title: Glycemia determines the effect of type 2 diabetes risk genes on insulin secretion.
abstract: OBJECTIVE
  Several single nucleotide polymorphisms (SNPs) in diabetes risk genes reduce glucose- and/or incretin-induced insulin secretion. Here, we investigated interactions between glycemia and such diabetes risk polymorphisms.
  
  
  METHODS
  Insulin secretion was assessed by insulinogenic index and areas under the curve of C-peptide/glucose in 1,576 subjects using an oral glucose tolerance test (OGTT). Participants were genotyped for 10 diabetes risk SNPs associated with β-cell dysfunction: rs5215 (KCNJ11), rs13266634 (SLC30A8), rs7754840 (CDKAL1), rs10811661 (CDKN2A/2B), rs10830963 (MTNR1B), rs7903146 (TCF7L2), rs10010131 (WFS1), rs7923837 (HHEX), rs151290 (KCNQ1), and rs4402960 (IGF2BP2). Furthermore, the impact of the interaction between genetic variation in TCF7L2 and glycemia on changes in insulin secretion was tested in 315 individuals taking part in a lifestyle intervention study.
  
  
  RESULTS
  For the SNPs in TCF7L2 and WFS1, we found a significant interaction between glucose control and insulin secretion (all P ≤ 0.0018 for glucose × genotype). When plotting insulin secretion against glucose at 120 min OGTT, the compromising SNP effects on insulin secretion are most apparent under high glucose. In the longitudinal study, rs7903146 in TCF7L2 showed a significant interaction with baseline glucose tolerance upon change in insulin secretion (P = 0.0027). Increased glucose levels at baseline predicted an increase in insulin secretion upon improvement of glycemia by lifestyle intervention only in carriers of the risk alleles.
  
  
  CONCLUSIONS
  For the diabetes risk genes TCF7L2 and WFS1, which are associated with impaired incretin signaling, the level of glycemia determines SNP effects on insulin secretion. This indicates the increasing relevance of these SNPs during the progression of prediabetes stages toward clinically overt type 2 diabetes.
authors.affiliation: Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Eberhard Karls University Tübingen, Tübingen, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Heni
authors.forename: Caroline
authors.initials: C
authors.lastname: Ketterer
authors.forename: Claus
authors.initials: C
authors.lastname: Thamer
authors.forename: Silke A
authors.initials: SA
authors.lastname: Herzberg-Schäfer
authors.forename: Martina
authors.initials: M
authors.lastname: Guthoff
authors.forename: Norbert
authors.initials: N
authors.lastname: Stefan
authors.forename: Fausto
authors.initials: F
authors.lastname: Machicao
authors.forename: Harald
authors.initials: H
authors.lastname: Staiger
authors.forename: Andreas
authors.initials: A
authors.lastname: Fritsche
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Häring
mesh_terms: D001786:Blood Glucose / Q000378:metabolism*; D002096:C-Peptide / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000235:genetics*; D005786:Gene Expression Regulation; D014644:Genetic Variation; D005838:Genotype; D005951:Glucose Tolerance Test; D054795:Incretins / Q000502:physiology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000502:physiology; D008565:Membrane Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D018570:Risk Assessment; D058118:Transcription Factor 7-Like 2 Protein / Q000235:genetics*
chemical_list: D001786:Blood Glucose; D002096:C-Peptide; D054795:Incretins; D007328:Insulin; D008565:Membrane Proteins; C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein; C114987:wolframin protein
references.citation: Endocr Rev. 2008 May;29(3):351-66
references.pmid: 18048763
references.citation: N Engl J Med. 2006 Jul 20;355(3):241-50
references.pmid: 16855264
references.citation: PLoS One. 2008;3(12):e3962
references.pmid: 19088850
references.citation: Diabetologia. 2008 Apr;51(4):597-601
references.pmid: 18264689
references.citation: Curr Diab Rep. 2009 Apr;9(2):164-71
references.pmid: 19323962
references.citation: Diabetes. 2002 Sep;51(9):2854-60
references.pmid: 12196481
references.citation: J Mol Med (Berl). 2007 Feb;85(2):107-17
references.pmid: 17165091
references.citation: Curr Opin Clin Nutr Metab Care. 2007 Jul;10(4):420-6
references.pmid: 17563459
references.citation: PLoS One. 2007 Sep 05;2(9):e832
references.pmid: 17786204
references.citation: Eur J Clin Invest. 2007 Jul;37(7):535-43
references.pmid: 17576204
references.citation: Lancet. 2005 Apr 9-15;365(9467):1333-46
references.pmid: 15823385
references.citation: Diabetologia. 2009 Jun;52(6):1075-82
references.pmid: 19330314
references.citation: Diabetes. 2009 Jul;58(7):1715-20
references.pmid: 19366866
references.citation: Cell Metab. 2006 Mar;3(3):153-65
references.pmid: 16517403
references.citation: Endocr Rev. 2009 Oct;30(6):557-85
references.pmid: 19749172
references.citation: Diabetologia. 2007 Dec;50(12):2443-50
references.pmid: 17661009
references.citation: Nutrition. 2009 Oct;25(10):998-1003
references.pmid: 19596186
references.citation: Diabetes. 2003 Feb;52(2):380-6
references.pmid: 12540611
references.citation: Endocrinol Metab Clin North Am. 2002 Sep;31(3):553-66
references.pmid: 12227119
references.citation: N Engl J Med. 2001 May 3;344(18):1343-50
references.pmid: 11333990
references.citation: Diabetes. 2010 Mar;59(3):747-50
references.pmid: 20028944
references.citation: Lancet. 2009 Jun 27;373(9682):2215-21
references.pmid: 19515410
references.citation: Nature. 2006 Dec 14;444(7121):840-6
references.pmid: 17167471
references.citation: N Engl J Med. 2002 Feb 7;346(6):393-403
references.pmid: 11832527
references.citation: Diabetologia. 2007 Jun;50(6):1192-200
references.pmid: 17437080