Vincenzo Trischitta

Publications (93)558.83 Total impact

• Article: Development and Validation of a Predicting Model of All-Cause Mortality in Patients With Type 2 Diabetes Mellitus.

  Salvatore De Cosmo, Massimiliano Copetti, Olga Lamacchia, Andrea Fontana, Michela Massa, Eleonora Morini, Antonio Pacilli, Stefania Fariello, Antonio Palena, Anna Rauseo, Rafaella Viti, Rosa Di Paola, Claudia Menzaghi, Mauro Cignarelli, Fabio Pellegrini, Vincenzo Trischitta
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  ABSTRACT: OBJECTIVE To develop and validate a parsimonious model for predicting short-term all-cause mortality in patients with type 2 diabetes mellitus (T2DM).RESEARCH DESIGN AND METHODS Two cohorts of patients with T2DM were investigated. The Gargano Mortality Study (GMS, n = 679 patients) was the training set and the Foggia Mortality Study (FMS, n = 936 patients) represented the validation sample. GMS and FMS cohorts were prospectively followed-up for 7.40 ± 2.15 and 4.51 ± 1.69 years, respectively, and all-cause mortality was registered. A new forward variable selection within a multivariate Cox regression was implemented. Starting from the empty model, each step selected the predictor that, once included into the multivariate Cox model, yielded the maximum continuous net reclassification improvement (cNRI). The selection procedure stopped when no further statistically significant cNRI increase was detected.RESULTSNine variables (age, BMI, diastolic blood pressure, LDL cholesterol, triglycerides, HDL cholesterol, urine albumin-to-creatinine ratio, and antihypertensive and insulin therapy) were included in the final predictive model with a C statistic of 0.88 (95% CI 0.82-0.94) in the GMS and 0.82 (0.76-0.87) in the FMS. Finally, we used a recursive partition and amalgamation algorithm to identify patients at intermediate and high mortality risk (hazard ratio 7.0 and 24.4, respectively, as compared with those at low risk). A web-based risk calculator was also developed.CONCLUSIONS We developed and validated a parsimonious all-cause mortality equation in T2DM, providing also a user-friendly web-based risk calculator. Our model may help prioritize the use of available resources for targeting aggressive preventive and treatment strategies in a subset of very high-risk individuals.
  Diabetes care 05/2013; · 8.09 Impact Factor
• Article: Joint Effect of Insulin Signaling Genes on Insulin Secretion and Glucose Homeostasis.

  Sabrina Prudente, Eleonora Morini, Lorella Marselli, Roberto Baratta, Massimiliano Copetti, Christine Mendonca, Francesco Andreozzi, Manisha Chandalia, Fabio Pellegrini, Diego Bailetti, Federica Alberico, Hetal Shah, Nicola Abate, Giorgio Sesti, Lucia Frittitta, Piero Marchetti, Alessandro Doria, Vincenzo Trischitta
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  ABSTRACT: Context: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).Design:Insulin secretion was evaluated by 1) the disposition index (DI) from an oral glucose tolerance test (OGTT) in 829 individuals; or 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.
  The Journal of clinical endocrinology and metabolism 04/2013; · 6.50 Impact Factor
• Source

  Available from: Rosa Di Paola

  Article: Role of GALNT2 in the modulation of ENPP1 expression, insulin signaling and action: GALNT2: A novel modulator of insulin signaling.

  Antonella Marucci, Flora Cozzolino, Claudia Dimatteo, Maria Monti, Piero Pucci, Vincenzo Trischitta, Rosa Di Paola
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  ABSTRACT: Ectonucleotide pyrophosphatase phosphodiesterase 1 (ENPP1) inhibits insulin signaling and action. Understanding the mechanisms underlying ENPP1 expression may help unravel molecular mechanisms of insulin resistance. Recent data suggest a role of ENPP1-3'untraslated region (UTR), in controlling ENPP1 expression. We sought to identify trans-acting ENPP1-3'UTR binding proteins, and investigate their role on insulin signaling. By RNA pull-down, 49 proteins bound to ENPP1-3'UTR RNA were identified by mass spectrometry (MS). Among these, in silico analysis of genome wide association studies and expression profile datasets pointed to N-acetylgalactosaminyltransferase 2 gene (GALNT2) for subsequent investigations. Gene expression levels were evaluated by RT-PCR. Protein expression levels, IRS-1 and Akt phosphorylation were evaluated by Western blot. Insulin receptor (IR) autophosphorylation was evaluated by ELISA. GALNT2 down-regulation increased while GALNT2 over-expression reduced ENPP1 expression levels. In addition, GALNT2 down-regulation reduced insulin stimulation of IR, IRS-1 and Akt phosphorylation and insulin inhibition of phosphoenolpyruvate carboxykinase (PEPCK) expression, a key neoglucogenetic enzyme. Our data point to GALNT2 as a novel factor involved in the modulation of ENPP1 expression as well as insulin signaling and action in human liver HepG2 cells.
  Biochimica et Biophysica Acta 03/2013; · 4.66 Impact Factor
• Article: Role of relationship between HbA1c, fibrinogen and HDL-cholesterol on cardiovascular disease in patients with type 2 diabetes mellitus.

