47 results on '"Claudia Menzaghi"'
Search Results
2. The Synergic Association of hs-CRP and Serum Amyloid P Component in Predicting All-Cause Mortality in Patients With Type 2 Diabetes
- Author
-
Massimiliano Copetti, Monia Garofolo, Lucia Salvemini, Claudia Menzaghi, Andrea Fontana, Vincenzo Trischitta, Maria Giovanna Scarale, Giuseppe Penno, Olga Lamacchia, Salvatore De Cosmo, Scarale, M. G., Copetti, M., Garofolo, M., Fontana, A., Salvemini, L., de Cosmo, S., Lamacchia, O., Penno, G., Trischitta, V., and Menzaghi, C. more...
- Subjects
Male ,Research design ,prediction model ,all-cause mortality ,diabetes ,Endocrinology, Diabetes and Metabolism ,Type 2 diabetes ,Gastroenterology ,Cohort Studies ,0302 clinical medicine ,Cause of Death ,030212 general & internal medicine ,Cause of death ,ENFORCE ,Aged, 80 and over ,biology ,Mortality rate ,Hazard ratio ,Middle Aged ,Prognosis ,Type 2 Diabetes ,Serum Amyloid P-Component ,RECODe ,hs-CRP ,serum amyloid P ,C-Reactive Protein ,Italy ,Female ,Cohort study ,Adult ,medicine.medical_specialty ,030209 endocrinology & metabolism ,03 medical and health sciences ,Internal medicine ,Diabetes mellitus ,Internal Medicine ,medicine ,Humans ,Serum amyloid P component ,Aged ,Advanced and Specialized Nursing ,business.industry ,medicine.disease ,Diabetes Mellitus, Type 2 ,biology.protein ,business ,Biomarkers ,Diabetic Angiopathies - Abstract
OBJECTIVE Type 2 diabetes is characterized by increased death rate. In order to tackle this dramatic event, it becomes essential to discover novel biomarkers capable of identifying high-risk patients to be exposed to more aggressive preventive and treatment strategies. hs-CRP and serum amyloid P component (SAP) are two acute-phase inflammation proteins, which interact physically and share structural and functional features. We investigated their combined role in associating with and improving prediction of mortality in type 2 diabetes. RESEARCH DESIGN AND METHODS Four cohorts comprising 2,499 patients with diabetes (643 all-cause deaths) were analyzed. The improvement of mortality prediction was addressed using two well-established prediction models, namely, EstimatioN oF mORtality risk in type 2 diabetiC patiEnts (ENFORCE) and Risk Equations for Complications of Type 2 Diabetes (RECODe). RESULTS Both hs-CRP and SAP were independently associated with all-cause mortality (hazard ratios [HRs] [95% CIs]: 1.46 [1.34–1.58] [P < 0.001] and 0.82 [0.76–0.89] [P < 0.001], respectively). Patients with SAP ≤33 mg/L were at increased risk of death versus those with SAP >33 mg/L only if hs-CRP was relatively high (>2 mg/L) (HR 1.96 [95% CI 1.52–2.54] [P < 0.001] and 1.20 [0.91–1.57] [P = 0.20] in hs-CRP >2 and ≤2 mg/L subgroups, respectively; hs-CRP-by-SAP strata interaction P < 0.001). The addition of hs-CRP and SAP significantly (all P < 0.05) improved several discrimination and reclassification measures of both ENFORCE and RECODe all-cause mortality prediction models. CONCLUSIONS In type 2 diabetes, hs-CRP and SAP show opposite and synergic associations with all-cause mortality. The use of both markers, possibly in combination with others yet to be unraveled, might improve the ability to predict the risk of death in the real-life setting. more...
- Published
- 2020
- Full Text
- View/download PDF
Catalog
3. Circulating Metabolites Associate With and Improve the Prediction of All-Cause Mortality in Type 2 Diabetes
- Author
-
Maria Giovanna Scarale, Mario Mastroianno, Cornelia Prehn, Massimiliano Copetti, Lucia Salvemini, Jerzy Adamski, Salvatore De Cosmo, Vincenzo Trischitta, and Claudia Menzaghi
- Subjects
Inflammation ,Diabetes Mellitus, Type 2 ,Endocrinology, Diabetes and Metabolism ,Internal Medicine ,Tryptophan ,prediction models ,all-cause mortality ,Humans ,prediction models, metabolites, all-cause mortality ,metabolites ,Biomarkers ,Kynurenine - Abstract
Death rate is increased in type 2 diabetes. Unraveling biomarkers of novel pathogenic pathways capable to identify high-risk patients is instrumental to tackle this burden. We investigated the association between serum metabolites and all-cause mortality in type 2 diabetes and then whether the associated metabolites mediate the effect of inflammation on mortality risk and improve ENFORCE (EstimatioN oF mORtality risk in type2 diabetic patiEnts) and RECODe (Risk Equation for Complications Of type 2 Diabetes), two well-established all-cause mortality prediction models in diabetes. Two cohorts comprising 856 individuals (279 all-cause deaths) were analyzed. Serum metabolites (n = 188) and pro- and anti-inflammatory cytokines (n = 7) were measured. In the pooled analysis, hexanoylcarnitine, kynurenine, and tryptophan were significantly and independently associated with mortality (hazard ratio [HR] 1.60 [95% CI 1.43–1.80]; 1.53 [1.37–1.71]; and 0.71 [0.62–0.80] per 1 SD). The kynurenine-to-tryptophan ratio (KTR), a proxy of indoleamine-2,3-dioxygenase, which degrades tryptophan to kynurenine and contributes to a proinflammatory status, mediated 42% of the significant association between the antiatherogenic interleukin (IL) 13 and mortality. Adding the three metabolites improved discrimination and reclassification (all P < 0.01) of both mortality prediction models. In type 2 diabetes, hexanoylcarnitine, tryptophan, and kynurenine are associated to and improve the prediction of all-cause mortality. Further studies are needed to investigate whether interventions aimed at reducing KTR also reduce the risk of death, especially in patients with low IL-13. more...
- Published
- 2022
4. Correction to: MODY patients carrying mutation in syndromic diabetes genes. An Italian single-center experience
- Author
-
Antonella Marucci, Rosa Di Paola, Irene Rutigliano, Grazia Fini, Serena Pezzilli, Claudia Menzaghi, and Vincenzo Trischitta
- Subjects
Endocrinology ,Endocrinology, Diabetes and Metabolism ,Internal Medicine ,General Medicine - Published
- 2023
- Full Text
- View/download PDF
5. A Serum Resistin and Multicytokine Inflammatory Pathway Is Linked with and Helps Predict All-cause Death in Diabetes
- Author
-
Massimiliano Copetti, Claudia Menzaghi, Tommaso Mazza, Maria Giovanna Scarale, Alessandra Antonucci, Salvatore De Cosmo, Rosa Di Paola, Marina Cardellini, Viviana Casagrande, Rossella Menghini, Vincenzo Trischitta, Massimo Federici, Olga Lamacchia, Lucia Salvemini, Gianluigi Ferrazza, Scarale, M. G., Antonucci, A., Cardellini, M., Copetti, M., Salvemini, L., Menghini, R., Mazza, T., Casagrande, V., Ferrazza, G., Lamacchia, O., De Cosmo, S., Di Paola, R., Federici, M., Trischitta, V., and Menzaghi, C. more...
