title: Combined risk allele score of eight type 2 diabetes genes is associated with reduced first-phase glucose-stimulated insulin secretion during hyperglycemic clamps.
abstract: OBJECTIVE
  At least 20 type 2 diabetes loci have now been identified, and several of these are associated with altered beta-cell function. In this study, we have investigated the combined effects of eight known beta-cell loci on insulin secretion stimulated by three different secretagogues during hyperglycemic clamps.
  
  
  METHODS
  A total of 447 subjects originating from four independent studies in the Netherlands and Germany (256 with normal glucose tolerance [NGT]/191 with impaired glucose tolerance [IGT]) underwent a hyperglycemic clamp. A subset had an extended clamp with additional glucagon-like peptide (GLP)-1 and arginine (n = 224). We next genotyped single nucleotide polymorphisms in TCF7L2, KCNJ11, CDKAL1, IGF2BP2, HHEX/IDE, CDKN2A/B, SLC30A8, and MTNR1B and calculated a risk allele score by risk allele counting.
  
  
  RESULTS
  The risk allele score was associated with lower first-phase glucose-stimulated insulin secretion (GSIS) (P = 7.1 x 10(-6)). The effect size was equal in subjects with NGT and IGT. We also noted an inverse correlation with the disposition index (P = 1.6 x 10(-3)). When we stratified the study population according to the number of risk alleles into three groups, those with a medium- or high-risk allele score had 9 and 23% lower first-phase GSIS. Second-phase GSIS, insulin sensitivity index and GLP-1, or arginine-stimulated insulin release were not significantly different.
  
  
  CONCLUSIONS
  A combined risk allele score for eight known beta-cell genes is associated with the rapid first-phase GSIS and the disposition index. The slower second-phase GSIS, GLP-1, and arginine-stimulated insulin secretion are not associated, suggesting that especially processes involved in rapid granule recruitment and exocytosis are affected in the majority of risk loci.
authors.affiliation: Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, the Netherlands. l.m.t_hart@lumc.nl
authors.forename: Leen M
authors.initials: LM
authors.lastname: 't Hart
authors.forename: Annemarie M
authors.initials: AM
authors.lastname: Simonis-Bik
authors.forename: Giel
authors.initials: G
authors.lastname: Nijpels
authors.forename: Timon W
authors.initials: TW
authors.lastname: van Haeften
authors.forename: Silke A
authors.initials: SA
authors.lastname: Schäfer
authors.forename: Jeanine J
authors.initials: JJ
authors.lastname: Houwing-Duistermaat
authors.forename: Dorret I
authors.initials: DI
authors.lastname: Boomsma
authors.forename: Marlous J
authors.initials: MJ
authors.lastname: Groenewoud
authors.forename: Erwin
authors.initials: E
authors.lastname: Reiling
authors.forename: Els C
authors.initials: EC
authors.lastname: van Hove
authors.forename: Michaela
authors.initials: M
authors.lastname: Diamant
authors.forename: Mark H H
authors.initials: MH
authors.lastname: Kramer
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Heine
authors.forename: J Antonie
authors.initials: JA
authors.lastname: Maassen
authors.forename: Kerstin
authors.initials: K
authors.lastname: Kirchhoff
authors.forename: Fausto
authors.initials: F
authors.lastname: Machicao
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Häring
authors.forename: P Eline
authors.initials: PE
authors.lastname: Slagboom
authors.forename: Gonneke
authors.initials: G
authors.lastname: Willemsen
authors.forename: Elisabeth M
authors.initials: EM
authors.lastname: Eekhoff
authors.forename: Eco J
authors.initials: EJ
authors.lastname: de Geus
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Dekker
authors.forename: Andreas
authors.initials: A
authors.lastname: Fritsche
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D015992:Body Mass Index; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D005838:Genotype; D005858:Germany / Q000453:epidemiology; D005947:Glucose / Q000494:pharmacology*; D015309:Glucose Clamp Technique; D018149:Glucose Intolerance / Q000453:epidemiology / Q000235:genetics; D006801:Humans; D006943:Hyperglycemia / Q000097:blood / Q000139:chemically induced; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D008297:Male; D008875:Middle Aged; D009426:Netherlands / Q000453:epidemiology; D020641:Polymorphism, Single Nucleotide; D012016:Reference Values; D018570:Risk Assessment; D012307:Risk Factors
chemical_list: D007328:Insulin; D005947:Glucose