  Antonio Pacilli, Salvatore De Cosmo, Vincenzo Trischitta, Simonetta Bacci
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  ABSTRACT: OBJECTIVE: To assess the impact of relationship between glycated hemoglobin (HbA1c), fibrinogen and HDL-cholesterol (HDL-c) on cardiovascular disease in type 2 diabetes. METHODS: We investigated i) the relationship of HbA1c, fibrinogen and HDL-c in 375 coronary artery disease (CAD)-negative and 320 CAD-positive diabetic patients and ii) the association between clustering of these three factors and incident major cardiovascular events in 317/320 CAD-positive patients. RESULTS: i) The relationships between HbA1c and both fibrinogen and HDL-c and between HDL-c and fibrinogen were significant only in CAD-positive patients (β = 10.655, p = 0.002; β = -1.056, p = 0.013; β = -1.751, p = 0.000008, respectively); ii) patients with worse-than-median levels of the three factors showed higher risk for major cardiovascular events than others (HR: 2.22, 95%CI = 1.23-4.02, p = 0.008). Both findings were independent of LDL-c, blood pressure or ongoing therapies. CONCLUSION: Our findings suggest interwoven actions of poor glycemic control, low grade inflammation and low HDL-c on atherosclerotic processes in type 2 diabetes.
  Atherosclerosis 02/2013; · 3.79 Impact Factor
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  Available from: Rosa Di Paola

  Article: Role of Somatomedin-B-like domains on ENPP1 inhibition of insulin signaling.

  Claudia Dimatteo, Antonella Marucci, Antonio Palazzo, Carmela Cisternino, René Massimiliano Marsano, Vincenzo Trischitta, Rosa Di Paola
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  ABSTRACT: The exact mechanism by which ectonucleotide pyrophosphatase phosphodiesterase 1 (ENPP1) inhibits insulin signaling is not known. ENPP1 contains two somatomedin-B-like domains (i.e. SMB 1 and 2) involved in ENPP1 dimerization in animal cells. The aim of the present study was to investigate if these domains modulate ENPP1 inhibitory activity on insulin signaling in human insulin target cells (HepG2). ENPP1 (ENPP1-3'myc), ENPP1 deleted of SMB 1 (ENPP1-ΔI-3'myc) or of SMB 2 (ENPP1-ΔII-3'myc) domain were cloned in frame with myc tag in mammalian expression vector pRK5. Plasmids were transiently transfected in human liver HepG2 cells. ENPP1 inhibitory activity on insulin signaling, dimerization and protein-protein interaction with insulin receptor (IR), reported to mediate the modulation of ENPP1 inhibitory activity, were studied. As compared to untransfected cells, a progressive increase of ENPP1 inhibitory activity on insulin-induced IR β-subunit autophosphorylation and on Akt-S(473) phosphorylation was observed in ENPP1-3'myc, ENPP1-ΔI-3'myc and ENPP1-ΔII-3'myc cells. Under non reducing conditions a 260kDa homodimer, indicating ENPP1 dimerization, was observed. The ratio of non reduced (260kDa) to reduced (130kDa) ENPP1 was significantly decreased by two thirds in ENPP1-ΔII-3'myc vs. ENPP1-3'myc but not in ENPP1-ΔI-3'myc. A similar ENPP1/ IR interaction was detectable by co-immunoprecipitation in ENPP1-3'myc, ENPP1-ΔI-3'myc and ENPP1-ΔII-3'myc cells. In conclusion, SMB 1 and SMB 2 are negative modulators of ENPP1 inhibitory activity on insulin signaling. For SMB 2 such effect might be mediated by a positive role on protein dimerization.
  Biochimica et Biophysica Acta 10/2012; · 4.66 Impact Factor
• Source

  Available from: Carmine Zoccali

  Article: Joint effect of insulin signaling genes on cardiovascular events and on whole body and endothelial insulin resistance.

  Simonetta Bacci, Sabrina Prudente, Massimiliano Copetti, Belinda Spoto, Stefano Rizza, Roberto Baratta, Natalia Di Pietro, Eleonora Morini, Rosa Di Paola, Alessandra Testa, [......], Renato Lauro, Lorenzo Malatino, Agostino Consoli, Fabio Pellegrini, Assunta Pandolfi, Lucia Frittitta, Carmine Zoccali, Massimo Federici, Alessandro Doria, Vincenzo Trischitta
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  ABSTRACT: 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.
  Atherosclerosis 10/2012; · 3.79 Impact Factor
• Article: Genome-wide association analysis identifies TYW3/CRYZ and NDST4 loci associated with circulating resistin levels.

