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San Giovanni Rotondo, Italy

De Cosmo S.,Clinical Unit of Endocrinology | Prudente S.,Mendel Laboratory | Lamacchia O.,University of Foggia | Pucci L.,University of Pisa | And 12 more authors.
Nephrology Dialysis Transplantation | Year: 2013

Background. In Mexican Americans, the IRS1 G972R polymorphism (rs1801278) has been associated to such a marked reduction in glomerular filtration rate (GFR) (i.e. β = -8.3 mL/ min/1.73 m2) to be considered a major determinant of kidney function. Methods. This was a cross-sectional study to investigate whether a similarly strong effect can also be observed among individuals of European ancestry. We investigated a total of 3973 White patients with type 2 diabetes. Standardized serum creatinine was measured by the modified kinetic Jaffè reaction and estimated GFR (eGFR) calculated by the modification diet renal disease (MDRD) formula; rs1801278 was genotyped by TaqMan assay. Results. No significant association was observed, with R972 carriers showing only a modestly, not significant, lower eGFR level as compared with other subjects (β = -1.82 mL/min/ 1.73 m2, P = 0.086). Conclusions. Our data indicate that IRS1 G972R is not a strong determinant of GFR in diabetic patients of European ancestry as in Mexican Americans. Since we had 100% power to detect the previously reported association, the risk our finding is a false negative one is minimal. Kidney dysfunction predisposes to end-stage renal disease both in the general population and in diabetic patients. Several pieces of evidence indicate that low glomerular filtration rate (GFR) is heritable, thus suggesting it is under the influence of genetic determinants. A number of genetic variations known to affect whole body insulin sensitivity have been associated with reduced GFR in diabetic patients. In contrast to what was reported in Mexican Americans, IRS1 G972R polymorphism has no a strong effect on eGFR) in patients with type 2 diabetes of European ancestry. © The Author 2013. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

Prudente S.,Mendel Laboratory | Morini E.,University of Rome La Sapienza | Lucchesi D.,University of Pisa | Lamacchia O.,University of Foggia | And 14 more authors.
Diabetes | Year: 2014

This study tried to replicate in a large sample of white patients with type 2 diabetes (T2D) from Italy a previously reported association of the IRS1 G972R polymorphism with failure to oral antidiabetes drugs (OAD). A total of 2,409 patients from four independent studies were investigated. Case subjects (n = 1,193) were patients in whom, because of uncontrolled diabetes (i.e., HbA1c >8%), insulin therapy had been added either on, or instead of, maximal or near-maximal doses of OAD, mostly metformin and sulfonylureas; control subjects (n = 1,216) were patients with HbA1c >8% in the absence of insulin therapy. The IRS1 G972R polymorphism was typed by TaqMan allele discrimination. In all samples, individuals carrying the IRS1 R972 risk variant tended to be more frequent among case than control subjects, though reaching statistical significance only in one case. As no IRS1 G972R-by-study sample interaction was observed, data from the four samples were analyzed together; a significant association was observed (allelic odds ratio [OR] 1.30, 95% CI 1.03-1.63). When our present data were meta-Analyzed with those obtained in a previous study, an overall R972 allelic OR of 1.37 (1.12-1.69) was observed. This study confirms in a large and ethnically homogeneous sample that IRS1 G972R polymorphism is associated with failure to OAD among patients with T2D. © 2014 by the American Diabetes Association.

Bacci S.,Clinical Unit of Endocrinology | Prudente S.,IRCCS Casa Sollievo della Sofferenza Mendel Laboratory | Copetti M.,Unit of Biostatistics | Spoto B.,CNR Institute of Biomedicine and Molecular Immunology Alberto Monroy | And 24 more authors.
Atherosclerosis | Year: 2013

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. © 2012 Elsevier Ireland Ltd.

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