Abstract
IntroductionRecent meta-analyses of genome-wide association studies revealed new genetic loci associated with fasting glycemia. For several of these loci, the mechanism of action in glucose homeostasis is unclear. The objective of the study was to establish metabolic phenotypes for these genetic variants to deliver clues to their pathomechanism.MethodsIn this cross-sectional study 1782 non-diabetic volunteers at increased risk for type 2 diabetes underwent an oral glucose tolerance test. Insulin, C-peptide and proinsulin were measured and genotyping was performed for 12 single nucleotide polymorphisms (SNP) in or near the genes GCK (rs4607517), DGKB (rs2191349), GCKR (rs780094), ADCY5 (rs11708067), MADD (rs7944584), ADRA2A (rs10885122), FADS1 (rs174550), CRY2 (rs11605924), SLC2A2 (rs11920090), PROX1 (rs340874), GLIS3 (rs7034200) and C2CD4B (rs11071657). Parameters of insulin secretion (AUC Insulin0–30/AUC Glucose0–30, AUC C-peptide0–120/AUC Glucose0–120), proinsulin-to-insulin conversion (fasting proinsulin, fasting proinsulin/insulin, AUC Proinsulin0–120/AUCInsulin0–120) and insulin resistance (HOMA-IR, Matsuda-Index) were assessed.ResultsAfter adjustment for confounding variables, the effect alleles of the ADCY5 and MADD SNPs were associated with an impaired proinsulin-to-insulin conversion (p = 0.002 and p = 0.0001, respectively). GLIS3 was nominally associated with impaired proinsulin-to-insulin conversion and insulin secretion. The diabetogenic alleles of DGKB and PROX1 were nominally associated with reduced insulin secretion. Nominally significant effects on insulin sensitivity could be found for MADD and PROX1.DiscussionBy examining parameters of glucose-stimulated proinsulin-to-insulin conversion during an OGTT, we show that the SNP in ADCY5 is implicated in defective proinsulin-to-insulin conversion. In addition, we confirmed previous findings on the role of a genetic variant in MADD on proinsulin-to-insulin conversion. These effects may also be related to neighboring regions of the genome.
Highlights
Recent meta-analyses of genome-wide association studies revealed new genetic loci associated with fasting glycemia
Key parameters of insulin secretion, proinsulin-to-insulin conversion and insulin sensitivity were investigated after genotyping the cohort of 1782 subjects for 12 single nucleotide polymorphisms (SNP) using an additive model
In order to attempt a replication of significant findings related to insulin secretion and insulin sensitivity, IVGTT and hyperinsulinemiceuglycemic clamp data were analyzed for the respective SNPs
Summary
Recent meta-analyses of genome-wide association studies revealed new genetic loci associated with fasting glycemia For several of these loci, the mechanism of action in glucose homeostasis is unclear. Most of the approximately 40 known genetic variants conferring increased risk for type 2 diabetes have been discovered by genome-wide association studies (GWAS) [3]. With this method, associations between genomic variants and diabetes prevalence or quantitative glycemic traits like increased fasting glucose (FG) can be established. Most of the recently discovered SNPs are located in non-coding DNA regions They may regulate the expression of nearby or far away genes [4,5], the exact target genes and their function in glucose homeostasis are in most cases still elusive. Detailed metabolic characterization of these variants can provide further data to elucidate their mechanism of action
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