Genome-wide association study and functional characterization identifies candidate genes for insulin-stimulated glucose uptake.
Alice WilliamsonDougall M NorrisXianyong YinK Alaine BroadawayAnne H MoxleySwarooparani VadlamudiEmma P WilsonAnne U JacksonVasudha AhujaMette K AndersenZorayr ArzumanyanLori L BonnycastleStefan R BornsteinMaxi P BretschneiderThomas A BuchananYi-Cheng ChangLee-Ming ChuangRen-Hua ChungTine D ClausenNis Peter DammGraciela E DelgadoVanessa D de MelloJosée DupuisOm Prakash DwivediMichael R ErdosLilian Fernandes SilvaTimothy M FraylingChristian GiegerMark O GoodarziXiuqing GuoStefan GustafssonLiisa HakasteUlf HammarGad HatemSandra HerrmannKurt HøjlundKatrin HornWilla A HsuehYi-Jen HungChii-Min HwaAnna JonssonLine L KårhusMarcus Edi KleberPeter KovacsTimo A LakkaMarie LauzonI-Te LeeCecilia M LindgrenJaana LindströmAllan LinnebergChing-Ti LiuJian'an LuanDina Mansour AlyElisabeth MathiesenAngela P MoisslAndrew P MorrisNarisu NarisuNikolaos PerakakisAnnette PetersRashmi B PrasadRoman N RodionovKathryn RollCarsten F RundstenChloe SarnowskiKai SavonenMarkus ScholzSapna SharmaSara E StinsonSufyan SulemanJingyi TanKent D TaylorMatti UusitupaDorte VistisenDaniel R WitteRomy WaltherPeitao WuAnny H XiangBjörn Zetheliusnull nullEmma AhlqvistRichard N BergmanYii-Der Ida ChenFrancis S CollinsChristoph NowakJose C FlorezAndreas FritscheHarald GrallertLeif C GroopTorben HansenHeikki A KoistinenPirjo KomulainenMarkku LaaksoLars LindMarkus LoefflerWinfried MärzJames B MeigsLeslie J RaffelRainer RauramaaJerome I RotterPeter E H SchwarzMichael StumvollJohan SundströmAnke TönjesTiinamaija TuomiJaakko TuomilehtoRobert WagnerInês A BarrosoMark WalkerNiels GrarupMichael BoehnkeNicholas J WarehamKaren L MohlkeEleanor WheelerStephen I O'RahillyDaniel J FazakerleyClaudia LangenbergPublished in: Nature genetics (2023)
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.
Keyphrases
- blood glucose
- glycemic control
- type diabetes
- genome wide association study
- genome wide
- insulin resistance
- adipose tissue
- dna methylation
- weight loss
- skeletal muscle
- cardiovascular disease
- metabolic syndrome
- high fat diet
- induced apoptosis
- genome wide association
- polycystic ovary syndrome
- copy number
- cell cycle arrest
- poor prognosis
- case control
- endothelial cells
- gene expression
- blood pressure
- signaling pathway
- endoplasmic reticulum stress
- cell death