  Qibin Qi, Claudia Menzaghi, Shelly Smith, Liming Liang, Nathalie de Rekeneire, Melissa E Garcia, Kurt K Lohman, Iva Miljkovic, Elsa S Strotmeyer, Steve R Cummings, Alka M Kanaya, Frances A Tylavsky, Suzanne Satterfield, Jingzhong Ding, Eric B Rimm, Vincenzo Trischitta, Frank B Hu, Yongmei Liu, Lu Qi
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  ABSTRACT: Resistin is a polypeptide hormone that was reported to be associated with insulin resistance, inflammation and risk of type 2 diabetes and cardiovascular disease. We conducted a genome-wide association (GWA) study on circulating resistin levels in individuals of European ancestry drawn from the two independent studies: the Nurses' Health Study (n = 1590) and the Health, Aging and Body Composition Study (n = 1658). Single-nucleotide polymorphisms (SNPs) identified in the GWA analysis were replicated in an independent cohort of Europeans: the Gargano Family Study (n = 659). We confirmed the association with a previously known locus, the RETN gene (19p13.2), and identified two novel loci near the TYW3/CRYZ gene (1p31) and the NDST4 gene (4q25), associated with resistin levels at a genome-wide significant level, best represented by SNP rs3931020 (P = 6.37 × 10(-12)) and SNP rs13144478 (P = 6.19 × 10(-18)), respectively. Gene expression quantitative trait loci analyses showed a significant cis association between the SNP rs3931020 and CRYZ gene expression levels (P = 3.68 × 10(-7)). We also found that both of these two SNPs were significantly associated with resistin gene (RETN) mRNA levels in white blood cells from 68 subjects with type 2 diabetes (both P = 0.02). In addition, the resistin-rising allele of the TYW3/CRYZ SNP rs3931020, but not the NDST4 SNP rs13144478, showed a consistent association with increased coronary heart disease risk [odds ratio = 1.18 (95% CI, 1.03-1.34); P = 0.01]. Our results suggest that genetic variants in TYW3/CRYZ and NDST4 loci may be involved in the regulation of circulating resistin levels. More studies are needed to verify the associations of the SNP rs13144478 with NDST4 gene expression and resistin-related disease.
  Human Molecular Genetics 07/2012; 21(21):4774-80. · 7.64 Impact Factor
• Article: The 9p21 coronary artery disease locus and kidney dysfunction in patients with Type 2 diabetes mellitus.

  Salvatore De Cosmo, Sabrina Prudente, Olga Lamacchia, Daniela Lucchesi, Hetal Shah, Christine Mendonca, Laura Pucci, Luana Mercuri, Ernest V Gervino, Thomas H Hauser, Diego Bailetti, Giuseppe Penno, Mauro Cignarelli, Alessandro Doria, Vincenzo Trischitta
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  ABSTRACT: BACKGROUND: We investigated whether the coronary artery disease (CAD) locus on chromosome 9p21 (as represented by single nucleotide polymorphism rs2383206) is associated with low estimated glomerular filtration rate (eGFR) or increased urinary albumin excretion in patients with Type 2 diabetes mellitus (T2DM).METHODS: Four samples, including a total of 3167 patients, were studied. The presence of low eGFR (<60 mL/min/1.73m(2)) was estimated from serum creatinine by means of the Modification of Diet in Renal Disease Study equation. Increased urinary albumin excretion was defined as an albumin-creatinine ratio (ACR) ≥2.5 mg/mmol in men and ≥3.5 mg/mmol in women.RESULTS: No association was found between rs2383206 and low eGFR or increased ACR in each sample as well as in a pooled analysis (overall odds ratio = 1.07, 95% confidence interval 0.94-1.22, P = 0.31 and overall odds ratio = 1.00, 95% confidence interval 0.90-1.12, P = 0.95, respectively). No interaction was observed between rs2383206 and poor glycemic control [HbA1c was above the median in the pooled sample (7.7%) in modulating eGFR or ACR (P for interaction = 0.42 and 0.90, respectively)].CONCLUSION: Variability at the 9p21 CAD locus is unlikely to play a role in modulating susceptibility to kidney dysfunction in patients with T2DM.
  Nephrology Dialysis Transplantation 05/2012; · 3.40 Impact Factor
• Article: The mammalian tribbles homolog TRIB3, glucose homeostasis, and cardiovascular diseases.

