Effects of a genetic variant rs13266634 in the zinc transporter 8 gene (SLC30A8) on insulin and lipid levels before and after a high-fat mixed macronutrient tolerance test in U.S. adults

Authors: YANG, ZHONGYUE - University Of California, Davis; WANG, YINING - University Of California, Davis; Kirschke, Catherine; Stephensen, Charles; Newman, John; Keim, Nancy; CAI, YIMENG - University Of California, Davis; Huang, Liping

Submitted to: Journal of Trace Elements in Medicine and Biology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/17/2023
Publication Date: 2/18/2023
Citation: Yang, Z., Wang, Y.E., Kirschke-Schneide, C.P., Stephensen, C.B., Newman, J.W., Keim, N.L., Cai, Y., Huang, L. 2023. Effects of a genetic variant rs13266634 in the zinc transporter 8 gene (SLC30A8) on insulin and lipid levels before and after a high-fat mixed macronutrient tolerance test in U.S. adults. Journal of Trace Elements in Medicine and Biology. 77. Article 127142. https://doi.org/10.1016/j.jtemb.2023.127142.
DOI: https://doi.org/10.1016/j.jtemb.2023.127142

Interpretive Summary: Single nucleotide polymorphisms (SNPs) are the most popular type of genetic variation among humans. The nucleotide cytosine (C), which replaces the nucleotide thymine (T) in a SNP (ID rs13266634) in ZNT8 (a zinc transporter that carries zinc ions to insulin for insulin crystallization in pancreatic beta-cells), is associated with increased risk of type 2 diabetes. While previous studies have examined the correlation of the variants with insulin and glucose metabolism, the effects of the variants on insulin and lipid responses after a lipid challenge remain elusive. The goal of this study was to determine whether the C variant had an impact on an individual’s risk to metabolic syndromes in healthy U.S. adults. We studied genotypes of rs13266634 in 348 healthy individuals aged between 18-65 years old with BMI (body mass index) ranging from 18.5-45 kg/m2 after consent was obtained. The subjects were evaluated for insulin, glucose, HbA1c, ghrelin, and lipid profiles before and after a lipid challenge meal. Blood insulin levels after lipid challenge was significantly decreased in men with the CC genotype (p < 0.05). Men with the CC genotype also had the lowest fasting free fatty acid levels. Interestingly, the TT genotype slowed triglyceride clearance after lipid challenge in men. The reduced triglyceride clearance was also observed in subjects of both men and women with the T variant and BMI = 30 (obese individuals). We conclude that the C variant negatively affects insulin response after a high-fat challenge meal and the T variant is associated with reduced fasting free fatty acids and postprandial triglyceride clearance in men or obese subjects.

Technical Abstract: The C-allele of rs13266634 in ZNT8 is associated with increased risk of type 2 diabetes. While previous studies have examined the correlation of the variants with insulin and glucose metabolism, the effects of the variants on insulin and lipid responses after a lipid challenge remain elusive. The goal of this study was to determine whether the common C allele had an impact on an individual’s risk to metabolic syndromes in healthy U.S. adults. We studied genotypes of rs13266634 in 348 healthy individuals aged between 18-65 y with BMI ranging from 18.5-45 kg/m2 after consent was obtained. The subjects were evaluated for insulin, glucose, HbA1c, ghrelin, and lipid profiles before and after a lipid challenge meal. Insulin incremental area under the curve after lipid challenge was significantly decreased in men with the CC genotype (p < 0.05). Men with the CC genotype also had the lowest fasting free fatty acid levels among three genetic groups. Interestingly, the TT genotype slowed triglyceride clearance after lipid challenge in men. The reduced triglyceride clearance was also observed in subjects of both men and women with BMI = 30 and having either the TT or CT allele. Additionally, variants of rs13266634 had little to no effect on fasting or postprandial glucose and cholesterol levels in the circulation. The CC genotype negatively affects insulin response after a high-fat challenge meal. The associations of fasting free fatty acids and postprandial triglyceride clearance with the T-allele in men or obese subjects were novel findings.