title: Gene variants in the novel type 2 diabetes loci CDC123/CAMK1D, THADA, ADAMTS9, BCL11A, and MTNR1B affect different aspects of pancreatic beta-cell function.
abstract: OBJECTIVE
  Recently, results from a meta-analysis of genome-wide association studies have yielded a number of novel type 2 diabetes loci. However, conflicting results have been published regarding their effects on insulin secretion and insulin sensitivity. In this study we used hyperglycemic clamps with three different stimuli to test associations between these novel loci and various measures of beta-cell function.
  
  
  METHODS
  For this study, 336 participants, 180 normal glucose tolerant and 156 impaired glucose tolerant, underwent a 2-h hyperglycemic clamp. In a subset we also assessed the response to glucagon-like peptide (GLP)-1 and arginine during an extended clamp (n = 123). All subjects were genotyped for gene variants in JAZF1, CDC123/CAMK1D, TSPAN8/LGR5, THADA, ADAMTS9, NOTCH2/ADAMS30, DCD, VEGFA, BCL11A, HNF1B, WFS1, and MTNR1B.
  
  
  RESULTS
  Gene variants in CDC123/CAMK1D, ADAMTS9, BCL11A, and MTNR1B affected various aspects of the insulin response to glucose (all P < 6.9 x 10(-3)). The THADA gene variant was associated with lower beta-cell response to GLP-1 and arginine (both P < 1.6 x 10(-3)), suggesting lower beta-cell mass as a possible pathogenic mechanism. Remarkably, we also noted a trend toward an increased insulin response to GLP-1 in carriers of MTNR1B (P = 0.03), which may offer new therapeutic possibilities. The other seven loci were not detectably associated with beta-cell function.
  
  
  CONCLUSIONS
  Diabetes risk alleles in CDC123/CAMK1D, THADA, ADAMTS9, BCL11A, and MTNR1B are associated with various specific aspects of beta-cell function. These findings point to a clear diversity in the impact that these various gene variants may have on (dys)function of pancreatic beta-cells.
authors.affiliation: Diabetes Center, VU University Medical Center, Amsterdam, the Netherlands.
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: Jeanine J
authors.initials: JJ
authors.lastname: Houwing-Duistermaat
authors.forename: Dorret I
authors.initials: DI
authors.lastname: Boomsma
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: P Eline
authors.initials: PE
authors.lastname: Slagboom
authors.forename: Gonneke
authors.initials: G
authors.lastname: Willemsen
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Dekker
authors.forename: Elisabeth M
authors.initials: EM
authors.lastname: Eekhoff
authors.forename: Eco J
authors.initials: EJ
authors.lastname: de Geus
authors.forename: Leen M
authors.initials: LM
authors.lastname: 't Hart
mesh_terms: D051722:ADAM Proteins / Q000235:genetics*; D000071119:ADAMTS9 Protein; D000328:Adult; D000368:Aged; D054729:Calcium-Calmodulin-Dependent Protein Kinase Type 1 / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics*; D002353:Carrier State; D018797:Cell Cycle Proteins / Q000235:genetics*; D002874:Chromosome Mapping; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D014644:Genetic Variation; D015309:Glucose Clamp Technique; D006801:Humans; D050417:Insulin-Secreting Cells / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D012097:Repressor Proteins; D018570:Risk Assessment
chemical_list: C486563:BCL11A protein, human; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; C477698:THADA protein, human; C098828:CDC123 protein, human; C517601:CAMK1D protein, human; D054729:Calcium-Calmodulin-Dependent Protein Kinase Type 1; D051722:ADAM Proteins; D000071119:ADAMTS9 Protein; C412869:ADAMTS9 protein, human