  Sabrina Prudente, Giorgio Sesti, Assunta Pandolfi, Francesco Andreozzi, Agostino Consoli, Vincenzo Trischitta
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  ABSTRACT: Insulin signaling plays a physiological role in traditional insulin target tissues controlling glucose homeostasis as well as in pancreatic β-cells and in the endothelium. Insulin signaling abnormalities may, therefore, be pathogenic for insulin resistance, impaired insulin secretion, endothelial dysfunction, and eventually, type 2 diabetes mellitus (T2DM) and cardiovascular disease. Tribbles homolog 3 (TRIB3) is a 45-kDa pseudokinase binding to and inhibiting Akt, a key mediator of insulin signaling. Akt-mediated effects of TRIB3 in the liver, pancreatic β-cells, and skeletal muscle result in impaired glucose homeostasis. TRIB3 effects are also modulated by its direct interaction with other signaling molecules. In humans, TRIB3 overactivity, due to TRIB3 overexpression or to Q84R genetic polymorphism, with R84 being a gain-of-function variant, may be involved in shaping the risk of insulin resistance, T2DM, and cardiovascular disease. TRIB3 overexpression has been observed in the liver, adipose tissue, skeletal muscle, and pancreatic β-cells of individuals with insulin resistance and/or T2DM. The R84 variant has also proved to be associated with insulin resistance, T2DM, and cardiovascular disease. TRIB3 direct effects on the endothelium might also play a role in increasing the risk of atherosclerosis, as indicated by studies on human endothelial cells carrying the R84 variant that are dysfunctional in terms of Akt activation, NO production, and other proatherogenic changes. In conclusion, studies on TRIB3 have unraveled new molecular mechanisms underlying metabolic and cardiovascular abnormalities. Additional investigations are needed to verify whether such acquired knowledge will be relevant for improving care delivery to patients with metabolic and cardiovascular alterations.
  Endocrine reviews 05/2012; 33(4):526-46. · 19.76 Impact Factor
• Article: MODY type 2 P59S GCK mutant: founder effect in South of Italy.

  M Delvecchio, O Ludovico, E Bellacchio, R Stallone, T Palladino, S Mastroianno, L Zelante, M Sacco, V Trischitta, M Carella
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  ABSTRACT: Mutations in the glucokinase (GCK) gene are the most frequent cause of maturity onset diabetes of the young (MODY) in Italy. We evaluated GCK mutations in 32 unrelated patients younger than 18 years who had been diagnosed with MODY. Eleven different GCK heterozygous mutations were identified in 22 (68.7%) of the 32 probands. Nine mutations were missense and two were nonsense. Three of these mutations (E17X, P59S and E372X) have not been described previously and were shown to be associated with hyperglycaemia. Several prediction methods suggested that the E17X and E372X mutations result in a premature truncated protein and that the P59S mutation is pathogenic. This idea was further supported by evidence suggesting that Proline 59 is a highly conserved amino acid residue and that the P59S mutation does not appear to be present in non-diabetic controls and in sequence variant databases. Furthermore, this mutation was found in six (27.3%) of the patients from the same geographical area, Gargano, pointing to the existence of a founder effect, which was confirmed by microsatellite analysis.
  Clinical Genetics 02/2012; · 3.13 Impact Factor
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  Available from: Rosa Di Paola

  Article: Serum resistin and kidney function: a family-based study in non-diabetic, untreated individuals.

  Claudia Menzaghi, Lucia Salvemini, Grazia Fini, Ryan Thompson, Davide Mangiacotti, Rosa Di Paola, Eleonora Morini, Maddalena Giorelli, Concetta De Bonis, Salvatore De Cosmo, Alessandro Doria, Vincenzo Trischitta
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  ABSTRACT: High serum resistin levels have been associated with kidney dysfunction. Most of these studies have been carried out in individuals with severe kidney impairment, diabetes, cardiovascular disease and related treatments. Thus, the observed association might have been influenced by these confounders. Our aim was to study the relationship between serum resistin, urinary albumin/creatinine ratio (ACR) and glomerular filtration rate (GFR) in a family-based sample, the Gargano Family Study (GFS) of 635 non diabetic, untreated Whites. A linear mixed effects model and bivariate analyses were used to evaluate the phenotypic and genetic relations between serum resistin and both ACR and eGFR. All analyses were adjusted for sex, age, age squared, BMI, systolic blood pressure, smoking habits and physical exercise. After adjustments, resistin levels were slightly positively associated with ACR (β±SE = 0.049±0.023, p = 0.035) and inversely related to eGFR (β±SE = -1.43±0.61, p = 0.018) levels. These associations remained significant when either eGFR or ACR were, reciprocally, added as covariates. A genetic correlation (ρg = -0.31±0.12; adjusted p = 0.013) was observed between resistin and eGFR (but not ACR) levels. Serum resistin levels are independently associated with ACR and eGFR in untreated non-diabetic individuals. Serum resistin and eGFR share also some common genetic background. Our data strongly suggest that resistin plays a role in modulating kidney function.
  PLoS ONE 01/2012; 7(6):e38414. · 4.09 Impact Factor
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  Available from: Natalia Di Pietro

  Article: The SH2B1 obesity locus is associated with myocardial infarction in diabetic patients and with NO synthase activity in endothelial cells.

