Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Eberhard Karls University Tübingen, Tübingen, Germany.
PLoS One. 2011;6(8):e23639. doi: 10.1371/journal.pone.0023639. Epub 2011 Aug 22.
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. The objective of the study was to establish metabolic phenotypes for these genetic variants to deliver clues to their pathomechanism.
In 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 Insulin(0-30)/AUC Glucose(0-30), AUC C-peptide(0-120)/AUC Glucose(0-120)), proinsulin-to-insulin conversion (fasting proinsulin, fasting proinsulin/insulin, AUC Proinsulin(0-120)/AUCInsulin(0-120)) and insulin resistance (HOMA-IR, Matsuda-Index) were assessed.
After 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.
By 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.
最近的全基因组关联研究荟萃分析揭示了与空腹血糖相关的新遗传位点。对于其中的几个位点，其在葡萄糖稳态中的作用机制尚不清楚。本研究的目的是为这些遗传变异建立代谢表型，以提供其发病机制的线索。
在这项横断面研究中，1782 名患有 2 型糖尿病风险增加的非糖尿病志愿者接受了口服葡萄糖耐量试验。测量胰岛素、C 肽和胰岛素原，并对位于 GCK（rs4607517）、DGKB（rs2191349）、GCKR（rs780094）、ADCY5（rs11708067）、MADD（rs7944584）、ADRA2A（rs10885122）、FADS1（rs174550）、CRY2（rs11605924）、SLC2A2（rs11920090）、PROX1（rs340874）、GLIS3（rs7034200）和 C2CD4B（rs11071657）基因内或附近的 12 个单核苷酸多态性（SNP）进行基因分型。评估胰岛素分泌参数（AUC 胰岛素（0-30）/AUC 葡萄糖（0-30）、AUC C 肽（0-120）/AUC 葡萄糖（0-120））、胰岛素原到胰岛素的转化（空腹胰岛素原、空腹胰岛素原/胰岛素、AUC 胰岛素原（0-120）/AUCInsulin（0-120））和胰岛素抵抗（HOMA-IR、Matsuda-Index）。
在调整混杂变量后，ADCY5 和 MADD SNP 的效应等位基因与胰岛素原到胰岛素的转化受损相关（p=0.002 和 p=0.0001）。GLIS3 与胰岛素原到胰岛素的转化和胰岛素分泌受损呈显著相关。DGKB 和 PROX1 的致糖尿病等位基因与胰岛素分泌减少有关。MADD 和 PROX1 与胰岛素敏感性的显著影响呈显著相关。
通过在 OGTT 期间检查葡萄糖刺激的胰岛素原到胰岛素的转化参数，我们发现 ADCY5 中的 SNP 与胰岛素原到胰岛素的转化缺陷有关。此外，我们还证实了先前关于 MADD 中遗传变异对胰岛素原到胰岛素的转化作用的发现。这些影响可能也与基因组的邻近区域有关。