- Subjects
Oncology ,Male ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Clinical Biochemistry ,cytokines ,mortality ,plaque instability ,prediction models ,resistin ,type 2 diabetes ,Settore MED/09 ,Disease ,Carotid endarterectomy ,Type 2 diabetes ,030204 cardiovascular system & hematology ,Biochemistry ,Cohort Studies ,0302 clinical medicine ,Endocrinology ,Risk Factors ,Medicine ,Resistin ,Prospective Studies ,Mortality rate ,Hazard ratio ,Middle Aged ,Plaque, Atherosclerotic ,Cohort ,Cytokines ,Female ,medicine.medical_specialty ,030209 endocrinology & metabolism ,Diabetes Complications ,03 medical and health sciences ,Diabetes mellitus ,Internal medicine ,Humans ,Aged ,Inflammation ,business.industry ,Tumor Necrosis Factor-alpha ,Interleukins ,Biochemistry (medical) ,medicine.disease ,Atherosclerosis ,Diabetes Mellitus, Type 2 ,business ,Biomarkers - Abstract
Context Type 2 diabetes (T2D) shows a high mortality rate, partly mediated by atherosclerotic plaque instability. Discovering novel biomarkers may help identify high-risk patients who would benefit from more aggressive and specific managements. We recently described a serum resistin and multicytokine inflammatory pathway (REMAP), including resistin, interleukin (IL)-1β, IL-6, IL-8, and TNF-α, that is associated with cardiovascular disease. Objective We investigated whether REMAP is associated with and improves the prediction of mortality in T2D. Methods A REMAP score was investigated in 3 cohorts comprising 1528 patients with T2D (409 incident deaths) and in 59 patients who underwent carotid endarterectomy (CEA; 24 deaths). Plaques were classified as unstable/stable according to the modified American Heart Association atherosclerosis classification. Results REMAP was associated with all-cause mortality in each cohort and in all 1528 individuals (fully adjusted hazard ratio [HR] for 1 SD increase = 1.34, P Conclusion REMAP is independently associated with and improves predict all-cause mortality in T2D; it can therefore be used to identify high-risk individuals to be targeted with more aggressive management. Whether REMAP can also identify patients who are more responsive to IL-6 and IL-1β monoclonal antibodies that reduce cardiovascular burden and total mortality is an intriguing possibility to be tested. more...
- Published
- 2021
6. Circulating Adiponectin Levels Are Paradoxically Associated With Mortality Rate: A Systematic Review and Meta-Analysis
- Author
-
Andrea Fontana, Claudia Menzaghi, Maria Giovanna Scarale, Massimiliano Copetti, Vincenzo Trischitta, Scarale, M. G., Fontana, A., Trischitta, V., Copetti, M., and Menzaghi, C.
- Subjects
medicine.medical_specialty ,Adiponectin ,business.industry ,Endocrinology, Diabetes and Metabolism ,Mortality rate ,Biochemistry (medical) ,Clinical Biochemistry ,Hazard ratio ,030209 endocrinology & metabolism ,Context (language use) ,all-cause mortality ,cardovasular disease ,030204 cardiovascular system & hematology ,Cochrane Library ,Biochemistry ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Systematic review ,Meta-analysis ,Internal medicine ,medicine ,business ,Prospective cohort study - Abstract
Context Some studies have surprisingly indicated that serum adiponectin level is positively related to mortality rate, thus casting doubts on its role as a therapeutic target for cardiovascular disease. Objective To summarize evidence about direction, strength, and modulators of this controversial association. Methods MEDLINE, Web of Science, CINHAL, Cochrane Library, and Scopus databases were searched from their inception dates through June 2018 for English-language prospective studies reporting the association between adiponectin and all-cause or cardiovascular mortality. Two investigators independently extracted data and assessed study quality using standard criteria following the Preferred Reporting Items for Systematic Reviews and Meta-analyses and The Newcastle-Ottawa Scale. Pooled hazard ratios (HRs) and 95% CIs were derived using fixed- or random-effects models when appropriate, and results were expressed to a 1-SD increment of adiponectin. Results We identified 55 studies (n = 61,676 subjects) with all-cause mortality data and 28 (n = 43,979 subjects) studies with cardiovascular mortality data. Pooled HRs were 1.24 (1.17-1.31) and 1.28 (1.19-1.37) for all-cause and cardiovascular mortality, respectively. Similar results were obtained for high-molecular-weight adiponectin. When meta-analyses were restricted to studies reporting data on natriuretic peptides, reductions of 43% and 28% on a log scale of these respective associations were observed after adjusting for natriuretic peptides. Conclusions Our results point strongly to a paradoxical association between high adiponectin levels and increased mortality rate, which is partly modulated by natriuretic peptides. more...
- Published
- 2018
- Full Text
- View/download PDF
7. The Adiponectin Paradox for All-Cause and Cardiovascular Mortality
- Author
-
Claudia Menzaghi and Vincenzo Trischitta
- Subjects
Endocrinology, Diabetes and Metabolism ,Adiponectin ,Cardiovascular Diseases ,Diabetes Mellitus, Type 2 ,Humans ,Natriuretic Peptides ,Oxidative Stress ,Risk Factors ,Internal Medicine ,Adipokine ,030209 endocrinology & metabolism ,Disease ,Type 2 diabetes ,030204 cardiovascular system & hematology ,Bioinformatics ,03 medical and health sciences ,Endocrinology ,0302 clinical medicine ,Diabetes mellitus ,Diabetes Mellitus ,Medicine ,Glucose homeostasis ,business.industry ,Mortality rate ,Confounding ,medicine.disease ,Diabetes and Metabolism ,Perspectives in Diabetes ,business ,Type 2 - Abstract
Basic science studies have shown beneficial effects of adiponectin on glucose homeostasis, chronic low-grade inflammation, apoptosis, oxidative stress, and atherosclerotic processes, so this molecule usually has been considered a salutary adipokine. It was therefore quite unexpected that large prospective human studies suggested that adiponectin is simply a marker of glucose homeostasis, with no direct favorable effect on the risk of type 2 diabetes and cardiovascular disease. But even more unforeseen were data addressing the role of adiponectin on the risk of death. In fact, a positive, rather than the expected negative, relationship was reported between adiponectin and mortality rate across many clinical conditions, comprising diabetes. The biology underlying this paradox is unknown. Several explanations have been proposed, including adiponectin resistance and the confounding role of natriuretic peptides. In addition, preliminary genetic evidence speaks in favor of a direct role of adiponectin in increasing the risk of death. However, none of these hypotheses are based on robust data, so further efforts are needed to unravel the elusive role of adiponectin on cardiometabolic health and, most important, its paradoxical association with mortality rate. more...
