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Di Paola R.,Research Unit of Diabetes and Endocrine Diseases | Marucci A.,Research Unit of Diabetes and Endocrine Diseases | Trischitta V.,Research Unit of Diabetes and Endocrine Diseases | Trischitta V.,University of Rome La Sapienza
Nutrition, Metabolism and Cardiovascular Diseases | Year: 2016

A wide range of studies both in humans and animal models point GALNT2 as a shaper of serum HDL-C and TG levels. Available data in humans indicate that, while under conditions of extreme GALNT2 loss-of-function HDL-C is the main target, a fine-tuning of GALNT2 changes is mostly associated with TG levels. Understanding whether different degrees of GALNT2 change do modulate different serum lipid fractions and, if so, addressing the mechanisms underlying such pleiotropic effects has the potential not only to improve our understanding of HDL-C and TG metabolism, but also to make GALNT2 becoming a target for treating atherogenic dyslipidemia and related clinical events. © 2016 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University.


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.


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.


Marucci A.,Research Unit of Diabetes and Endocrine Diseases | Cozzolino F.,University of Naples Federico II | Dimatteo C.,Research Unit of Diabetes and Endocrine Diseases | Monti M.,University of Naples Federico II | And 4 more authors.
Biochimica et Biophysica Acta - Molecular Cell Research | Year: 2013

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. © 2013 Elsevier B.V.


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.


De Cosmo S.,Unit of Endocrinology | Copetti M.,Unit of Biostatistics | Lamacchia O.,University of Foggia | Fontana A.,Unit of Biostatistics | And 13 more authors.
Diabetes Care | Year: 2013

OBJECTIVE-To develop and validate a parsimonious model for predicting short-term allcause 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. RESULTS-Nine 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. © 2013 by the American Diabetes Association.


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.


Ortega Moreno L.,Research Unit of Diabetes and Endocrine Diseases | Copetti M.,IRCCS Casa Sollievo della Sofferenza | Fontana A.,IRCCS Casa Sollievo della Sofferenza | Bonis C.,Research Unit of Diabetes and Endocrine Diseases | And 4 more authors.
Cardiovascular Diabetology | Year: 2016

Background: Despite its beneficial role on insulin resistance and atherosclerosis, adiponectin has been repeatedly reported as an independent positive predictor of cardiovascular mortality. Methods: A Mendelian randomization approach was used, in order to evaluate whether such counterintuitive association recognizes a cause-effect relationship. To this purpose, single nucleotide polymorphism rs822354 in the ADIPOQ locus which has been previously associated with serum adiponectin at genome-wide level, was used as an instrument variable. Our investigation was carried out in the Gargano Heart Study-prospective design, comprising 356 patients with type 2 diabetes, in whom both total and high molecular weight (HMW) adiponectin were measured and cardiovascular mortality was recorded (mean follow-up = 5.4 ± 2.5 years; 58 events/1922 person-year). Results: The A allele of rs822354 was associated with both total and HMW adiponectin [β (SE) = 0.10 (0.042), p = 0.014 and 0.17 (0.06), p = 0.003; respectively]. In a Poisson model comprising age, sex, smoking habits, BMI, HbA1c, total cholesterol, HDL-cholesterol, triglycerides, insulin therapy and hypertension, both rs822354 (IRR = 1.94, 95 % CI 1.23-3.07; p = 0.005), as well as the genetic equivalent of total adiponectin change (IRR = 1.07, 95 % CI 1.02-1.12; p = 0.003) were significantly associated with cardiovascular mortality. The observed genetic effect was significantly greater than that exerted by the genetic equivalent change of serum adiponectin (p for IRR heterogeneity = 0.012). In the above-mentioned adjusted model, very similar results were obtained when HMW, rather than total, adiponectin was used as the exposure variable of interest. Conclusions: Our data suggest that the paradoxical association between high serum adiponectin levels and increased cardiovascular mortality rate is based on a cause-effect relationship, thus pointing to an unexpected deleterious role of adiponectin action/metabolism on atherosclerotic processes. © 2016 Ortega Moreno et al.


Ortega Moreno L.,Research Unit of Diabetes and Endocrine Diseases | Lamacchia O.,University of Foggia | Salvemini L.,Research Unit of Diabetes and Endocrine Diseases | De Bonis C.,Research Unit of Diabetes and Endocrine Diseases | And 5 more authors.
Atherosclerosis | Year: 2016

Background: The paradoxical relationship between high adiponectin and increased mortality, described in several clinical subsets, has been reported only once in type 2 diabetes (T2D) and only in selected elderly patients. We investigated this relationship in unselected patients with T2D and, then, addressed its possible modulation by several demographic and clinical conditions, known to affect per se mortality rate. Methods: Patients from the Gargano Mortality Study (GMS; N = 897, follow-up = 10.5 ± 3.7 years; 290 events) and the Foggia Mortality Study (FMS; N = 529, follow-up = 7.1 ± 2.5 years; 143 events), were investigated. Results: For each SD adiponectin increase, HRs (95% CI) for all-cause mortality were 1.30 (1.19-1.43) in GMS, 1.43 (1.26-1.64) in FMS and 1.34 (1.24-1.45) in the combined studies. This association was independent of the possible confounding effect of demographics, adiposity measures, diabetes-related features, kidney function-related parameters and medications (p = 9.34 × 10-9). While no interaction was observed between adiponectin and sex, age, smoking habits, BMI, waist circumference, HbA1c, diabetes duration, micro-/macro-albuminuria and medications, a strong interaction was observed with GFR, with a significant adiponectin-mortality association observed in individuals with GFR≥ but not those with GFR < 60 ml/min/1.73 m2; p for adiponectin-by-GFR status interaction = 2.13 × 10-6). Conclusion: This is the first study reporting a paradoxical association of adiponectin with all-cause mortality in a large sample of unselected diabetic patients and indicating that such counterintuitive effect is observed only among patients with preserved kidney function. Further studies are needed to address if the strong interwoven effect of adiponectin and GFR turns to be useful in improving previously validated tools for predicting mortality in T2D. © 2015 Elsevier Ireland Ltd.


Qi L.,Harvard University | Menzaghi C.,Research Unit of Diabetes and Endocrine Diseases | Salvemini L.,Research Unit of Diabetes and Endocrine Diseases | De Bonis C.,Research Unit of Diabetes and Endocrine Diseases | And 4 more authors.
Diabetes | Year: 2011

OBJECTIVE - 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. RESEARCH DESIGN AND METHODS - 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. RESULTS - We identified a novel locus near the FER gene (5q21) at a genome-wide significance level, best represented by SNP rs10447248 (P = 4.69 x 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). CONCLUSIONS - 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. © 2011 by the American Diabetes Association.

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