  Sabrina Prudente, Eleonora Morini, Jay Larmon, Francesco Andreozzi, Natalia Di Pietro, Angela Nigro, Ernest V Gervino, Gaia Chiara Mannino, Simonetta Bacci, Thomas H Hauser, Emanuele Bellacchio, Gloria Formoso, Fabio Pellegrini, Vittoria Proto, Claudia Menzaghi, Lucia Frittitta, Assunta Pandolfi, Giorgio Sesti, Alessandro Doria, Vincenzo Trischitta
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  ABSTRACT: Obesity and cardiovascular disease recognize a common metabolic soil and may therefore share part of their genetic background. Genome-wide association studies have identified variability at the SH2B1 locus as a predictor of obesity. We investigated whether SNP rs4788102, which captures the entire SH2B1 variability, is associated with coronary artery disease (CAD) and/or myocardial infarction (MI) in patients with type 2 diabetes mellitus (T2DM). SNP rs4788102 was typed in 2015 White subjects with T2DM from three CAD case-control studies [n=740 from the Gargano Hearth Study (GHS, Italy); n=818 from the Joslin Hearth Study (JHS, Boston); n=457 from the University of Catanzaro (CZ, Italy)]. SNP rs4788102 (G/A) was not associated with CAD (overall allelic OR=1.06, 95% CI=0.93-1.21; p=0.37). On the contrary, it was associated with MI in GHS (1.42, 1.12-1.81; p=0.004) and in the three samples analyzed together (1.21, 1.04-1.41; p=0.016). Insulin stimulated nitric oxide synthase (NOS) activity in human vein endothelial cells from G/G (n=4, p=0.03) but not the G/A (n=5, p=0.83) genotype. Of the SNPs in perfect LD with rs4788102, one (rs7498665) affects amino acid polarity (Ala484Thr) and falls into a highly conserved protein segment of SH2B1 containing a class II SH3 domain binding site. Variability at the SH2B1 obesity locus is associated with MI in diabetic patients and with reduced insulin-stimulated NOS activity in human endothelial cells. Further studies are needed to replicate this association and dissect the biology underlying this finding.
  Atherosclerosis 08/2011; 219(2):667-72. · 3.79 Impact Factor
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  Available from: Claudia Menzaghi

  Article: Novel locus FER is associated with serum HMW adiponectin levels.

  Lu Qi, Claudia Menzaghi, Lucia Salvemini, Concetta De Bonis, Vincenzo Trischitta, Frank B Hu
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  ABSTRACT: High molecular weight (HMW) adiponectin is a predominant isoform of circulating adiponectin and has been related to type 2 diabetes. Previous linkage studies suggest that different genetic components might be involved in determining HMW and total adiponectin levels. We performed a genome-wide association study (GWAS) of serum HMW adiponectin levels in individuals of European ancestry drawn from the Nurses' Health Study (NHS) (N = 1,591). The single nucleotide polymorphisms (SNPs) identified in the GWAS analysis were replicated in an independent cohort of Europeans (N = 626). We examined the associations of the identified variations with diabetes risk and metabolic syndrome. We identified a novel locus near the FER gene (5q21) at a genome-wide significance level, best represented by SNP rs10447248 (P = 4.69 × 10(-8)). We also confirmed that variations near the adiponectin-encoding ADIPOQ locus (3q27) were related to serum HMW adiponectin levels. In addition, we found that FER SNP rs10447248 was related to HDL cholesterol levels (P = 0.009); ADIPOQ variation was associated with fasting glucose (P = 0.04), HDL cholesterol (P = 0.04), and a metabolic syndrome score (P = 0.002). Our results suggest that different loci may be involved in regulation of circulating HMW adiponectin levels and provide novel insight into the mechanisms that affect HMW adiponectin homeostasis.
  Diabetes 06/2011; 60(8):2197-201. · 8.29 Impact Factor
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  Available from: Carmine Zoccali

  Article: Insulin resistance and left ventricular hypertrophy in end-stage renal disease: association between the ENPP1 gene and left ventricular concentric remodelling.

  Belinda Spoto, Alessandra Testa, Rosa M Parlongo, Giovanni Tripepi, Vincenzo Trischitta, Francesca Mallamaci, Carmine Zoccali
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  ABSTRACT: Left ventricular hypertrophy (LVH) and insulin resistance (IR) are frequent complications of end-stage renal disease (ESRD). The ectonucleotide pyrophosphatase phosphodiesterase 1 (ENPP1) gene, whose variability has been repeatedly associated with IR, codes for a membrane glycoprotein which inhibits insulin-receptor signalling. We investigated the relationship of ENPP1 variability, as indicated by 10 single nucleotide polymorphisms (SNPs) representative of the gene haploblock structure, with left ventricular mass and geometry (by echocardiography) in an ethnically homogeneous series of 238 Caucasian ESRD patients. ENPP1 rs1974201 and rs9402349 polymorphisms were coherently associated (P ranging from 0.04 to 0.005) with indicators of left ventricular (LV) myocardial hypertrophy (mean wall thickness) and concentric remodelling (relative wall thickness and LV mass-to-volume ratio) but unrelated with the cavitary component of the LV (left ventricular end-diastolic volume). As compared to individuals carrying the alternative genotypes, the risk of LV concentric remodelling was approximately doubled in major allele homozygous for rs1974201 [odds ratio (OR) of GG versus GC + CC: 2.31, 95% confidence interval (CI): 1.30-4.12, P = 0.004] and rs9402349 (OR of AA versus AC + CC: 1.91, 95% CI: 1.02-3.56, P = 0.04) polymorphisms. Coherent associations exists between echocardiographic parameters of LV myocardial hypertrophy and concentric remodelling and ENPP1 variability in ESRD patients. These data support the hypothesis that IR is a relevant factor in the pathogenesis of myocardiopathy in this population.
  Nephrology Dialysis Transplantation 05/2011; 27(2):661-6. · 3.40 Impact Factor
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  Available from: Rosa Di Paola

