title: Joint effect of insulin signaling genes on insulin secretion and glucose homeostasis.
abstract: BACKGROUND
  Reduced insulin signaling in insulin secreting β-cells causes defective insulin secretion and hyperglycemia in mice.
  
  
  OBJECTIVE
  We investigated whether functional polymorphisms affecting insulin signaling (ie, ENPP1 K121Q, rs1044498; IRS1 G972R, rs1801278; and TRIB3 Q84R, rs2295490) exert a joint effect on insulin secretion and abnormal glucose homeostasis (AGH).
  
  
  METHODS
  Insulin secretion was evaluated by 1) the disposition index (DI) from an oral glucose tolerance test (OGTT) in 829 individuals; 2) insulin secretion stimulation index (SI) in islets from nondiabetic donors after glucose (n = 92) or glibenclamide (n = 89) stimulation. AGH (including impaired fasting glucose and/or impaired glucose tolerance or type 2 diabetes; T2D) was evaluated in case-control studies from the GENetics of Type 2 Diabetes in Italy and the United States (GENIUS T2D) Consortium (n = 6607).
  
  
  RESULTS
  Genotype risk score, obtained by totaling individual weighted risk allele effects, was associated with the following: 1) DI (P = .005); 2) glucose and glibenclamide SI (P = .046 and P = .009); or 3) AGH (odds ratio 1.08, 95% confidence interval 1.03-1.13; P = .001). We observed an inverse relationship between genetic effect and age at AGH onset, as indicated by a linear correlation between AGH-genotype risk score odds ratios and age-at-diagnosis cutoffs (R(2) = 0.80, P < .001).
  
  
  CONCLUSIONS
  Functional polymorphisms affecting insulin signaling exert a joint effect on both in vivo and in vitro insulin secretion as well as on early-onset AGH. Our data provide further evidence that abnormal insulin signaling reduces β-cell function and impairs glucose homeostasis.
authors: Casa Sollievo della Sofferenza-Mendel Laboratory, Istituto di Ricovero e Cura a Carattere Scientifico, Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy. s.prudente@css-mendel.it
authors: Sabrina
authors: S
authors: Prudente
authors: Eleonora
authors: E
authors: Morini
authors: Lorella
authors: L
authors: Marselli
authors: Roberto
authors: R
authors: Baratta
authors: Massimiliano
authors: M
authors: Copetti
authors: Christine
authors: C
authors: Mendonca
authors: Francesco
authors: F
authors: Andreozzi
authors: Manisha
authors: M
authors: Chandalia
authors: Fabio
authors: F
authors: Pellegrini
authors: Diego
authors: D
authors: Bailetti
authors: Federica
authors: F
authors: Alberico
authors: Hetal
authors: H
authors: Shah
authors: Nicola
authors: N
authors: Abate
authors: Giorgio
authors: G
authors: Sesti
authors: Lucia
authors: L
authors: Frittitta
authors: Piero
authors: P
authors: Marchetti
authors: Alessandro
authors: A
authors: Doria
authors: Vincenzo
authors: V
authors: Trischitta
mesh_terms: D000328:Adult; D000368:Aged; D018797:Cell Cycle Proteins / Q000235:genetics; D005260:Female; D005947:Glucose / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics; D000078790:Insulin Secretion; D008297:Male; D008875:Middle Aged; D010727:Phosphoric Diester Hydrolases / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics; D011755:Pyrophosphatases / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics; D015398:Signal Transduction
chemical_list: D018797:Cell Cycle Proteins; C526292:IRS1 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D012097:Repressor Proteins; C474831:TRIB3 protein, human; D017346:Protein Serine-Threonine Kinases; D010727:Phosphoric Diester Hydrolases; C065962:ectonucleotide pyrophosphatase phosphodiesterase 1; D011755:Pyrophosphatases; D005947:Glucose
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