Kirchhoff K, Machicao F, Haupt A, Schäfer S A, Tschritter O, Staiger H, Stefan N, Häring H-U, Fritsche A
Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Medicine, Nephrology and Clinical Chemistry, Eberhard-Karls-Universität Tübingen, Otfried-Müller-Str. 10, 72076 Tübingen, Germany.
Diabetologia. 2008 Apr;51(4):597-601. doi: 10.1007/s00125-008-0926-y. Epub 2008 Feb 9.
AIMS/HYPOTHESIS: Variation within six novel genetic loci has been reported to confer risk of type 2 diabetes and may be associated with beta cell dysfunction. We investigated whether these polymorphisms are also associated with impaired proinsulin to insulin conversion.
We genotyped 1,065 German participants for single nucleotide polymorphisms rs7903146 in TCF7L2, rs7754840 in CDKAL1, rs7923837 and rs1111875 in HHEX, rs13266634 in SLC30A8, rs10811661 in CDKN2A/B and rs4402960 in IGF2BP2. All participants underwent an OGTT. Insulin, proinsulin and C-peptide concentrations were measured at 0, 30, 60, 90 and 120 min during the OGTT. Insulin secretion was estimated from C-peptide or insulin levels during the OGTT using validated indices. We used the ratio proinsulin/insulin during the OGTT as indicator of proinsulin conversion.
In our cohort, we confirmed the significant association of variants in TCF7L2, CDKAL1 and HHEX with reduced insulin secretion during the OGTT (p<0.05 for all). Variation in SLC30A8, CDKN2A/B and IGF2BP2 was not associated with insulin secretion. The risk alleles of the variants in TCF7L2, CDKAL1 and SLC30A8 reduced proinsulin to insulin conversion (p<0.05 for all), whereas the risk alleles in HHEX, CDKN2A/B and IGF2BP2 were not associated with reduced proinsulin to insulin conversion (p>0.6).
CONCLUSIONS/INTERPRETATION: Diabetes-associated variants in TCF7L2 and CDKAL1 impair insulin secretion and conversion of proinsulin to insulin. However, both aspects of beta cell function are not necessarily linked, as impaired insulin secretion is specifically present in variants of HHEX and impaired proinsulin conversion is specifically present in a variant of SLC30A8.
目的/假设：据报道，六个新的基因位点内的变异会增加患2型糖尿病的风险，并且可能与β细胞功能障碍有关。我们研究了这些多态性是否也与胰岛素原向胰岛素转化受损有关。
我们对1065名德国参与者进行基因分型，检测其在TCF7L2基因中的单核苷酸多态性rs7903146、CDKAL1基因中的rs7754840、HHEX基因中的rs7923837和rs1111875、SLC30A8基因中的rs13266634、CDKN2A/B基因中的rs10811661以及IGF2BP2基因中的rs4402960。所有参与者均接受口服葡萄糖耐量试验（OGTT）。在OGTT期间的0、30、60、90和120分钟测量胰岛素、胰岛素原和C肽浓度。使用经过验证的指标，根据OGTT期间的C肽或胰岛素水平估计胰岛素分泌情况。我们将OGTT期间胰岛素原/胰岛素的比值用作胰岛素原转化的指标。
在我们的队列中，我们证实了TCF7L2、CDKAL1和HHEX基因变异与OGTT期间胰岛素分泌减少显著相关（所有p<0.05）。SLC30A8、CDKN2A/B和IGF2BP2基因的变异与胰岛素分泌无关。TCF7L2、CDKAL1和SLC30A8基因变异的风险等位基因会降低胰岛素原向胰岛素的转化（所有p<0.05），而HHEX、CDKN2A/B和IGF2BP2基因的风险等位基因与胰岛素原向胰岛素转化减少无关（p>0.6）。
结论/解读：TCF7L2和CDKAL1基因中与糖尿病相关的变异会损害胰岛素分泌以及胰岛素原向胰岛素的转化。然而，β细胞功能的这两个方面不一定相关，因为HHEX基因变异中存在特异性的胰岛素分泌受损，而SLC30A8基因变异中存在特异性的胰岛素原转化受损。
