Genetic Polymorphism of Zinc Transporter-8 Gene (SLC30A8), Serum Zinc Concentrations, and Proteome Profiles Related to Type 2 Diabetes in Elderly

Background and Aims: Older adults are particularly susceptible to type 2 diabetes mellitus (T2DM) due to factors such as age-related insulin resistance, decreased physical activity, and deficiency of micronutrients, especially zinc. Studies have suggested that the risk allele of the zinc transporter 8 gene (SLC30A8) single-nucleotide poly-morphism (SNP) rs13266634 may contribute to T2DM susceptibility in addition to the complex protein interactions and alterations in the protein expressions and modifications associated with T2DM. This study was implemented to study the associations between SLC30A8 polymorphism, serum zinc levels, and the profiles of proteins differentially expressed in nondiabetic (n = 116) and prediabetic/diabetic (n = 149) subjects. Methods: SNP genotyping using TaqMan^® assay and proteomic analysis by LC-MS/MS were performed in each group. Results: The results showed a higher risk of diabetes in individuals with the risk genotype CC accompanied by a low serum zinc level than in those with other genotypes. Profiles of proteins differentially expressed between the groups were identified and shown to be particularly associated with zinc-related functions, zinc transporter 8, and glucose metabolism. Proteins exclusively expressed in prediabetes/diabetes were assigned to a Reactome pathway related to zinc transporter and insulin processing. Conclusions: Our findings suggest that individuals carrying at least one copy of SLC30A8 rs13266634 accompanied by a low serum zinc level might be susceptible to T2DM, which could be due to alterations in insulin signaling and zinc metabolism. Understanding this relationship deepens our understanding of the genetic and molecular mechanisms underlying T2DM risk, offering potential targets for therapeutic intervention and prevention strategies.