325W. Although this amino acid variant determines the epitope specificity of ZnT8A in type 1 diabetes, either ZnT8RA or ZnT8WA, its association with risk of the disease itself is less clear.
ZnT8RA have been reported as associated with HLADQB1* 0302 genotypes and both ZnT8RA and ZnT8WA
have been correlated with HLA-DQB1*0604 (Genetic association of zinc transporter 8 (ZnT8) autoantibodies in type 1 diabetes cases, 2012)
Although islet autoimmunity is responsible for the large majority of childhood and adolescent-onset diabetes, it can be found also in 4 to 10% of adult-onset diabetes. This sub-group of patients tests positive for humoral markers of islet autoreactivity, despite having clinical features indistinguishable from those of classical type 2 diabetes and is referred to as LADA (Latent Autoimmune Diabetes of Adult). LADA patients are solely identified by the detection of circulating islet autoantibodies, with Islet Cell Antibodies (ICA) and GADA being the antibody markers with the highest prevalence, followed by IA-2A antibodies, that are detected in a minority of cases and almost invariably associated with GADA, while insulin autoantibodies, that constitute a specific marker of juvenile diabetes inversely related to age and rare in adults, are unlikely to be useful for LADA screening.
ZnT8A, recently identified as autoantibodies associated with juvenile onset type 1 diabetes, are also a marker of adult onset autoimmune diabetes. Adult diabetes associated antibodies largely recognized the COOH terminal of the antigen (amino-acids 268-369), while antibodies against the NH2-terminal moiety (aminoacids 1-74) were rare. Therefore, in adult diabetes ZnT8A essentially correspond to ZnT8-COOH antibodies. The availability of ZnT8A as a marker additional to GADA and IA-2A allowed stratification across the intensity of islet autoimmune response which is clearly reflected by the clinical phenotype of patients
with adult diabetes, with features of more severe insulin insufficiency proportional to the number and, accordingly, titers of islet autoantibodies. (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, 2010.)