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Prudente S.,Instituto Of Ricovero E Cura A Carattere Scientifico Casa Sollievo Della Sofferenza | Sesti G.,University of Catanzaro | Pandolfi A.,University of Chieti Pescara | Andreozzi F.,University of Catanzaro | And 4 more authors.
Endocrine Reviews | Year: 2012

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. © 2012 by The Endocrine Society. Source

Prudente S.,Mendel Laboratory | Dallapiccola B.,Bambino Gesu Pediatric Hospital | Pellegrini F.,IRCCS Casa Sollievo della Sofferenza | Doria A.,Joslin Diabetes Center | And 4 more authors.
Nutrition, Metabolism and Cardiovascular Diseases | Year: 2012

Genome-wide association studies (GWAS) have identified several loci associated with many common, multifactorial diseases which have been recently used to market genetic testing directly to the consumers. We here addressed the clinical utility of such GWAS-derived genetic information in predicting type 2 diabetes mellitus (T2DM) and coronary artery disease (CAD) in diabetic patients. In addition, the development of new statistical approaches, novel technologies of genome sequencing and ethical, legal and social aspects related to genetic testing have been also addressed. Available data clearly show that, similarly to what reported for most common diseases, genetic testing offered today by commercial companies cannot be used as predicting tools for T2DM and CAD. Further studies taking into account the complex interaction between genes as well as between genetic and non-genetic factors, including age, obesity and glycemic control which seem to modify genetic effects on the risk of T2DM and CAD, might mitigate such negative conclusions. Also, addressing the role of relatively rare variants by next generation sequencing may help identify novel and strong genetic markers with an important role in genetic prediction. Finally, statistical tools concentrated on reclassifying patients might be a useful application of genetic information for predicting many common diseases. By now, prediction of such diseases, including those of interest for the clinical diabetologist, have to be pursued by using traditional clinical markers which perform well and are not costly. © 2012 Elsevier B.V. Source

Prudente S.,Mendel Laboratory | Trischitta V.,Mendel Laboratory | Trischitta V.,Research Unit of Diabetes and Endocrine Diseases | Trischitta V.,University of Rome La Sapienza
Biochemical Society Transactions | Year: 2015

Insulin resistance is pathogenic for many prevalent disorders including type 2 diabetes mellitus (T2DM), cardiovascular disease (CVD), polycystic ovary syndrome, non-alcoholic fatty liver disease, Alzheimer's and Parkinson's diseases and several cancers. Unravelling molecular abnormalities of insulin resistance may therefore pave the way for tackling such heavy weight on healthcare systems. This review will be focused on studies addressing the role of genetic variability of TRIB3, an inhibitor of insulin signalling at the AKT level on insulin resistance and several related abnormalities. Studies carried out in several cultured cells clearly report that the TRIB3 Q84R missense polymorphism, is a gain-of-function amino acid substitution, with the Arg84 variant being a stronger inhibitor of insulin-mediated AKT activation as compared with the more frequent Gln84 variant. Given the key role of AKT in modulating not only insulin signalling but also insulin secretion, it was not surprising that β-cells and human pancreatic islets carrying the Arg84 variant showed also impaired insulin secretion. Also, of note is that in human vein endothelial cells carrying the Arg84 variant showed a reduced insulin-induced nitric oxide release, an established early atherosclerotic step. Accordingly with in vitro studies, in vivo studies indicate that TRIB3 Arg84 is associated with insulin resistance, T2DM and several aspects of atherosclerosis, including overt CVD. In all, several data indicate that the TRIB3 Arg84 variant plays a role on several aspects of glucose homoeostasis and atherosclerotic processes, thus unravelling new molecular pathogenic mechanisms of highly prevalent disorders such as T2DM and CVD. © 2015 Authors; published by Portland Press Limited. Source

De Cosmo S.,Unit of Endocrinology | Menzaghi C.,Research Unit of Diabetes and Endocrine Diseases | Prudente S.,IRCSS Casa Sollievo della Sofferenza Mendel Laboratoy | Trischitta V.,Research Unit of Diabetes and Endocrine Diseases | And 2 more authors.
Nephrology Dialysis Transplantation | Year: 2013