  Article: PPARγ2 P12A polymorphism and albuminuria in patients with type 2 diabetes: a meta-analysis of case-control studies.

  Salvatore De Cosmo, Sabrina Prudente, Olga Lamacchia, Emanuela Lapice, Eleonora Morini, Rosa Di Paola, Massimiliano Copetti, Piero Ruggenenti, Giuseppe Remuzzi, Olga Vaccaro, Mauro Cignarelli, Vincenzo Trischitta
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  ABSTRACT: Insulin resistance has a role in diabetic nephropathy. The A12 variant of the PPARγ2 P121A polymorphism has been firmly associated with reduced risk of insulin resistance, while its role on the risk of albuminuria in patients with type 2 diabetes is uncertain. This study investigated whether the PPARγ2 P12A polymorphism modulates the risk of albuminuria in these patients. We tested the association between the A12 variant and albuminuria in three new case-control studies in diabetic patients from Italy (n = 841, n = 623 and n = 714 patients, respectively) and then performed a meta-analysis of all studies available to date. The nine studies we meta-analysed (six previously published and three presented here) comprised a total of 2376 cases and 4188 controls. In none of the three new studies was a significant association observed with odds ratio (OR) [95% confidence intervals (95% CI)] being 1.115, 0.799 and 0.849 (P = 0.603, 0.358 and 0.518, respectively). At meta-analysis, the overall OR (95% CI) for association between A12 and albuminuria was 0.694 (0.528-0.912). A significant heterogeneity of the genetic effect was observed (P = 0.026), which was totally explained by the different method of urine collection and albuminuria definition utilized across the studies. In fact, most of the effect was observed in the four studies determining albumin excretion rate rather than in those using albumin concentration in a single spot (OR, 95% CI: 0.529, 0.397-0.706, P = 0.0000164 and 0.919, 0.733-1.153, P = 0.47, respectively). The present study shows that the PPARγ2 Ala12 variant is significantly associated with a reduced risk of albuminuria among patients with type 2 diabetes.
  Nephrology Dialysis Transplantation 04/2011; 26(12):4011-6. · 3.40 Impact Factor
• Article: The type 2 diabetes and insulin-resistance locus near IRS1 is a determinant of HDL cholesterol and triglycerides levels among diabetic subjects.

  Rajani Sharma, Sabrina Prudente, Francesco Andreozzi, Christine Powers, Gaia Mannino, Simonetta Bacci, Ernest V Gervino, Thomas H Hauser, Elena Succurro, Luana Mercuri, Elizabeth H Goheen, Hetal Shah, Vincenzo Trischitta, Giorgio Sesti, Alessandro Doria
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  ABSTRACT: SNP rs2943641 near the insulin receptor substrate 1 (IRS1) gene has been found to be associated with type 2 diabetes (T2D) and insulin-resistance in genome-wide association studies. We investigated whether this SNP is associated with cardiovascular risk factors and coronary artery disease (CAD) among diabetic individuals. SNP rs2943641 was typed in 2133 White T2D subjects and tested for association with BMI, serum HDL cholesterol and triglycerides, hypertension history, and CAD risk. HDL cholesterol decreased by 1mg/dl (p = 0.004) and serum triglycerides increased by 6 mg/dl (p = 0.016) for each copy of the insulin-resistance allele. Despite these effects, no association was found with increased CAD risk (OR = 1.00, 95% CI 0.88-1.13). The insulin-resistance and T2D locus near the IRS1 gene is a determinant of lower HDL cholesterol among T2D subjects. However, this effect is small and does not translate into a detectable increase in CAD risk in this population.
  Atherosclerosis 01/2011; 216(1):157-60. · 3.79 Impact Factor
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  Available from: Alessandra Testa

  Article: The ENPP1 Q121 variant predicts major cardiovascular events in high-risk individuals: evidence for interaction with obesity in diabetic patients.