- Published
- 2017
- Full Text
- View/download PDF
8. 1610-P: On the Combined Effect of C-Reactive Protein (CRP) and Serum Amyloid Component P (SAP) on Mortality Risk in Type 2 Diabetes
- Author
-
Lucia Salvemini, Claudia Menzaghi, Massimiliano Copetti, Monia Garofolo, Salvatore De Csomo, Olga Lamacchia, Vincenzo Trischitta, Giuseppe Penno, and Maria Giovanna Scarale
- Subjects
medicine.medical_specialty ,Amyloid ,biology ,Pentraxins ,business.industry ,Endocrinology, Diabetes and Metabolism ,Mortality rate ,C-reactive protein ,Context (language use) ,Type 2 diabetes ,medicine.disease ,Gastroenterology ,Internal medicine ,Internal Medicine ,medicine ,biology.protein ,Biomarker (medicine) ,In patient ,business - Abstract
CRP and SAP are the two short, strongly homologous pentraxins produced in response to inflammation. Though their common contribution to innate immunity, they seem to differently affect atherosclerosis and related clinical outcomes. In the specific context of mortality rate i) CRP is a recognized risk biomarker; ii) data on SAP are sparse and conflicting; iii) no data are available on their possibly combined effect. Accordingly, the combined effect of CRP and SAP on mortality risk was investigated in the high-risk subset of patients with type 2 diabetes (T2D). Four cohorts of patients with T2D [i.e., Gargano Heart Study (GHS; n=358; follow-up (f-u)=5±3 years; 81 events); Gargano Mortality Study (n=650; f-u=11±4 years; 190 events); Foggia Mortality Study (n=530; f-u=7±3 years; 146 events) and Pisa Mortality Study (n=986; f-u=13±3 years; 230 events)] were analyzed by Cox proportional hazard models. In the pooled sample, with a total of 2,524 individuals experiencing 647 events, hs-CRP was positively [HR=1.53 (95% CI 1.41-1.66)] whereas SAP was negatively [HR=0.80 (95% CI 0.74-0.86)] associated with all-cause mortality. Similar results were observed on cardiovascular death in GHS: HR (95% CI) being 1.90 (1.48-2.44) and 0.78 (0.61-0.98) for hs-CRP and SAP, respectively. The whole sample was then stratified according to relatively low and high hs-CRP and SAP (< or > the median value), so to obtain four groups: low/high (1), low/low (2), high/high (3), and high/low (4) hs-CRP/SAP levels. As compared to group 1, group 2, 3 and 4 had HRs (95% CIs) of 1.25 (0.96-1.64), 1.80 (1.39-2.33) and 2.40 (1.81-3.17) for all-cause mortality (p for trend=1.1x10-11 or, in a model comprising study sample, age, sex, smoking habit, BMI, HbA1c, diabetes duration and all ongoing treatments, p=4.1x10-8). In conclusion, in patients with T2D, hs-CRP and SAP show a combined effect on all-cause death. Whether their simultaneous use may prove to be useful in predicting mortality in T2D needs further investigation. Disclosure M. Scarale: None. M. Copetti: None. M. Garofolo: None. L. Salvemini: None. S. De Csomo: None. O. Lamacchia: None. G. Penno: None. V. Trischitta: None. C. Menzaghi: None. Funding Italian Ministry of Health (RF-2013-02356459) more...
- Published
- 2019
- Full Text
- View/download PDF
9. The combined effect of adiponectin and resistin on all-cause mortality in patients with type 2 diabetes: Evidence of synergism with abdominal adiposity
- Author
-
Claudia Menzaghi, Massimiliano Copetti, Concetta De Bonis, Andrea Fontana, Mauro Cignarelli, Lucia Salvemini, Lorena Ortega Moreno, Olga Lamacchia, and Vincenzo Trischitta
- Subjects
Blood Glucose ,Male ,medicine.medical_specialty ,Time Factors ,Waist ,endocrine system diseases ,Adipokine ,030209 endocrinology & metabolism ,Kaplan-Meier Estimate ,Type 2 diabetes ,030204 cardiovascular system & hematology ,03 medical and health sciences ,0302 clinical medicine ,Risk Factors ,Internal medicine ,medicine ,Humans ,Resistin ,In patient ,Mortality ,Adiposity ,Aged ,Adiponectin ,business.industry ,Mortality rate ,nutritional and metabolic diseases ,Middle Aged ,Additive effect ,Mortality risk ,Waist circumference ,Diabetes Mellitus, Type 2 ,Female ,Follow-Up Studies ,Italy ,Obesity, Abdominal ,Treatment Outcome ,Waist Circumference ,Cardiology and Cardiovascular Medicine ,medicine.disease ,Endocrinology ,business ,hormones, hormone substitutes, and hormone antagonists ,All cause mortality - Abstract
While elevated serum adiponectin and resistin levels have been singly associated with all-cause mortality in patients with type 2 diabetes (T2D), their combined effect has never been studied. We investigated such joint effect in patients with T2D and its possible modulation by several demographic and clinical conditions, known to affect per se mortality rate.Patients with T2D from the Gargano Mortality Study (GMS; N = 895, follow-up = 10.5 ± 3.7 years; 290 events) and the Foggia Mortality Study (FMS; N = 519, follow-up = 7.1 ± 2.5 years; 140 events) were examined.As singly considered, adiponectin and resistin were independently associated with mortality rate in GMS and FMS (p 0.0001 for both). The two studies were then pooled, for investigating the nature of the joint effect of the two adipokines. In such sample, both adipokines were associated with death, independent of each other and of several additional covariates (p = 0.01-4.58 × 10(-12)). Of note, no adiponectin-by-resistin interaction was observed (p = 0.40), thus pointing to an additive effect of the two adipokines. As compared to individuals with low levels of both adiponectin and resistin (i.e. below median values), those with high levels of both adipokines had an HR (95%CI) for death of 3.02 (2.26-4.03). Such increased risk was more pronounced in individuals with relatively low abdominal adiposity (p for HR heterogeneity below or above the median value of waist circumference = 0.03).Adiponectin and resistin show an additive independent effect on all-cause mortality in patients with T2D. Such effect is modified by abdominal adiposity. more...
