title: Association of indices of liver and adipocyte insulin resistance with 19 confirmed susceptibility loci for type 2 diabetes in 6,733 non-diabetic Finnish men.
abstract: OBJECTIVE
  Of the confirmed type 2 diabetes susceptibility loci only a few are known to affect insulin sensitivity. We examined the association of indices of hepatic and adipocyte insulin resistance (IR) with 19 confirmed type 2 diabetes risk loci in a large population-based study.
  
  
  METHODS
  Non-diabetic participants (n = 8,460, age 57.3 ± 7.0 years, BMI 26.8 ± 3.8 kg/m(2); mean ± SD) from a population-based cohort underwent an OGTT. Of them, 6,733 non-diabetic men were genotyped for single nucleotide polymorphisms (SNPs) in or near PPARG2 (also known as PPARG), KCNJ11, TCF7L2, SLC30A8, HHEX, CDKN2B, IGF2BP2, CDKAL1, HNF1B, WFS1, JAZF1, CDC123, TSPAN8, THADA, ADAMTS9, NOTCH2, KCNQ1, MTNR1B and SNP rs7480010. We investigated hepatic IR with a new index of liver IR. The adipocyte IR index was defined as a product of fasting NEFA and plasma insulin levels.
  
  
  RESULTS
  Type 2 diabetes risk SNPs in or near KCNJ11 and HHEX were significantly (p < 0.0013), and those in or near CDKN2B, NOTCH2 and MTNR1B were nominally (p < 0.05), associated with decreased liver IR index. The Pro12 allele of PPARG2 was significantly associated with a high adipocyte IR index and nominally associated with high liver IR.
  
  
  CONCLUSIONS
  The Pro12 allele of PPARG2 seems to impair insulin's antilipolytic effect, leading to high NEFA release in the fasting state and IR. In addition, the type 2 diabetes risk alleles of KCNJ11 and HHEX, which are known to impair insulin secretion, were associated with increased hepatic insulin sensitivity.
authors.affiliation: Department of Medicine, University of Eastern Finland, Kuopio University Hospital, 70210, Kuopio, Finland.
authors.forename: J
authors.initials: J
authors.lastname: Vangipurapu
authors.forename: A
authors.initials: A
authors.lastname: Stančáková
authors.forename: J
authors.initials: J
authors.lastname: Pihlajamäki
authors.forename: T M
authors.initials: TM
authors.lastname: Kuulasmaa
authors.forename: T
authors.initials: T
authors.lastname: Kuulasmaa
authors.forename: J
authors.initials: J
authors.lastname: Paananen
authors.forename: J
authors.initials: J
authors.lastname: Kuusisto
authors.forename: E
authors.initials: E
authors.lastname: Ferrannini
authors.forename: M
authors.initials: M
authors.lastname: Laakso
mesh_terms: D051722:ADAM Proteins / Q000235:genetics; D000071119:ADAMTS9 Protein; D017667:Adipocytes / Q000378:metabolism / Q000502:physiology*; D000951:Antigens, Neoplasm / Q000235:genetics; D027682:Cation Transport Proteins / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics; D056970:Co-Repressor Proteins; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics; D004268:DNA-Binding Proteins; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000503:physiopathology*; D005387:Finland; D020022:Genetic Predisposition to Disease / Q000235:genetics; D051539:Hepatocyte Nuclear Factor 1-beta / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology*; D008099:Liver / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics; D047495:PPAR gamma / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics; D051883:Receptor, Notch2 / Q000235:genetics; D059470:Tetraspanins; D058118:Transcription Factor 7-Like 2 Protein / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D000075703:Zinc Transporter 8; D012359:tRNA Methyltransferases; D000099161:Kcnj11 Channel
chemical_list: D051722:ADAM Proteins; D000071119:ADAMTS9 Protein; D000951:Antigens, Neoplasm; D027682:Cation Transport Proteins; D018797:Cell Cycle Proteins; D056970:Co-Repressor Proteins; D051360:Cyclin-Dependent Kinase 5; D050762:Cyclin-Dependent Kinase Inhibitor p15; D004268:DNA-Binding Proteins; D051539:Hepatocyte Nuclear Factor 1-beta; D018398:Homeodomain Proteins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D047495:PPAR gamma; D024661:Potassium Channels, Inwardly Rectifying; D016601:RNA-Binding Proteins; D051883:Receptor, Notch2; D059470:Tetraspanins; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors; D000075703:Zinc Transporter 8; D012359:tRNA Methyltransferases; D000099161:Kcnj11 Channel; C493966:CDKN2B protein, human; C078492:HHEX protein, human; C496495:HNF1B protein, human; C498779:IGF2BP2 protein, human; C430460:JAZF1 protein, human; C497764:NOTCH2 protein, human; C492522:SLC30A8 protein, human; C544894:TCF7L2 protein, human; C477698:THADA protein, human; C065609:TSPAN8 protein, human; C114987:wolframin protein; C098828:CDC123 protein, human; C525110:CDKAL1 protein, human; C412869:ADAMTS9 protein, human