title: Effects of common genetic variants associated with type 2 diabetes and glycemic traits on α- and β-cell function and insulin action in humans.
abstract: Although meta-analyses of genome-wide association studies have identified >60 single nucleotide polymorphisms (SNPs) associated with type 2 diabetes and/or glycemic traits, there is little information on whether these variants also affect α-cell function. The aim of the current study was to evaluate the effects of glycemia-associated genetic loci on islet function in vivo and in vitro. We studied 43 SNPs in 4,654 normoglycemic participants from the Finnish population-based Prevalence, Prediction, and Prevention of Diabetes-Botnia (PPP-Botnia) Study. Islet function was assessed, in vivo, by measuring insulin and glucagon concentrations during oral glucose tolerance test, and, in vitro, by measuring glucose-stimulated insulin and glucagon secretion from human pancreatic islets. Carriers of risk variants in BCL11A, HHEX, ZBED3, HNF1A, IGF1, and NOTCH2 showed elevated whereas those in CRY2, IGF2BP2, TSPAN8, and KCNJ11 showed decreased fasting and/or 2-h glucagon concentrations in vivo. Variants in BCL11A, TSPAN8, and NOTCH2 affected glucagon secretion both in vivo and in vitro. The MTNR1B variant was a clear outlier in the relationship analysis between insulin secretion and action, as well as between insulin, glucose, and glucagon. Many of the genetic variants shown to be associated with type 2 diabetes or glycemic traits also exert pleiotropic in vivo and in vitro effects on islet function.
authors.affiliation: Department of Clinical Sciences, Diabetes and Endocrinology, Lund University Diabetes Centre, Lund University, Malmö, Sweden. jonsson@sund.ku.dk
authors.forename: Anna
authors.initials: A
authors.lastname: Jonsson
authors.forename: Claes
authors.initials: C
authors.lastname: Ladenvall
authors.forename: Tarunveer Singh
authors.initials: TS
authors.lastname: Ahluwalia
authors.forename: Jasmina
authors.initials: J
authors.lastname: Kravic
authors.forename: Ulrika
authors.initials: U
authors.lastname: Krus
authors.forename: Jalal
authors.initials: J
authors.lastname: Taneera
authors.forename: Bo
authors.initials: B
authors.lastname: Isomaa
authors.forename: Tiinamaija
authors.initials: T
authors.lastname: Tuomi
authors.forename: Erik
authors.initials: E
authors.lastname: Renström
authors.forename: Leif
authors.initials: L
authors.lastname: Groop
authors.forename: Valeriya
authors.initials: V
authors.lastname: Lyssenko
mesh_terms: D000328:Adult; D001786:Blood Glucose / Q000235:genetics* / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism; D005387:Finland; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D050416:Glucagon-Secreting Cells / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide
chemical_list: D001786:Blood Glucose; D007328:Insulin
references.citation: Cell. 2012 Dec 21;151(7):1595-607
references.pmid: 23260145
references.citation: Diabetologia. 2010 Aug;53(8):1709-13
references.pmid: 20454776
references.citation: Diabetes. 2010 Jan;59(1):293-301
references.pmid: 19833888
references.citation: Diabetes. 2010 Apr;59(4):836-43
references.pmid: 20107109
references.citation: Nat Genet. 2010 Feb;42(2):105-16
references.pmid: 20081858
references.citation: J Clin Invest. 2007 Aug;117(8):2155-63
references.pmid: 17671651
references.citation: Curr Diab Rep. 2010 Dec;10(6):485-97
references.pmid: 20886378
references.citation: Am J Hum Genet. 2007 Sep;81(3):559-75
references.pmid: 17701901
references.citation: Diabetes. 2009 Oct;58(10):2409-13
references.pmid: 19584308
references.citation: Diabetologia. 2011 Dec;54(12):3132-42
references.pmid: 21901280
references.citation: N Engl J Med. 2008 Nov 20;359(21):2220-32
references.pmid: 19020324
references.citation: Am J Epidemiol. 2000 Jan 15;151(2):190-8
references.pmid: 10645822
references.citation: Diabetes Care. 1999 Sep;22(9):1462-70
references.pmid: 10480510
references.citation: Diabetologia. 2009 Jul;52(7):1298-307
references.pmid: 19288077
references.citation: Nat Genet. 2010 Jul;42(7):579-89
references.pmid: 20581827