- Published
- 2016
- Full Text
- View/download PDF
10. Estimation of Mortality Risk in Type 2 Diabetic Patients (ENFORCE): An Inexpensive and Parsimonious Prediction Model
- Author
-
Giuseppe Penno, Massimiliano Copetti, Claudia Menzaghi, Andrea Fontana, Vincenzo Trischitta, Monia Garofolo, Maria Giovanna Scarale, Maria Rosaria Sorrentino, Hetal Shah, Salvatore De Cosmo, Alessandro Doria, Olga Lamacchia, Copetti, M., Shah, H., Fontana, A., Scarale, M. G., Menzaghi, C., De Cosmo, S., Garofolo, M., Sorrentino, M. R., Lamacchia, O., Penno, G., Doria, A., and Trischitta, V. more...
- Subjects
Male ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Clinical Biochemistry ,Statistics as Topic ,030209 endocrinology & metabolism ,Context (language use) ,Type 2 diabetes ,Biochemistry ,Risk Assessment ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Randomized controlled trial ,law ,Prediction model ,Risk Factors ,Internal medicine ,medicine ,all-cause mortality ,diabete ,Humans ,030212 general & internal medicine ,Prospective Studies ,Prospective cohort study ,Clinical Research Articles ,Glycemic ,Aged ,Randomized Controlled Trials as Topic ,Models, Statistical ,business.industry ,Biochemistry (medical) ,Middle Aged ,medicine.disease ,Prognosis ,Clinical trial ,Diabetes Mellitus, Type 2 ,Observational study ,Female ,Risk assessment ,business - Abstract
ContextWe previously developed and validated an inexpensive and parsimonious prediction model of 2-year all-cause mortality in real-life patients with type 2 diabetes.ObjectiveThis model, now named ENFORCE (EstimatioN oF mORtality risk in type 2 diabetiC patiEnts), was investigated in terms of (i) prediction performance at 6 years, a more clinically useful time-horizon; (ii) further validation in an independent sample; and (iii) performance comparison in a real-life vs a clinical trial setting.DesignObservational prospective randomized clinical trial.SettingWhite patients with type 2 diabetes.PatientsGargano Mortality Study (GMS; n = 1019), Foggia Mortality Study (FMS; n = 1045), and Pisa Mortality Study (PMS; n = 972) as real-life samples and the standard glycemic arm of the ACCORD (Action to Control Cardiovascular Risk in Diabetes) clinical trial (n = 3150).Main Outcome MeasureThe endpoint was all-cause mortality. Prediction accuracy and calibration were estimated to assess the model's performances.ResultsENFORCE yielded 6-year mortality C-statistics of 0.79, 0.78, and 0.75 in GMS, FMS, and PMS, respectively (P heterogeneity = 0.71). Pooling the three cohorts showed a 6-year mortality C-statistic of 0.80. In the ACCORD trial, ENFORCE achieved a C-statistic of 0.68, a value significantly lower than that obtained in the pooled real-life samples (P < 0.0001). This difference resembles that observed with other models comparing real-life vs clinical trial settings, thus suggesting it is a true, replicable phenomenon.ConclusionsThe time horizon of ENFORCE has been extended to 6 years and validated in three independent samples. ENFORCE is a free and user-friendly risk calculator of all-cause mortality in white patients with type 2 diabetes from a real-life setting. more...
- Published
- 2019
11. The Adiponectin-Mortality Paradox—A Systematic Review and Meta-analysis
- Author
-
Massimiliano Copetti, Maria Giovanna Scarale, Vincenzo Trischitta, Andrea Fontana, Claudia Menzaghi, Scarale, MARIA GIOVANNA, Fontana, Andrea, Trischitta, Vincenzo, Copetti, Massimiliano, and Menzaghi, Claudia more...
- Subjects
medicine.medical_specialty ,education.field_of_study ,Adiponectin ,business.industry ,Endocrinology, Diabetes and Metabolism ,Mortality rate ,Population ,Hazard ratio ,Type 2 diabetes ,medicine.disease ,Study heterogeneity ,Meta-analysis ,Internal medicine ,Internal Medicine ,Medicine ,business ,Prospective cohort study ,education - Abstract
Surprisingly, several, though not all, studies have shown a positive relationship between serum adiponectin (ADPN) and mortality rate. In order to deeply address direction and strength of this paradoxical association, we carried out a systematic review and meta-analysis (MA) of prospective studies present in MEDLINE, Cochrane Library and Scopus by December, 1st 2017, with ADPN being the exposure and all-cause (AC) and cardiovascular (CV) mortality the outcomes. We performed random effect MA to pool individual hazard ratios (HRs; 95% CIs). To address the role of Natriuretic Peptides (NPs), known to increase both ADPN expression and mortality rate, a MA focused only on studies reporting HRs before and after NPs adjustment was also carried out. We assessed study heterogeneity by Q statistic and then performed meta-regressions considering male percentage, age, BMI, eGFR and clinical setting (general population, type 2 diabetes, CV disease, dialysis) as study level covariates. We identified 56 (n=64,775 subjects) and 30 (n=48,439) studies for AC and CV mortality, respectively. Heterogeneity across studies was observed for both outcomes (Q-test p0.1). For CV mortality (6 studies, n=15,252), HRs were 1.21 (1.10-1.33) and 1.15 (1.06-1.24) without and with NPs adjustment, respectively (p0.8). Male percentage, age, BMI, eGFR and clinical setting did not explain the observed heterogeneity among studies. Our results confirm the existence of a paradoxical association between high ADPN levels and increased mortality rate. Such paradox seems to be only partly explained by NPs levels. Disclosure M. Scarale: None. A. Fontana: None. V. Trischitta: None. M. Copetti: None. C. Menzaghi: None. more...
