Detailed physiologic characterization reveals diverse mechanisms for novel genetic Loci regulating glucose and insulin metabolism in humans.
Detailed physiologic characterization reveals diverse mechanisms for novel genetic Loci regulating glucose and insulin metabolism in humans.
复制标题
DOI：
10.2337/db09-1568
复制
发表时间：
2010-05
期刊：
影响因子：
7.7
通讯作者：
MAGIC investigators
中科院分区：
文献类型：
--
作者：
Ingelsson E;Langenberg C;Hivert MF;Prokopenko I;Lyssenko V;Dupuis J;Mägi R;Sharp S;Jackson AU;Assimes TL;Shrader P;Knowles JW;Zethelius B;Abbasi FA;Bergman RN;Bergmann A;Berne C;Boehnke M;Bonnycastle LL;Bornstein SR;Buchanan TA;Bumpstead SJ;Böttcher Y;Chines P;Collins FS;Cooper CC;Dennison EM;Erdos MR;Ferrannini E;Fox CS;Graessler J;Hao K;Isomaa B;Jameson KA;Kovacs P;Kuusisto J;Laakso M;Ladenvall C;Mohlke KL;Morken MA;Narisu N;Nathan DM;Pascoe L;Payne F;Petrie JR;Sayer AA;Schwarz PE;Scott LJ;Stringham HM;Stumvoll M;Swift AJ;Syvänen AC;Tuomi T;Tuomilehto J;Tönjes A;Valle TT;Williams GH;Lind L;Barroso I;Quertermous T;Walker M;Wareham NJ;Meigs JB;McCarthy MI;Groop L;Watanabe RM;Florez JC;MAGIC investigators
最近的全基因组关联研究揭示了与葡萄糖和胰岛素相关特征相关的基因座。我们的目的是使用胰岛素加工、分泌和敏感性的详细测量来表征 19 个此类基因座，以帮助阐明它们在调节血糖控制、胰岛素分泌和/或作用中的作用。我们研究了葡萄糖和胰岛素相关性状荟萃分析联盟 (MAGIC) 确定的位点与循环胰岛素原、胰岛素分泌测量和口服葡萄糖耐量试验 (OGTT)、正常血糖钳夹、胰岛素抑制试验或频繁采样的静脉内葡萄糖耐量试验的敏感性之间的关联。 非糖尿病人 (n = 29,084)。 MADD 中的血糖升高等位基因与胰岛素加工异常相关（对较高的胰岛素原水平有显着影响，但与胰岛素生成指数无关），具有极有说服力的统计显着性水平（P = 2.1 × 10−71）。 TCF7L2、SCL30A8、GIPR 和 C2CD4B 的葡萄糖升高等位基因携带者观察到胰岛素加工和胰岛素分泌缺陷。 MTNR1B、GCK、FADS1、DGKB 和 PROX1 的葡萄糖升高等位基因携带者提示早期胰岛素分泌异常（较低的胰岛素生成指数；与胰岛素原或胰岛素敏感性无关）。先前与空腹胰岛素相关的两个基因座（GCKR 和 IGF1）与 OGTT 衍生的胰岛素敏感性指数相关，方向一致。通过对高血糖和/或高胰岛素血症的影响而鉴定的遗传位点表现出与胰岛素加工、分泌和敏感性测量相关的相当大的异质性。我们的研究结果强调了这些位点的详细生理特征对于提高对葡萄糖稳态改变以及最终 2 型糖尿病相关途径的理解的重要性。
Recent genome-wide association studies have revealed loci associated with glucose and insulin-related traits. We aimed to characterize 19 such loci using detailed measures of insulin processing, secretion, and sensitivity to help elucidate their role in regulation of glucose control, insulin secretion and/or action. We investigated associations of loci identified by the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) with circulating proinsulin, measures of insulin secretion and sensitivity from oral glucose tolerance tests (OGTTs), euglycemic clamps, insulin suppression tests, or frequently sampled intravenous glucose tolerance tests in nondiabetic humans (n = 29,084). The glucose-raising allele in MADD was associated with abnormal insulin processing (a dramatic effect on higher proinsulin levels, but no association with insulinogenic index) at extremely persuasive levels of statistical significance (P = 2.1 × 10−71). Defects in insulin processing and insulin secretion were seen in glucose-raising allele carriers at TCF7L2, SCL30A8, GIPR, and C2CD4B. Abnormalities in early insulin secretion were suggested in glucose-raising allele carriers at MTNR1B, GCK, FADS1, DGKB, and PROX1 (lower insulinogenic index; no association with proinsulin or insulin sensitivity). Two loci previously associated with fasting insulin (GCKR and IGF1) were associated with OGTT-derived insulin sensitivity indices in a consistent direction. Genetic loci identified through their effect on hyperglycemia and/or hyperinsulinemia demonstrate considerable heterogeneity in associations with measures of insulin processing, secretion, and sensitivity. Our findings emphasize the importance of detailed physiological characterization of such loci for improved understanding of pathways associated with alterations in glucose homeostasis and eventually type 2 diabetes.
登录
查看更多内容
G6PC2启动子的甲基化FOXA2结合位点中的单核苷酸多态性与体内胰岛素分泌有关，体外启动子活性增加。
影响因子：
7.7
作者：
Dos Santos C;Bougnères P;Fradin D
通讯作者：
Fradin D
影响因子：
16.2
作者：
BIRKELAND, KI;TORJESEN, PA;GROOP, L
通讯作者：
GROOP, L
影响因子：
7.7
作者：
Hanley, AJG;D'Agostino, R;Haffner, SM
通讯作者：
Haffner, SM
新的遗传基因座涉及禁食葡萄糖稳态及其对2型糖尿病风险的影响。
影响因子：
30.8
作者：
通讯作者：
--
影响因子：
30.8
作者：
Abecasis, GR;Cherny, SS;Cardon, LR
通讯作者：
Cardon, LR