Abstract
HypothesisSerum- and Glucocorticoid-inducible Kinase 1 (SGK1) is involved in the regulation of insulin secretion and may represent a candidate gene for the development of type 2 diabetes mellitus in humans.MethodsThree independent European populations were analyzed for the association of SGK1 gene (SGK) variations and insulin secretion traits. The German TUEF project provided the screening population (N = 725), and four tagging SNPs (rs1763527, rs1743966, rs1057293, rs9402571) were investigated. EUGENE2 (N = 827) served as a replication cohort for the detected associations. Finally, the detected associations were validated in the METSIM study, providing 3798 non-diabetic and 659 diabetic (type 2) individuals.ResultsCarriers of the minor G allele in rs9402571 had significantly higher C-peptide levels in the 2 h OGTT (+10.8%, p = 0.04; dominant model) and higher AUCC-Peptide/AUCGlc ratios (+7.5%, p = 0.04) compared to homozygous wild type TT carriers in the screening population. As interaction analysis for BMI×rs9402571 was significant (p = 0.04) for the endpoint insulin secretion, we stratified the TUEF cohort for BMI, using a cut off point of BMI = 25. The effect on insulin secretion only remained significant in lean TUEF participants (BMI≤25). This finding was replicated in lean EUGENE2 rs9402571 minor allele carriers, who had a significantly higher AUCIns/AUCGlc (TT: 226±7, XG: 246±9; p = 0.019). Accordingly, the METSIM trial revealed a lower prevalence of type 2 diabetes (OR: 0.85; 95%CI: 0.71–1.01; p = 0.065, dominant model) in rs9402571 minor allele carriers.ConclusionsThe rs9402571 SGK genotype associates with increased insulin secretion in lean non-diabetic TUEF/EUGENE2 participants and with lower diabetes prevalence in METSIM. Our study in three independent European populations supports the conclusion that SGK variability affects diabetes risk.
Highlights
Type 2 diabetes arises when insulin resistance cannot be compensated for with increased insulin secretion owing to a gradual loss of pancreatic beta-cell function [1]
Informed written consent was obtained from all participants, and all study procedures were approved by the local medical ethic research committee of the Faculty of Medicine at the University of Tuebingen. 1000 TUEF participants were genotyped for SGK1 gene (SGK) and phenotyped by Oral glucose tolerance test (OGTT) and AUCCP/AUC of plasma glucose (AUCGlc)
SGK association analyses in the TUEF screening cohort There was no association between genotypes, anthropometrics, and insulin sensitivity in the south German screening cohort, which was investigated for all four tagging SNPs
Summary
Type 2 diabetes arises when insulin resistance cannot be compensated for with increased insulin secretion owing to a gradual loss of pancreatic beta-cell function [1]. One interesting candidate for the regulation of insulin secretory function is the serum and glucocorticoid inducible kinase SGK1, which is a ubiquitously expressed serine-threonine kinase in humans that is encoded by the gene SGK on chromosome 6q23. In INS1 cells, SGK gene transcription and protein expression is strongly regulated, and SGK1 up-regulates the activity of voltage-gated K+ channels, which in turn reduces Ca++ influx and inhibits insulin release [22]. Another SGK1-dependent molecular mechanism in insulin secretion is the activation of Na+/K+-ATPase during plasma membrane repolarisation [23]
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