- Published
- 2018
12. Suggestive evidence of a multi-cytokine resistin pathway in humans and its role on cardiovascular events in high-risk individuals
- Author
-
Concetta De Bonis, Massimiliano Copetti, Claudia Menzaghi, Lorena Ortega Moreno, Vincenzo Trischitta, Lucia Salvemini, Antonella Marucci, Alessandra Antonucci, and Rosa Di Paola
- Subjects
Male ,Interleukin-1beta ,Blood Pressure ,Coronary Artery Disease ,Type 2 diabetes ,030204 cardiovascular system & hematology ,resistin pathway ,Body Mass Index ,Coronary artery disease ,0302 clinical medicine ,Risk Factors ,Medicine ,Resistin ,Prospective Studies ,Middle Aged ,Interleukin-12 ,Female ,Waist Circumference ,hormones, hormone substitutes, and hormone antagonists ,Signal Transduction ,Adult ,cardiovascular risk ,medicine.medical_specialty ,030209 endocrinology & metabolism ,Article ,03 medical and health sciences ,Insulin resistance ,Internal medicine ,Diabetes mellitus ,Humans ,Triglycerides ,Aged ,Interleukin-6 ,Tumor Necrosis Factor-alpha ,business.industry ,Cholesterol, HDL ,Interleukin-8 ,Case-control study ,Cholesterol, LDL ,multidisciplinary ,medicine.disease ,Blood pressure ,Endocrinology ,Diabetes Mellitus, Type 2 ,Gene Expression Regulation ,Case-Control Studies ,Insulin Resistance ,business ,Mace - Abstract
In cells and tissues resistin affects IL-1β, IL-6, IL-8, IL-12 and TNF-α expression, thus suggesting the existence of a multi-cytokine “resistin pathway”. We investigated whether such pathway does exist in humans and, if so, if it is associated with cardiovascular risk factors and with major adverse cardiovascular events (MACE). Serum cytokines were measured in 280 healthy subjects from the Gargano Study 2 (GS2) whose BMI, waist circumference, HOMAIR, triglycerides, HDL-cholesterol, systolic and diastolic blood pressure data were available and in 353 patients with type 2 diabetes and coronary artery disease from the Gargano Heart Study (GHS)-prospective design (follow-up 5.4 ± 2.5 years; 71 MACE). In GS2, cytokines mRNA levels in white blood cells were also measured. In GS2, resistin mRNA was correlated with all cytokines expression (all p more...
- Published
- 2017
- Full Text
- View/download PDF
13. Joint effect of insulin signaling genes on all-cause mortality
- Author
-
Simonetta Bacci, Timothy Hastings, Antonella Marucci, Massimiliano Copetti, Stefano Rizza, Francesca Mallamaci, Salvatore De Cosmo, Christine Mendonca, Belinda Spoto, Vincenzo Trischitta, Alessandro Doria, Massimo Federici, Alessandra Testa, Andrea Fontana, Carmine Zoccali, Giovanni Tripepi, Claudia Menzaghi, Diego Bailetti, and Patinut Buranasupkajorn more...
- Subjects
Male ,Oncology ,medicine.medical_specialty ,Settore MED/09 - Medicina Interna ,Genotype ,medicine.medical_treatment ,Myocardial Infarction ,Single-nucleotide polymorphism ,Type 2 diabetes ,Polymorphism, Single Nucleotide ,Article ,Insulin resistance ,Internal medicine ,medicine ,Humans ,Insulin ,Genetic Predisposition to Disease ,Prospective Studies ,Settore MED/49 - Scienze Tecniche Dietetiche Applicate ,Mortality ,Alleles ,Aged ,Proportional Hazards Models ,Genetics ,ENPP1 IRS1 TRIB3 Prospective study ,Proportional hazards model ,business.industry ,Mortality rate ,Confounding ,Genetic Variation ,Middle Aged ,Atherosclerosis ,medicine.disease ,Treatment Outcome ,Diabetes Mellitus, Type 2 ,Italy ,Cardiovascular Diseases ,Female ,Insulin Resistance ,Cardiology and Cardiovascular Medicine ,business ,Signal Transduction - Abstract
Objective : We have previously reported the combined effect of SNPs perturbing insulin signaling ( ENPP1 K121Q, rs1044498; IRS1 G972R, rs1801278; TRIB3 Q84R, rs2295490) on insulin resistance (IR), type 2 diabetes (T2D) and cardiovascular events. We here investigated whether such a combined effect affects also all-cause mortality in a sample of 1851 Whites of European ancestry. Methods : We investigated a first sample of 721 patients, 232 deaths, 3389 person-years (py). Replication was assessed in two samples of patients with T2D: the Gargano Mortality Study (GMS) of 714 patients, 127 deaths, 5426 py and the Joslin Kidney Study (JKS) comprising 416 patients, 214 deaths, 5325 py. Results : In the first sample, individuals carrying 1 or ≥2 risk alleles had 33% ( p = 0.06) and 51% ( p = 0.02) increased risk of mortality, as compared with individuals with no risk alleles. A similar, though not significant, trend was obtained in the two replication samples only for subject carrying ≥ 2 risk alleles. In a pooled analysis, individuals carrying ≥2 risk alleles had higher mortality rate as compared to those carrying 0 risk alleles (HR = 1.34, 95%CI = 1.08–1.67; p = 0.008), and as compared to those carrying only one risk allele (HR = 1.41, 95%CI = 1.13–1.75; p = 0.002). This association was independent from several possible confounders including sex, age, BMI, hypertension and diabetes status. Conclusion : Our data suggest that variants affecting insulin signaling exert a joint effect on all-cause mortality and is consistent with a role of abnormal insulin signaling on mortality risk. more...
- Published
- 2014
- Full Text
- View/download PDF
14. Role of obesity on all-cause mortality in whites with type 2 diabetes from Italy
- Author
-
Claudia Menzaghi, Massimiliano Copetti, R. Di Paola, Andrea Fontana, S. De Cosmo, Fabio Pellegrini, Lucia Salvemini, Antonella Marucci, and Vincenzo Trischitta
- Subjects
Male ,medicine.medical_specialty ,paradoxical effect ,Endocrinology, Diabetes and Metabolism ,Genome-wide association study ,Type 2 diabetes ,Polymorphism, Single Nucleotide ,White People ,Body Mass Index ,Cohort Studies ,Endocrinology ,Cause of Death ,Diabetes mellitus ,Internal medicine ,mortality prediction ,mendelian randomization ,reverse epidemiology ,Internal Medicine ,Humans ,Medicine ,Genetic Predisposition to Disease ,Obesity ,Aged ,Framingham Risk Score ,business.industry ,Mortality rate ,General Medicine ,Middle Aged ,medicine.disease ,Genetic load ,Diabetes Mellitus, Type 2 ,Italy ,Female ,business ,Body mass index ,Genome-Wide Association Study - Abstract
Mortality rate of diabetic patients is twice as much that of non-diabetic individuals. The role of obesity on mortality risk in patients with type 2 diabetes is controversial. Aim of our study was to address the relationship between obesity and all-cause mortality in a real-life set of white patients with type 2 diabetes from central-southern Italy from the Gargano Mortality Study (GMS). In addition, we used genetic data from genome-wide association studies (GWAs)-derived single nucleotide polymorphisms (SNPs) firmly associated with body mass index (BMI), in order to investigate the intrinsic nature of reduced mortality rate we, in fact, observed in obese patients. Study subjects with type 2 diabetes (n = 764) are part of the GMS, which is aimed at unraveling predictors of incident all-cause mortality. Time-to-death analyses were performed by Cox regression. Association between genotype risk score and obesity was tested by logistic regression. Of the 32 SNPs firmly associated with BMI, we investigated those with BMI β value ≥0.10 kg/m(2) and allele frequency ≥10 %. Genotyping was performed by KBioscience (http://www.lgcgenomics.com/). In GMS, obesity predicted a 45 % reduction in all-cause mortality. Individuals with high "obesity genetic load" (i.e., those carrying >9 risk alleles) were 60 % more likely to be obese as compared to individuals with low "obesity genetic load." Most importantly, mortality rate was not different in individuals with high and low "obesity genetic load," thus indicating no role of obesity genes on all-cause mortality and speaking against a cause-effect relationship underlying the association between obesity and reduced mortality rate. more...