Several lines of evidence suggest a pathogenic role of insulin resistance on kidney dysfunction. Potential mechanisms are mostly due to the effect of single abnormalities related to insulin resistance and clustering into the metabolic syndrome. Hyperinsulinemia, which is inevitably associated to insulin resistance in non diabetic states, also appears to play a role on kidney function by inducing glomerular hyperfiltration and increased vascular permeability. More recently, adipocytokine which are linked to insulin resistance, low grade inflammation, endothelial dysfunction and vascular damage have been proposed as additional molecules able to modulate kidney function. In addition, recent evidences point also to a role of insulin resistance at the level of the podocyte, an important player in early phases of diabetic kidney damage, thus suggesting a new mechanism through which a reduction of insulin action can affect kidney function. In fact, mouse models not expressing the podocyte insulin receptor develop podocytes apoptosis, effacement of its foot processes along with thickening of the glomerular basement membrane, increased glomerulosclerosis and albuminuria.A great number of epidemiological studies have repeatedly reported the association between insulin resistance and kidney dysfunction in both non diabetic and diabetic subjects. Among these, studies addressing the impact of insulin resistance genes on kidney dysfunction have played the important role to help establish a cause-effect relationship between these two traits.Finally, numerous independent intervention studies have shown that a favourable modulation of insulin resistance has a positive effect also on urinary albumin and total protein excretion.In conclusion, several data of different nature consistently support the role of insulin resistance and related abnormalities on kidney dysfunction. Intervention trials designed to investigate whether treating insulin resistance ameliorates also hard renal end-points are both timely and needed. © 2013 The Author. Source

Menzaghi C.,Research Unit of Diabetes and Endocrine Diseases | Salvemini L.,Research Unit of Diabetes and Endocrine Diseases | Paroni G.,Research Unit of Diabetes and Endocrine Diseases | De Bonis C.,Research Unit of Diabetes and Endocrine Diseases | And 8 more authors.
Journal of Internal Medicine | Year: 2010

Menzaghi C, Salvemini L, Paroni G, De Bonis C, Mangiacotti D, Fini G, Doria A, Di Paola R, Trischitta V (IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo (FG), Italy, Joslin Diabetes Center and Harvard Medical School, Boston, MA, USA, "Sapienza" University; IRCCS Casa Sollievo della Sofferenza-Mendel Institute, Rome, Italy). Circulating HMW adiponectin isoform is heritable and shares a common genetic background with insulin resistance in nondiabetic White Caucasians from Italy: evidence from a family-based study. J Intern Med 2010; 267: 287-294. Objective. Reduced circulating adiponectin levels contribute to the aetiology of insulin resistance. Adiponectin circulates in three different isoforms: high molecular weight (HMW), medium molecular weight (MMW) and low molecular weight (LMW) isoforms. The genetics of adiponectin isoforms is mostly unknown. Our aim was to investigate whether and to which extent circulating adiponectin isoforms are heritable and whether they share common genetic backgrounds with insulin resistance-related traits. Methods. In a family-based sample of 640 nondiabetic White Caucasians from Italy, serum adiponectin isoforms concentrations were measured by ELISA. Three single nucleotide polymorphisms (SNPs) in the ADIPOQ gene previously reported to affect total adiponectin levels (rs17300539, rs1501299 and rs677395) were genotyped. The heritability of adiponectin isoform levels was assessed by variance component analysis. A linear mixed effects model was used to test the association between SNPs and adiponectin isoforms. Bivariate analyses were conducted to study genetic correlations between adiponectin isoforms levels and other insulin resistance-related traits. Results. All isoforms were highly heritable (h 2 = 0.60-0.80, P = 1.0 × 10 -13-1.0 × 10 -23). SNPs rs17300539, rs1501299 and rs6773957 explained a significant proportion of HMW variance (2-9%, P = 1.0 × 10 -3-1.0 × 10 -5). In a multiple-SNP model, only rs17300539 and rs1501299 remained associated with HMW adiponectin (P = 3.0 × 10 -4 and 2.0 × 10 -2). Significant genetic correlations (P = 1.0 × 10 -2-1.0 × 10 -5) were observed between HMW adiponectin and fasting insulin, homeostasis model assessment of insulin resistance, HDL cholesterol and the metabolic syndrome score. Only rs1501299 partly accounted for these genetic correlations. Conclusion. Circulating levels of adiponectin isoforms are highly heritable. The genetic control of HMW adiponectin is shared in part with insulin resistance-related traits and involves, but is not limited to, the ADIPOQ locus. © 2009 Blackwell Publishing Ltd. Source

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