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PMID: 19516902 Published · epublish English Journal Article Research Support, Non-U.S. Gov't

The type 2 diabetes associated minor allele of rs2237895 KCNQ1 associates with reduced insulin release following an oral glucose load.

PloS one ·Vol. 4 ·No. 6 ·2009-06-11 ·Pages e5872

Holmkvist J, Banasik K, Andersen G, Unoki H, Jensen TS, Pisinger C, Borch-Johnsen K, Sandbaek A, Lauritzen T, Brunak S, Maeda S, Hansen T, Pedersen O

Abstract

Polymorphisms in the potassium channel, voltage-gated, KQT-like subfamily, member 1 (KCNQ1) have recently been reported to associate with type 2 diabetes. The primary aim of the present study was to investigate the putative impact of these KCNQ1 polymorphisms (rs2283228, rs2237892, rs2237895, and rs2237897) on estimates of glucose stimulated insulin release. Genotypes were examined for associations with serum insulin levels following an oral glucose tolerance test (OGTT) in a population-based sample of 6,039 middle-aged and treatment-naïve individuals. Insulin release indices estimated from the OGTT and the interplay between insulin sensitivity and insulin release were investigated using linear regression and Hotelling T2 analyses. Applying an additive genetic model the minor C-allele of rs2237895 was associated with reduced serum insulin levels 30 min (mean+/-SD: (CC) 277+/-160 vs. (AC) 280+/-164 vs. (AA) 299+/-200 pmol/l, p = 0.008) after an oral glucose load, insulinogenic index (29.6+/-17.4 vs. 30.2+/-18.7vs. 32.2+/-22.1, p = 0.007), incremental area under the insulin curve (20,477+/-12,491 vs. 20,503+/-12,386 vs. 21,810+/-14,685, p = 0.02) among the 4,568 individuals who were glucose tolerant. Adjustment for the degree of insulin sensitivity had no effect on the measures of reduced insulin release. The rs2237895 genotype had a similar impact in the total sample of treatment-naïve individuals. No association with measures of insulin release were identified for the less common diabetes risk alleles of rs2237892, rs2237897, or rs2283228. The minor C-allele of rs2237895 of KCNQ1, which has a prevalence of about 42% among Caucasians was associated with reduced measures of insulin release following an oral glucose load suggesting that the increased risk of type 2 diabetes, previously reported for this variant, likely is mediated through an impaired beta cell function.