- Published
- 2013
- Full Text
- View/download PDF
15. Development and Validation of a Predicting Model of All-Cause Mortality in Patients With Type 2 Diabetes
- Author
-
Massimiliano Copetti, Michela Massa, Olga Lamacchia, Antonio Palena, Rosa Di Paola, Andrea Fontana, Stefania Fariello, Claudia Menzaghi, Anna Rauseo, Rafaella Viti, Eleonora Morini, Antonio Pacilli, Salvatore De Cosmo, Fabio Pellegrini, Mauro Cignarelli, and Vincenzo Trischitta more...
- Subjects
Research design ,Male ,Multivariate statistics ,medicine.medical_specialty ,Cardiovascular and Metabolic Risk ,Endocrinology, Diabetes and Metabolism ,Type 2 diabetes ,Kaplan-Meier Estimate ,Diabetes mellitus ,Internal medicine ,Cause of Death ,Internal Medicine ,medicine ,Humans ,Prospective Studies ,Prospective cohort study ,Cause of death ,Original Research ,Aged ,Advanced and Specialized Nursing ,Proportional hazards model ,business.industry ,Hazard ratio ,Middle Aged ,Models, Theoretical ,medicine.disease ,Diabetes Mellitus, Type 2 ,Female ,business - 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. 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. more...
- Published
- 2013
16. Letter by Menzaghi et al regarding article, 'plasma levels of fatty acid-binding protein 4, retinol-binding protein 4, high-molecular-weight adiponectin, and cardiovascular mortality among men with type 2 diabetes: A 22-year prospective study'
- Author
-
Vincenzo Trischitta, Massimiliano Copetti, and Claudia Menzaghi
- Subjects
Male ,0301 basic medicine ,medicine.medical_specialty ,Single-nucleotide polymorphism ,Type 2 diabetes ,030204 cardiovascular system & hematology ,Fatty Acid-Binding Proteins ,Article ,Fatty acid-binding protein ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Mendelian randomization ,Humans ,Medicine ,Prospective Studies ,Adiponectin ,Retinol-Binding Proteins, Plasma ,Cardiovascular Diseases ,Diabetes Mellitus, Type 2 ,Prospective cohort study ,Retinol binding protein 4 ,biology ,business.industry ,Type 2 Diabetes Mellitus ,medicine.disease ,030104 developmental biology ,Endocrinology ,biology.protein ,Cardiology and Cardiovascular Medicine ,business - Abstract
We read with interest the article on the paradoxical association between high-molecular-weight (HMW) adiponectin and cardiovascular mortality in men with type 2 diabetes mellitus from the HPFS (Health Professional Follow-Up Study).1 These data resemble those we have previously reported2 in men with type 2 diabetes mellitus, comprising a large subset of the same HPSF and additional Italian individuals.2 To address whether such association is sustained by a cause–effect relationship, a genetic risk score (GRS) built on 19 single nucleotide polymorphisms previously associated with adiponectin levels (Mendelian randomization) was used.1 Notably, GRS was not associated with cardiovascular mortality, thus speaking against a causal role of HMW adiponectin on it. This finding is in marked contrast with our recent report, showing a significant association between rs832354 (a single nucleotide polymorphism strongly associated with HMW … more...
- Published
- 2017
17. Role of insulin resistance in kidney dysfunction: insights into the mechanism and epidemiological evidence
- Author
-
Sabrina Prudente, Claudia Menzaghi, S. De Cosmo, and Vincenzo Trischitta
- Subjects
medicine.medical_specialty ,medicine.medical_treatment ,Kidney ,Mice ,Insulin resistance ,Hyperinsulinism ,Internal medicine ,Diabetes mellitus ,medicine ,Hyperinsulinemia ,Animals ,Humans ,Diabetic Nephropathies ,Transplantation ,biology ,Podocytes ,business.industry ,Insulin ,Glomerulosclerosis ,medicine.disease ,Insulin receptor ,insulin sensitizers ,metabolic syndrome ,genetic susceptibility ,insulin signalling ,diabetic kidney disease ,Endocrinology ,Nephrology ,Immunology ,biology.protein ,Kidney Diseases ,Insulin Resistance ,Metabolic syndrome ,business ,Glomerular hyperfiltration - Abstract
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. more...
- Published
- 2012
- Full Text
- View/download PDF
18. Relationship between ADIPOQ gene, circulating high molecular weight adiponectin and albuminuria in individuals with normal kidney function: evidence from a family-based study
- Author
-
Davide Mangiacotti, Grazia Fini, Massimiliano Copetti, S. De Cosmo, Fabio Pellegrini, Vincenzo Trischitta, C. De Bonis, Claudia Menzaghi, and Lucia Salvemini
- Subjects
Adult ,Male ,medicine.medical_specialty ,Adolescent ,Genotype ,mendelian randomisation ,albuminuria ,adipoq gene ,adiponectin hmw ,endocrine system diseases ,Endocrinology, Diabetes and Metabolism ,Adipokine ,Renal function ,Enzyme-Linked Immunosorbent Assay ,Biology ,ADIPOQ Gene ,urologic and male genital diseases ,Polymorphism, Single Nucleotide ,Young Adult ,Insulin resistance ,Nephelometry and Turbidimetry ,Internal medicine ,Diabetes mellitus ,Internal Medicine ,medicine ,Humans ,Protein Isoforms ,Cystatin C ,Aged ,Aged, 80 and over ,Adiponectin ,Confounding ,nutritional and metabolic diseases ,Middle Aged ,medicine.disease ,female genital diseases and pregnancy complications ,Molecular Weight ,Endocrinology ,Creatinine ,Albuminuria ,Female ,medicine.symptom ,hormones, hormone substitutes, and hormone antagonists - Abstract
Insulin resistance is associated with reduced serum adiponectin and increased albuminuria levels. Thus, one would anticipate an inverse relationship between circulating adiponectin and albuminuria. However, several studies have described a 'paradoxical' elevation of serum adiponectin in patients with elevated albuminuria. These findings may have been confounded by the presence of diseases and related treatments known to affect circulating adiponectin and albuminuria. We therefore studied the relationship between circulating adiponectin and albuminuria in the absence of such confounders.To this purpose, the relationship between adiponectin isoforms and albumin:creatinine ratio (ACR) was investigated in a family-based sample of 634 non-diabetic untreated white individuals with normal kidney function. We also investigated whether the two variables share a common genetic background and addressed the specific role of the gene encoding adiponectin on that background by genotyping several ADIPOQ single nucleotide polymorphisms (SNPs).ACR was directly associated with high molecular weight (HMW) adiponectin isoform (p = 0.024). The two variables shared some genetic correlation (ρ(g) = 0.38, p = 0.04). ADIPOQ promoter SNP rs17300539 was associated with HMW adiponectin (p = 4.8 × 10(-5)) and ACR (p =0.0027). The genetic correlation between HMW adiponectin and ACR was no longer significant when SNP rs17300539 was added to the model, thus reinforcing the role of this SNP in determining both traits.Our study shows a positive, independent correlation between HWM adiponectin and ACR. ADIPOQ variability is associated with HMW adiponectin and ACR, and explains some of the common genetic background shared by these traits, thus suggesting that ADIPOQ and HMW adiponectin modulate albuminuria levels. more...
