Genome-wide association study and functional characterization identifies candidate genes for insulin-stimulated glucose uptake
Journal
Nature genetics
Journal Volume
55
Journal Issue
6
Date Issued
2023-06
Author(s)
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
Chung, Ren-Hua
Clausen, Tine D
Damm, Peter
Delgado, Graciela E
de Mello, Vanessa D
Dupuis, Josée
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
Højlund, Kurt
Horn, Katrin
Hsueh, Willa A
Hung, Yi-Jen
Hwu, Chii-Min
Jonsson, Anna
Kårhus, Line L
Kleber, Marcus E
Kovacs, Peter
Lakka, Timo A
Lauzon, Marie
Lee, I-Te
Lindgren, Cecilia M
Lindström, Jaana
Linneberg, Allan
Liu, Ching-Ti
Luan, Jian'an
Aly, Dina Mansour
Mathiesen, Elisabeth
Moissl, Angela P
Morris, Andrew P
Narisu, Narisu
Perakakis, Nikolaos
Peters, Annette
Prasad, Rashmi B
Rodionov, Roman N
Roll, Kathryn
Rundsten, Carsten F
Sarnowski, Chloé
Savonen, Kai
Scholz, Markus
Sharma, Sapna
Stinson, Sara E
Suleman, Sufyan
Tan, Jingyi
Taylor, Kent D
Uusitupa, Matti
Vistisen, Dorte
Witte, Daniel R
Walther, Romy
Wu, Peitao
Xiang, Anny H
Zethelius, Björn
Ahlqvist, Emma
Bergman, Richard N
Chen, Yii-Der Ida
Collins, Francis S
Fall, Tove
Florez, Jose C
Fritsche, Andreas
Grallert, Harald
Groop, Leif
Hansen, Torben
Koistinen, Heikki A
Komulainen, Pirjo
Laakso, Markku
Lind, Lars
Loeffler, Markus
März, Winfried
Meigs, James B
Raffel, Leslie J
Rauramaa, Rainer
Rotter, Jerome I
Schwarz, Peter E H
Stumvoll, Michael
Sundström, Johan
Tönjes, Anke
Tuomi, Tiinamaija
Tuomilehto, Jaakko
Wagner, Robert
Barroso, Inês
Walker, Mark
Grarup, Niels
Boehnke, Michael
Wareham, Nicholas J
Mohlke, Karen L
Wheeler, Eleanor
O'Rahilly, Stephen
Fazakerley, Daniel J
Langenberg, Claudia
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 2 h after a glucose challenge in >55,000 participants from three ancestry groups. We identified ten new loci (P < 5 × 10-8) 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.
SDGs
Type
journal article