MeSH Terms
Alleles Case-Control Studies Computational Biology/methods Diabetes Mellitus, Type 2/genetics,pathology Genotype Glucose/metabolism Glucose Tolerance Test Humans Insulin/metabolism Insulin-Secreting Cells/metabolism KCNQ1 Potassium Channel/genetics Models, Genetic Multivariate Analysis Polymorphism, Genetic Protein Interaction Mapping
Chemicals
Insulin KCNQ1 Potassium Channel KCNQ1 protein, human Glucose
Authors & Affiliations
13 authors, click to expand affiliations / ORCID
Holmkvist Johan
Hagedorn Research Institute, Gentofte, Denmark.
Banasik Karina
Andersen Gitte
Unoki Hiroyuki
Jensen Thomas Skot
Pisinger Charlotta
Borch-Johnsen Knut
Sandbaek Annelli
Lauritzen Torsten
Brunak Sören
Maeda Shiro
Hansen Torben
Pedersen Oluf
References (36)
36 references, click to expand
  1. Action potentials and insulin secretion: new insights into the role of Kv channels.
    Diabetes Obes Metab. 2007 Nov;9 Suppl 2:89-98 PMID: 17919183
  2. QT interval, cardiovascular risk factors and risk of death in diabetes.
    J Endocrinol Invest. 2004 Feb;27(2):175-81 PMID: 15129815
  3. A randomized non-pharmacological intervention study for prevention of ischaemic heart disease: baseline results Inter99.
    Eur J Cardiovasc Prev Rehabil. 2003 Oct;10(5):377-86 PMID: 14663300
  4. SNPs in KCNQ1 are associated with susceptibility to type 2 diabetes in East Asian and European populations.
    Nat Genet. 2008 Sep;40(9):1098-102 PMID: 18711366
  5. Genome-wide search for type 2 diabetes in Japanese affected sib-pairs confirms susceptibility genes on 3q, 15q, and 20q and identifies two new candidate Loci on 7p and 11p.
    Diabetes. 2002 Apr;51(4):1247-55 PMID: 11916952
  6. Polymorphisms in the gene encoding the voltage-dependent Ca(2+) channel Ca (V)2.3 (CACNA1E) are associated with type 2 diabetes and impaired insulin secretion.
    Diabetologia. 2007 Dec;50(12):2467-75 PMID: 17934712
  7. Anchoring of protein kinase A facilitates hormone-mediated insulin secretion.
    Proc Natl Acad Sci U S A. 1997 Dec 23;94(26):14942-7 PMID: 9405718
  8. Effects of I(Ks) channel inhibitors in insulin-secreting INS-1 cells.
    Pflugers Arch. 2005 Dec;451(3):428-36 PMID: 16133261
  9. Studies of association of variants near the HHEX, CDKN2A/B, and IGF2BP2 genes with type 2 diabetes and impaired insulin release in 10,705 Danish subjects: validation and extension of genome-wide association studies.
    Diabetes. 2007 Dec;56(12):3105-11 PMID: 17827400
  10. Glucose-dependent regulation of rhythmic action potential firing in pancreatic beta-cells by K(ATP)-channel modulation.
    J Physiol. 2002 Dec 1;545(2):501-7 PMID: 12456829
  11. Pharmacological properties and functional role of Kslow current in mouse pancreatic beta-cells: SK channels contribute to Kslow tail current and modulate insulin secretion.
    J Gen Physiol. 2005 Oct;126(4):353-63 PMID: 16186562
  12. Variants in KCNQ1 are associated with susceptibility to type 2 diabetes mellitus.
    Nat Genet. 2008 Sep;40(9):1092-7 PMID: 18711367
  13. Members of the Kv1 and Kv2 voltage-dependent K(+) channel families regulate insulin secretion.
    Mol Endocrinol. 2001 Aug;15(8):1423-35 PMID: 11463864
  14. KCNQ potassium channels: physiology, pathophysiology, and pharmacology.
    Pharmacol Ther. 2001 Apr;90(1):1-19 PMID: 11448722
  15. hKCNE4 inhibits the hKCNQ1 potassium current without affecting the activation kinetics.
    Biochem Biophys Res Commun. 2005 Mar 25;328(4):1146-53 PMID: 15707997
  16. A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants.
    Science. 2007 Jun 1;316(5829):1341-5 PMID: 17463248
  17. Mutation of an A-kinase-anchoring protein causes long-QT syndrome.
    Proc Natl Acad Sci U S A. 2007 Dec 26;104(52):20990-5 PMID: 18093912
  18. Expression and function of pancreatic beta-cell delayed rectifier K+ channels. Role in stimulus-secretion coupling.
    J Biol Chem. 1996 Dec 13;271(50):32241-6 PMID: 8943282
  19. Studies of variations of the cyclin-dependent kinase inhibitor 1C and the cyclin-dependent kinase 4 genes in relation to type 2 diabetes mellitus and related quantitative traits.
    J Mol Med (Berl). 2005 May;83(5):353-61 PMID: 15821902
  20. Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels.
    Science. 2007 Jun 1;316(5829):1331-6 PMID: 17463246
  21. Common variants at ten loci modulate the QT interval duration in the QTSCD Study.
    Nat Genet. 2009 Apr;41(4):407-14 PMID: 19305409
  22. A human phenome-interactome network of protein complexes implicated in genetic disorders.
    Nat Biotechnol. 2007 Mar;25(3):309-16 PMID: 17344885
  23. Large-scale association studies of variants in genes encoding the pancreatic beta-cell KATP channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) confirm that the KCNJ11 E23K variant is associated with type 2 diabetes.
    Diabetes. 2003 Feb;52(2):568-72 PMID: 12540637
  24. Genetic variation in KCNQ1 associates with fasting glucose and beta-cell function: a study of 3,734 subjects comprising three ethnicities living in Singapore.
    Diabetes. 2009 Jun;58(6):1445-9 PMID: 19252135
  25. PLINK: a tool set for whole-genome association and population-based linkage analyses.
    Am J Hum Genet. 2007 Sep;81(3):559-75 PMID: 17701901
  26. Common variants at ten loci influence QT interval duration in the QTGEN Study.
    Nat Genet. 2009 Apr;41(4):399-406 PMID: 19305408
  27. A genome-wide association study identifies novel risk loci for type 2 diabetes.
    Nature. 2007 Feb 22;445(7130):881-5 PMID: 17293876
  28. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation.
    Diabet Med. 1998 Jul;15(7):539-53 PMID: 9686693
  29. Inhibition of Kv2.1 voltage-dependent K+ channels in pancreatic beta-cells enhances glucose-dependent insulin secretion.
    J Biol Chem. 2002 Nov 22;277(47):44938-45 PMID: 12270920
  30. The long QT syndrome. Prospective longitudinal study of 328 families.
    Circulation. 1991 Sep;84(3):1136-44 PMID: 1884444
  31. Requirement of a macromolecular signaling complex for beta adrenergic receptor modulation of the KCNQ1-KCNE1 potassium channel.
    Science. 2002 Jan 18;295(5554):496-9 PMID: 11799244
  32. A novel mutation in the potassium channel gene KVLQT1 causes the Jervell and Lange-Nielsen cardioauditory syndrome.
    Nat Genet. 1997 Feb;15(2):186-9 PMID: 9020846
  33. Properties of KvLQT1 K+ channel mutations in Romano-Ward and Jervell and Lange-Nielsen inherited cardiac arrhythmias.
    EMBO J. 1997 Sep 1;16(17):5472-9 PMID: 9312006
  34. The BIGTT test: a novel test for simultaneous measurement of pancreatic beta-cell function, insulin sensitivity, and glucose tolerance.
    Diabetes Care. 2007 Feb;30(2):257-62 PMID: 17259491
  35. A variant in CDKAL1 influences insulin response and risk of type 2 diabetes.
    Nat Genet. 2007 Jun;39(6):770-5 PMID: 17460697
  36. Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes.
    Science. 2007 Jun 1;316(5829):1336-41 PMID: 17463249
Article Info
Journal
PloS one
Abbr.
PLoS One
ISSN
1932-6203
DOI
10.1371/journal.pone.0005872
Published
2009-06-11
Epub
2009-00-11
Pages
e5872
Language
English
Region
United States
NLM ID
101285081
PMCID
PMC2689931
Subset
IM
External Links
PubMed source DOI: 10.1371/journal.pone.0005872 PMC Full Text View journal details
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