- Published
- 2011
- Full Text
- View/download PDF
19. Erratum. The Adiponectin Paradox for All-Cause and Cardiovascular Mortality. Diabetes 2018;67:12–22
- Author
-
Claudia Menzaghi and Vincenzo Trischitta
- Subjects
0106 biological sciences ,medicine.medical_specialty ,Adiponectin ,business.industry ,Endocrinology, Diabetes and Metabolism ,medicine.disease ,01 natural sciences ,Oxidative Stress ,Diabetes Mellitus, Type 2 ,Cardiovascular Diseases ,Risk Factors ,010608 biotechnology ,Internal medicine ,Diabetes mellitus ,Internal Medicine ,medicine ,Humans ,Endocrine system ,Erratum ,Natriuretic Peptides ,business ,All cause mortality ,Cardiovascular mortality - Abstract
Basic science studies have shown beneficial effects of adiponectin on glucose homeostasis, chronic low-grade inflammation, apoptosis, oxidative stress, and atherosclerotic processes, so this molecule usually has been considered a salutary adipokine. It was therefore quite unexpected that large prospective human studies suggested that adiponectin is simply a marker of glucose homeostasis, with no direct favorable effect on the risk of type 2 diabetes and cardiovascular disease. But even more unforeseen were data addressing the role of adiponectin on the risk of death. In fact, a positive, rather than the expected negative, relationship was reported between adiponectin and mortality rate across many clinical conditions, comprising diabetes. The biology underlying this paradox is unknown. Several explanations have been proposed, including adiponectin resistance and the confounding role of natriuretic peptides. In addition, preliminary genetic evidence speaks in favor of a direct role of adiponectin in increasing the risk of death. However, none of these hypotheses are based on robust data, so further efforts are needed to unravel the elusive role of adiponectin on cardiometabolic health and, most important, its paradoxical association with mortality rate. more...
- Published
- 2018
- Full Text
- View/download PDF
20. Circulating high molecular weight 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
- Author
-
R. Di Paola, Lucia Salvemini, Davide Mangiacotti, C. De Bonis, Grazia Fini, Claudia Menzaghi, Giulia Paroni, Alessandro Doria, and Vincenzo Trischitta
- Subjects
Adult ,Male ,medicine.medical_specialty ,Adolescent ,Genotype ,adiponectin isoforms ,medicine.medical_treatment ,Single-nucleotide polymorphism ,Biology ,ADIPOQ Gene ,Models, Biological ,Polymorphism, Single Nucleotide ,Article ,White People ,Young Adult ,Insulin resistance ,insulin resistance ,Internal medicine ,Internal Medicine ,medicine ,Homeostasis ,Humans ,Insulin ,Protein Isoforms ,adipoq gene ,Aged ,Aged, 80 and over ,Genetics ,Adiponectin ,Middle Aged ,Heritability ,medicine.disease ,Molecular Weight ,Endocrinology ,Italy ,Female ,Metabolic syndrome - Abstract
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.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.All isoforms were highly heritable (h(2) = 0.60-0.80, P = 1.0 x 10(-13)-1.0 x 10(-23)). SNPs rs17300539, rs1501299 and rs6773957 explained a significant proportion of HMW variance (2-9%, P = 1.0 x 10(-3)-1.0 x 10(-5)). In a multiple-SNP model, only rs17300539 and rs1501299 remained associated with HMW adiponectin (P = 3.0 x 10(-4) and 2.0 x 10(-2)). Significant genetic correlations (P = 1.0 x 10(-2)-1.0 x 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.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. more...
- Published
- 2010
- Full Text
- View/download PDF
21. Evidence of a causal relationship between high serum adiponectin levels and increased cardiovascular mortality rate in patients with type 2 diabetes
- Author
-
Lorena Ortega Moreno, Massimiliano Copetti, Andrea Fontana, Lucia Salvemini, Claudia Menzaghi, Vincenzo Trischitta, and Concetta De Bonis
- Subjects
Male ,Time Factors ,medicine.medical_treatment ,Endocrinology, Diabetes and Metabolism ,Type 2 diabetes ,030204 cardiovascular system & hematology ,0302 clinical medicine ,Endocrinology ,Gene Frequency ,Risk Factors ,Prospective Studies ,Prospective cohort study ,Original Investigation ,Single Nucleotide ,Middle Aged ,Up-Regulation ,Diabetes and Metabolism ,Italy ,Cardiovascular Diseases ,Female ,Adiponectin ,Cardiology and Cardiovascular Medicine ,Type 2 ,medicine.medical_specialty ,030209 endocrinology & metabolism ,Single-nucleotide polymorphism ,Polymorphism, Single Nucleotide ,Risk Assessment ,03 medical and health sciences ,Insulin resistance ,ADIPOQ ,Mendelian randomization ,Mortality ,Aged ,Biomarkers ,Diabetes Mellitus, Type 2 ,Genetic Association Studies ,Humans ,Mendelian Randomization Analysis ,Internal medicine ,Diabetes mellitus ,medicine ,Diabetes Mellitus ,Polymorphism ,business.industry ,Insulin ,medicine.disease ,business - Abstract
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. more...