  Simonetta Bacci, Stefano Rizza, Sabrina Prudente, Belinda Spoto, Christine Powers, Antonio Facciorusso, Antonio Pacilli, Davide Lauro, Alessandra Testa, Yuan-Yuan Zhang, [......], Renato Lauro, Ernest V Gervino, Thomas H Hauser, Massimiliano Copetti, Salvatore De Cosmo, Fabio Pellegrini, Carmine Zoccali, Massimo Federici, Alessandro Doria, Vincenzo Trischitta
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  ABSTRACT: Insulin resistance (IR) and cardiovascular disease may share a common genetic background. We investigated the role of IR-associated ENPP1 K121Q polymorphism (rs1044498) on cardiovascular disease in high-risk individuals. A prospective study (average follow-up, 37 months) was conducted for major cardiovascular events (myocardial infarction [MI], stroke, cardiovascular death) from the Gargano Heart Study (GHS; n = 330 with type 2 diabetes and coronary artery disease), the Tor Vergata Atherosclerosis Study (TVAS; n = 141 who had MI), and the Cardiovascular Risk Extended Evaluation in Dialysis (CREED) database (n = 266 with end-stage renal disease). Age at MI was investigated in cross-sectional studies of 339 type 2 diabetic patients (n = 169 from Italy, n = 170 from the U.S.). Incidence of cardiovascular events per 100 person--years was 4.2 in GHS, 10.8 in TVAS, and 11.7 in CREED. Hazard ratios (HRs) for KQ+QQ versus individuals carrying the K121/K121 genotype (KK) individuals were 1.47 (95% CI 0.80-2.70) in GHS, 2.31 (95% CI 1.22-4.34) in TVAS, and 1.36 (95% CI 0.88-2.10) in CREED, and 1.56 (95% CI 1.15-2.12) in the three cohorts combined. In the 395 diabetic patients, the Q121 variant predicted cardiovascular events among obese but not among nonobese individuals (HR 5.94 vs. 0.62, P = 0.003 for interaction). A similar synergism was observed in cross-sectional studies, with age at MI being 3 years younger in Q121 carriers than in KK homozygotes among obese but not among nonobese patients (P = 0.035 for interaction). The ENPP1 K121Q polymorphism is an independent predictor of major cardiovascular events in high-risk individuals. In type 2 diabetes, this effect is exacerbated by obesity. Future larger studies are needed to confirm our finding.
  Diabetes 01/2011; 60(3):1000-7. · 8.29 Impact Factor
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  Available from: Lucia Frittitta

  Article: ENPP1 affects insulin action and secretion: evidences from in vitro studies.

  Rosa Di Paola, Nunzia Caporarello, Antonella Marucci, Claudia Dimatteo, Claudia Iadicicco, Silvia Del Guerra, Sabrina Prudente, Dora Sudano, Claudia Miele, Cristina Parrino, Salvatore Piro, Francesco Beguinot, Piero Marchetti, Vincenzo Trischitta, Lucia Frittitta
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  ABSTRACT: The aim of this study was to deeper investigate the mechanisms through which ENPP1, a negative modulator of insulin receptor (IR) activation, plays a role on insulin signaling, insulin secretion and eventually glucose metabolism. ENPP1 cDNA (carrying either K121 or Q121 variant) was transfected in HepG2 liver-, L6 skeletal muscle- and INS1E beta-cells. Insulin-induced IR-autophosphorylation (HepG2, L6, INS1E), Akt-Ser(473), ERK1/2-Thr(202)/Tyr(204) and GSK3-beta Ser(9) phosphorylation (HepG2, L6), PEPCK mRNA levels (HepG2) and 2-deoxy-D-glucose uptake (L6) was studied. GLUT 4 mRNA (L6), insulin secretion and caspase-3 activation (INS1E) were also investigated. Insulin-induced IR-autophosphorylation was decreased in HepG2-K, L6-K, INS1E-K (20%, 52% and 11% reduction vs. untransfected cells) and twice as much in HepG2-Q, L6-Q, INS1E-Q (44%, 92% and 30%). Similar data were obtained with Akt-Ser(473), ERK1/2-Thr(202)/Tyr(204) and GSK3-beta Ser(9) in HepG2 and L6. Insulin-induced reduction of PEPCK mRNA was progressively lower in untransfected, HepG2-K and HepG2-Q cells (65%, 54%, 23%). Insulin-induced glucose uptake in untransfected L6 (60% increase over basal), was totally abolished in L6-K and L6-Q cells. GLUT 4 mRNA was slightly reduced in L6-K and twice as much in L6-Q (13% and 25% reduction vs. untransfected cells). Glucose-induced insulin secretion was 60% reduced in INS1E-K and almost abolished in INS1E-Q. Serum deficiency activated caspase-3 by two, three and four folds in untransfected INS1E, INS1E-K and INS1E-Q. Glyburide-induced insulin secretion was reduced by 50% in isolated human islets from homozygous QQ donors as compared to those from KK and KQ individuals. Our data clearly indicate that ENPP1, especially when the Q121 variant is operating, affects insulin signaling and glucose metabolism in skeletal muscle- and liver-cells and both function and survival of insulin secreting beta-cells, thus representing a strong pathogenic factor predisposing to insulin resistance, defective insulin secretion and glucose metabolism abnormalities.
  PLoS ONE 01/2011; 6(5):e19462. · 4.09 Impact Factor
• Article: The TRIB3 R84 variant is associated with increased carotid intima-media thickness in vivo and with enhanced MAPK signalling in human endothelial cells.

