OBJECTIVE: Insulin resistance (IR) and cardiovascular disease (CVD) share a common soil. We investigated the combined role of single nucleotide polymorphisms (SNPs) affecting insulin signaling (ENPP1 K121Q, rs1044498; IRS1 G972R, rs1801278; TRIB3 Q84R, rs2295490) on CVD, age at myocardial infarction (MI), in vivo insulin sensitivity and in vitro insulin-stimulated nitric oxide synthase (NOS) activity. DESIGN AND SETTING: 1. We first studied, incident cardiovascular events (a composite endpoint comprising myocardial infarction-MI, stroke and cardiovascular death) in 733 patients (2186 person-years, 175 events). 2. In a replication attempt, age at MI was tested in 331 individuals. 3. OGTT-derived insulin sensitivity index (ISI) was assessed in 829 individuals with fasting glucose <126 mg/dl. 4. NOS activity was measured in 40 strains of human vein endothelial cells (HUVECs). RESULTS: 1. Risk variants jointly predicted cardiovascular events (HR = 1.181; p = 0.0009) and, when added to clinical risk factors, significantly improved survival C-statistics; they also allowed a significantly correct reclassification (by net reclassification index) in the whole sample (135/733 individuals) and, even more, in obese patients (116/204 individuals). 2. Risk variants were jointly associated with age at MI (p = 0.006). 3. A significant association was also observed with ISI (p = 0.02). 4. Finally, risk variants were jointly associated with insulin-stimulated NOS activity in HUVECs (p = 0.009). CONCLUSIONS: Insulin signaling genes variants jointly affect cardiovascular disease, very likely by promoting whole body and endothelium-specific insulin resistance. Further studies are needed to address whether their genotyping help identify very high-risk patients who need specific and/or more aggressive preventive strategies.
OBJECTIVE:Insulin resistance (IR) and cardiovascular disease (CVD) share a common soil. We investigated the combined role of single nucleotide polymorphisms (SNPs) affecting insulin signaling (ENPP1 K121Q, rs1044498; IRS1G972R, rs1801278; TRIB3Q84R, rs2295490) on CVD, age at myocardial infarction (MI), in vivo insulin sensitivity and in vitro insulin-stimulated nitric oxide synthase (NOS) activity. DESIGN AND SETTING: 1. We first studied, incident cardiovascular events (a composite endpoint comprising myocardial infarction-MI, stroke and cardiovascular death) in 733 patients (2186 person-years, 175 events). 2. In a replication attempt, age at MI was tested in 331 individuals. 3. OGTT-derived insulin sensitivity index (ISI) was assessed in 829 individuals with fasting glucose <126 mg/dl. 4. NOS activity was measured in 40 strains of human vein endothelial cells (HUVECs). RESULTS: 1. Risk variants jointly predicted cardiovascular events (HR = 1.181; p = 0.0009) and, when added to clinical risk factors, significantly improved survival C-statistics; they also allowed a significantly correct reclassification (by net reclassification index) in the whole sample (135/733 individuals) and, even more, in obesepatients (116/204 individuals). 2. Risk variants were jointly associated with age at MI (p = 0.006). 3. A significant association was also observed with ISI (p = 0.02). 4. Finally, risk variants were jointly associated with insulin-stimulated NOS activity in HUVECs (p = 0.009). CONCLUSIONS:Insulin signaling genes variants jointly affect cardiovascular disease, very likely by promoting whole body and endothelium-specific insulin resistance. Further studies are needed to address whether their genotyping help identify very high-risk patients who need specific and/or more aggressive preventive strategies.
Authors: A Pizzuti; L Frittitta; A Argiolas; R Baratta; I D Goldfine; M Bozzali; T Ercolino; G Scarlato; L Iacoviello; R Vigneri; V Tassi; V Trischitta Journal: Diabetes Date: 1999-09 Impact factor: 9.461
Authors: Stephen S Rich; Donald W Bowden; Steven M Haffner; Jill M Norris; Mohammed F Saad; Braxton D Mitchell; Jerome I Rotter; Carl D Langefeld; Lynne E Wagenknecht; Richard N Bergman Journal: Diabetes Date: 2004-07 Impact factor: 9.461
Authors: G Howard; D H O'Leary; D Zaccaro; S Haffner; M Rewers; R Hamman; J V Selby; M F Saad; P Savage; R Bergman Journal: Circulation Date: 1996-05-15 Impact factor: 29.690
Authors: J O Clausen; T Hansen; C Bjørbaek; S M Echwald; S A Urhammer; S Rasmussen; C B Andersen; L Hansen; K Almind; K Winther Journal: Lancet Date: 1995-08-12 Impact factor: 79.321
Authors: Aditi Shendre; Marguerite R Irvin; Howard Wiener; Degui Zhi; Nita A Limdi; Edgar T Overton; Sadeep Shrestha Journal: J Am Heart Assoc Date: 2017-04-10 Impact factor: 5.501