Division of Endocrinology, Diabetes and Metabolism, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Room B-131, Los Angeles, CA 90048, USA.
Diabetologia. 2013 Jun;56(6):1282-90. doi: 10.1007/s00125-013-2880-6. Epub 2013 Mar 14.
AIMS/HYPOTHESIS: Insulin clearance is a highly heritable trait, for which few quantitative trait loci have been discovered. We sought to determine whether validated type 2 diabetes and/or glycaemic trait loci are associated with insulin clearance.
Hyperinsulinaemic-euglycaemic clamps were performed in two Hispanic-American family cohorts totalling 1329 participants in 329 families. The Metabochip was used to fine-map about 50 previously identified loci for type 2 diabetes, fasting glucose, fasting insulin, 2 h glucose or HbA1c. This resulted in 17,930 variants, which were tested for association with clamp-derived insulin clearance via meta-analysis of the two cohorts.
In the meta-analysis, 38 variants located within seven loci demonstrated association with insulin clearance (p < 0.001). The top signals for each locus were rs10241087 (DGKB/TMEM195 [TMEM195 also known as AGMO]) (p = 4.4 × 10(-5)); chr1:217605433 (LYPLAL1) (p = 3.25 × 10(-4)); rs2380949 (GLIS3) (p = 3.4 × 10(-4)); rs55903902 (FADS1) (p = 5.6 × 10(-4)); rs849334 (JAZF1) (p = 6.4 × 10(-4)); rs35749 (IGF1) (p = 6.7 × 10(-4)); and rs9460557 (CDKAL1) (p = 6.8 × 10(-4)).
CONCLUSIONS/INTERPRETATION: While the majority of validated loci for type 2 diabetes and related traits do not appear to influence insulin clearance in Hispanics, several of these loci do show evidence of association with this trait. It is therefore possible that these loci could have pleiotropic effects on insulin secretion, insulin sensitivity and insulin clearance.
目的/假设：胰岛素清除率是一个高度遗传的特征，目前已经发现了很少的数量性状基因座。我们试图确定已验证的 2 型糖尿病和/或血糖特征基因座是否与胰岛素清除率有关。
在两个西班牙裔美国家族队列中进行高胰岛素-正常血糖钳夹实验，总共涉及 329 个家庭的 1329 名参与者。使用代谢芯片对 50 个先前确定的 2 型糖尿病、空腹血糖、空腹胰岛素、2 小时血糖或 HbA1c 相关基因座进行精细定位。这导致了 17930 个变体，通过对两个队列的meta 分析，对这些变体与钳夹衍生的胰岛素清除率进行了关联测试。
在 meta 分析中，位于七个基因座内的 38 个变体与胰岛素清除率相关（p<0.001）。每个基因座的最高信号是 rs10241087（DGKB/TMEM195[TMEM195 也称为 AGMO]）（p=4.4×10(-5)）；chr1:217605433（LYPLAL1）（p=3.25×10(-4)）；rs2380949（GLIS3）（p=3.4×10(-4)）；rs55903902（FADS1）（p=5.6×10(-4)）；rs849334（JAZF1）（p=6.4×10(-4)）；rs35749（IGF1）（p=6.7×10(-4)）；和 rs9460557（CDKAL1）（p=6.8×10(-4)）。
结论/解释：虽然大多数已验证的 2 型糖尿病和相关特征基因座似乎不会影响西班牙裔人群的胰岛素清除率，但其中一些基因座确实显示出与该特征相关的证据。因此，这些基因座可能对胰岛素分泌、胰岛素敏感性和胰岛素清除率有多种影响。