  Gloria Formoso, Pamela Di Tomo, Francesco Andreozzi, Elena Succurro, Sara Di Silvestre, Sabrina Prudente, Francesco Perticone, Vincenzo Trischitta, Giorgio Sesti, Assunta Pandolfi, Agostino Consoli
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  ABSTRACT: TRIB3, a mammalian tribbles homologue, affects insulin signalling and action by inhibiting Akt phosphorylation. A TRIB3 Q84R gain-of-function polymorphism has been associated with insulin resistance both in vitro and in vivo and with several atherosclerotic phenotypes, including increased carotid intima-media thickness (IMT). We wanted to replicate this latter association and, if so, to get deeper insights about the molecular mechanisms underlying the role of the TRIB3 Q84R polymorphism in atherosclerosis. in 430 Caucasians of European ancestry, carotid IMT was increased in QR (n = 116) and RR (n = 15) when compared with QQ (n = 299) subjects (P= 0.009), thus replicating similar data recently obtained among Asians. In human umbilical vein endothelial cells (HUVECs) naturally carrying the QQ genotype, 24 h insulin stimulation increased monocyte adhesion, vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) expression, and mitogen-activated protein kinase (MAPK) kinase (MEK)-MAPK activation. Conversely, QR- and RR-HUVECs had increased unstimulated monocyte adhesion, VCAM-1 and ICAM-1 expression, and MEK-MAPK activation which did not increase further upon insulin stimulation. In addition, QQ-, QR-, and RR-HUVECs showed similar basal Akt phosphorylation and nitric oxide synthase activity which, however, were significantly increased by insulin only in QQ cells. the TRIB3 R4 variant is associated with increased carotid IMT also in Caucasians, thus replicating previous data obtained in Asians. In addition, in HUVECs, this variant is associated with unbalanced insulin signalling. This abnormality may favour vasoreactivity, intima-media thickening, and plaque formation and may, therefore, underlie the deleterious role exerted by the variant on the susceptibility to atherosclerosis.
  Cardiovascular research 01/2011; 89(1):184-92. · 5.80 Impact Factor
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  Available from: Antonello Cuttitta

  Article: Beneficial metabolic effects of prompt surgical treatment in patients with an adrenal incidentaloma causing biochemical hypercortisolism.

  Iacopo Chiodini, Valentina Morelli, Antonio Stefano Salcuni, Cristina Eller-Vainicher, Massimo Torlontano, Francesca Coletti, Laura Iorio, Antonello Cuttitta, Angelo Ambrosio, Leonardo Vicentini, Fabio Pellegrini, Massimiliano Copetti, Paolo Beck-Peccoz, Maura Arosio, Bruno Ambrosi, Vincenzo Trischitta, Alfredo Scillitani
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  ABSTRACT: In patients with adrenal incidentalomas, subclinical hypercortisolism (SH) is associated with an increased prevalence of the metabolic syndrome. The effect of surgical/conservative approach is debated. The objective of the study was to determine the effect of the surgical and conservative approaches on the metabolic syndrome in patients with adrenal incidentalomas. This was a retrospective longitudinal study (18-48 months follow-up). The study was conducted on an in- and outpatient basis. One hundred eight patients with adrenal incidentalomas were studied for the presence of SH, which was diagnosed in the presence of more than two of the following: urinary free cortisol greater than 70 microg per 24 h (193 nmol per 24 h), cortisol after 1 mg dexamethasone suppression test greater than 3.0 microg/dl (83 nmol/liter), ACTH less than 10 pg/ml (2.2 pmol/liter). Surgery was performed in 25 patients with SH (group TrSH+) and 30 without SH (group TrSH-), whereas the conservative approach was chosen by 16 patients with SH (group UntrSH+) and 37 without SH (group UntrSH-). During the follow-up, the improvement/worsening of body weight, blood pressure, or glucose and cholesterol levels was defined in the presence of a greater than 5% weight decrease/increase and following the European Society of Cardiology or the Adult Treatment Panel III criteria, respectively. In group TrSH+, weight, blood pressure, and glucose levels improved (32, 56, and 48%, respectively) more frequently than in group UntrSH+ (12.5%, P = 0.05; 0.0%, P < 0.0001; 0.0%, P = 0.001; and 0.0%, P = 0.0014, respectively). In group UntrSH+, blood pressure, glucose, and low-density lipoprotein levels worsened more frequently (50.0, 37.5, and 50.0%, respectively) than in group TrSH+ (0.0%, P < 0.0001; 0.0%, P = 0.001; and 20.0%, P = 0.05, respectively). Regarding the various components of the metabolic syndrome, in patients with adrenal incidentalomas and SH, surgery is beneficial.
  The Journal of clinical endocrinology and metabolism 04/2010; 95(6):2736-45. · 6.50 Impact Factor