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全基因组关联研究和功能表征确定胰岛素刺激葡萄糖摄取的候选基因
作者:小柯机器人 发布时间:2023/6/10 16:51:05

英国剑桥大学临床医学院Claudia Langenberg和美国北卡罗来纳大学Karen L. Mohlke共同合作,近期取得重要工作进展。他们通过全基因组关联研究和功能表征确定胰岛素刺激葡萄糖摄取的候选基因。相关研究 成果2023年6月8日在线发表于《自然—遗传学》杂志上。

据介绍,不同的组织特异性机制介导空腹和餐后状态下的胰岛素作用。先前的遗传学研究主要集中在禁食状态下的胰岛素抵抗,其中肝脏胰岛素的作用占主导地位。

研究人员探讨了来自三个祖先群体超过55000名参与者,在葡萄糖刺激后2小时测量的影响胰岛素水平的遗传变异。研究人员鉴定了10个新的基因座(P < 5. × 10−8),其中8种在共定位分析中显示与2型糖尿病具有相同的遗传结构。他们研究了培养细胞中相关基因座子集的候选基因,并确定了9个新涉及GLUT4表达或运输的候选基因。GLUT4是肌肉和脂肪餐后葡萄糖摄取的关键葡萄糖转运蛋白。

总之,通过关注餐后胰岛素抵抗,研究人员强调了2型糖尿病基因座的作用机制,而禁食血糖特征的研究并没有充分捕捉到这些作用机制。

附:英文原文

Title: Genome-wide association study and functional characterization identifies candidate genes for insulin-stimulated glucose uptake

Author: Williamson, Alice, Norris, Dougall M., Yin, Xianyong, Broadaway, K. Alaine, Moxley, Anne H., Vadlamudi, Swarooparani, Wilson, Emma P., Jackson, Anne U., Ahuja, Vasudha, Andersen, Mette K., Arzumanyan, Zorayr, Bonnycastle, Lori L., Bornstein, Stefan R., Bretschneider, Maxi P., Buchanan, Thomas A., Chang, Yi-Cheng, Chuang, Lee-Ming, Chung, Ren-Hua, Clausen, Tine D., Damm, Peter, Delgado, Graciela E., de Mello, Vanessa D., Dupuis, Jose, Dwivedi, Om P., Erdos, Michael R., Silva, Lilian Fernandes, Frayling, Timothy M., Gieger, Christian, Goodarzi, Mark O., Guo, Xiuqing, Gustafsson, Stefan, Hakaste, Liisa, Hammar, Ulf, Hatem, Gad, Herrmann, Sandra, Hjlund, Kurt, Horn, Katrin, Hsueh, Willa A., Hung, Yi-Jen, Hwu, Chii-Min, Jonsson, Anna, Krhus, Line L., Kleber, Marcus E., Kovacs, Peter, Lakka, Timo A., Lauzon, Marie, Lee, I-Te, Lindgren, Cecilia M., Lindstrm, Jaana, Linneberg, Allan, Liu, Ching-Ti, Luan, Jianan, Aly, Dina Mansour, Mathiesen, Elisabeth, Moissl, Angela P., Morris, Andrew P., Narisu, Narisu, Perakakis, Nikolaos, Peters, Annette

Issue&Volume: 2023-06-08

Abstract: Distinct tissue-specific mechanisms mediate insulin action in fasting and postprandial states. Previous genetic studies have largely focused on insulin resistance in the fasting state, where hepatic insulin action dominates. Here we studied genetic variants influencing insulin levels measured 2h after a glucose challenge in >55,000 participants from three ancestry groups. We identified ten new loci (P<5×108) not previously associated with postchallenge insulin resistance, eight of which were shown to share their genetic architecture with type 2 diabetes in colocalization analyses. We investigated candidate genes at a subset of associated loci in cultured cells and identified nine candidate genes newly implicated in the expression or trafficking of GLUT4, the key glucose transporter in postprandial glucose uptake in muscle and fat. By focusing on postprandial insulin resistance, we highlighted the mechanisms of action at type 2 diabetes loci that are not adequately captured by studies of fasting glycemic traits.

DOI: 10.1038/s41588-023-01408-9

Source: https://www.nature.com/articles/s41588-023-01408-9

期刊信息

Nature Genetics:《自然—遗传学》,创刊于1992年。隶属于施普林格·自然出版集团,最新IF:41.307
官方网址:https://www.nature.com/ng/
投稿链接:https://mts-ng.nature.com/cgi-bin/main.plex

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