- Published
- 2016
22. The paradoxical association of adiponectin with mortality rate in patients with type 2 diabetes: evidence of synergism with kidney function
- Author
-
Claudia Menzaghi, Concetta De Bonis, Lorena Ortega Moreno, Mauro Cignarelli, Olga Lamacchia, Vincenzo Trischitta, Lucia Salvemini, and Salvatore De Cosmo
- Subjects
Male ,medicine.medical_specialty ,Waist ,Adipokine ,Renal function ,030209 endocrinology & metabolism ,Adipokines ,Mortality ,Renal dysfunction ,Type 2 diabetes ,Adiponectin ,Diabetes Mellitus, Type 2 ,Diabetic Nephropathies ,Disease Progression ,Female ,Glomerular Filtration Rate ,Humans ,Italy ,Kidney ,Middle Aged ,Risk Factors ,Survival Rate ,Cardiology and Cardiovascular Medicine ,030204 cardiovascular system & hematology ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Medicine ,In patient ,business.industry ,Mortality rate ,nutritional and metabolic diseases ,medicine.disease ,Endocrinology ,medicine.anatomical_structure ,business - Abstract
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 2 ; 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. more...
- Published
- 2015
23. Strong evidence of sexual dimorphic effect of adiposity excess on insulin sensitivity
- Author
-
Rosa Di Paola, Lucia Frittitta, Claudia Menzaghi, Lucia Salvemini, Vincenzo Trischitta, Roberto Baratta, Federica Vinciguerra, Antonella Marucci, M. Copetti, and Eleonora Morini
- Subjects
Male ,medicine.medical_specialty ,Waist ,BMI ,Insulin resistance ,Sexual dimorphism ,Abdominal Fat ,Adiponectin ,Aged ,Body Mass Index ,Cohort Studies ,Female ,Humans ,Italy ,Middle Aged ,Overweight ,Resistin ,Sex Characteristics ,Waist Circumference ,Adiposity ,Insulin Resistance ,Internal Medicine ,Endocrinology, Diabetes and Metabolism ,Endocrinology ,Context (language use) ,Internal medicine ,Diabetes mellitus ,Medicine ,business.industry ,nutritional and metabolic diseases ,General Medicine ,medicine.disease ,Diabetes and Metabolism ,medicine.symptom ,business ,Body mass index - Abstract
Our aims were to investigate in several large samples, with a wide range of adiposity, whether: (1) the effect of BMI on insulin sensitivity is different between sexes; (2) also waist circumference plays a sex-specific role on insulin sensitivity; and (3) serum adiponectin and resistin are mediators of such sex-dimorphic effect. Samples used were: Gargano study 1 (GS1), GS2 and Catania study (CS) comprising 3274 individuals. Adiponectin and resistin were measured by ELISA. Associations between variables were tested by linear models. In all samples, relationship between BMI and HOMAIR was steeper in males than in females (BMI-by-sex interaction p = 0.04–0.0007). No interaction was observed on serum adiponectin and resistin (p = 0.40–059), which are therefore unlikely to mediate the sex-dimorphic effect of BMI on insulin resistance. Relationship between waist circumference and HOMAIR was similar between sexes in GS1 and GS2 but not in CS (waist-by-sex interaction p = 0.01), comprising much heavier individuals. This suggests that a sex-dimorphic effect of abdominal adiposity on insulin resistance is observable only in the context of high BMI. Our findings represent a proof of concept that BMI and insulin sensitivity are associated in a sex-specific manner. This may explain why females are protected from diabetes and cardiovascular disease, compared to males of similar BMI. more...
- Published
- 2015
24. Heritability of Serum Resistin and Its Genetic Correlation with Insulin Resistance-Related Features in Nondiabetic Caucasians
- Author
-
Claudia Menzaghi, Lucia Salvemini, Ryan W. Thompson, Angelo Coco, Alessandro Doria, Salvatore De Cosmo, and Vincenzo Trischitta
- Subjects
Adult ,Male ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Clinical Biochemistry ,Context (language use) ,Biology ,Biochemistry ,White People ,Body Mass Index ,Endocrinology ,Insulin resistance ,Internal medicine ,medicine ,Humans ,Resistin ,Pancreatic hormone ,Metabolic Syndrome ,Polymorphism, Genetic ,medicine.diagnostic_test ,Insulin ,Biochemistry (medical) ,medicine.disease ,Italy ,Female ,Insulin Resistance ,Metabolic syndrome ,Lipid profile ,Body mass index - Abstract
Context: Serum levels of resistin are believed to modulate insulin resistance in humans. Objective: The aim of this study was to investigate whether serum resistin levels are genetically controlled and whether this control is shared with other insulin resistance traits. Design and Methods: The study cohort included 264 nondiabetic probands, Caucasian from Italy, and their 473 adult family members. Phenotypic characterization included anthropometric variables, blood pressure, fasting glucose and insulin, lipid profile, and resistin levels. Genotypes were determined at position g.−420C→G (rs1862513), IVS2+181G→A (rs3745367), and GAT(n) polymorphisms of the resistin (RETN) gene. Results: In the 264 unrelated probands, resistin levels were significantly (P < 0.01) correlated with adiposity, blood pressure, C-reactive protein, and the metabolic syndrome score. In a variance component analysis of the 264 probands and their 473 relatives, about 70% of the observed variation of serum resistin levels was heritable (P < 0.0001). A small, but significant (P = 0.004) proportion of this variance was explained by the G→A variation at position IVS2+181 of the RETN gene. Significant genetic correlations (P < 0.05) were observed between resistin and body mass index (ρg = 0.30), waist circumference (ρg = 0.32), the insulin resistance index HOMAIR (ρg = 0.28), and the metabolic syndrome score (ρg = 0.35). Conclusions: These data indicate that serum resistin is highly heritable and has some common genetic background with traits related to insulin resistance, reinforcing the hypothesis that this adipokine may play a pathogenic role in insulin resistance-related abnormalities, including type 2 diabetes and cardiovascular disease. more...
- Published
- 2006
- Full Text
- View/download PDF
25. Association between Resistin Levels and All-Cause and Cardiovascular Mortality: A New Study and a Systematic Review and Meta-Analysis
- Author
-
Claudia Menzaghi, Massimiliano Copetti, Francesca Mallamaci, Vincenzo Trischitta, Sara Spadaro, Belinda Spoto, Fabio Pellegrini, Lucia Salvemini, Lucia Frittitta, Andrea Fontana, and Patrizia Pizzini
- Subjects
Male ,medicine.medical_specialty ,endocrine system diseases ,lcsh:Medicine ,Context (language use) ,Type 2 diabetes ,Coronary Artery Disease ,Bioinformatics ,Coronary artery disease ,Diabetes mellitus ,Internal medicine ,medicine ,Humans ,Resistin ,Prospective cohort study ,lcsh:Science ,biomarkers ,epidemiology ,cytokines ,Aged ,Multidisciplinary ,business.industry ,Mortality rate ,lcsh:R ,nutritional and metabolic diseases ,respiratory system ,Middle Aged ,medicine.disease ,Diabetes Mellitus, Type 2 ,Meta-analysis ,Cardiology ,Female ,lcsh:Q ,business ,hormones, hormone substitutes, and hormone antagonists ,Research Article - Abstract
Context Studies concerning the association between circulating resistin and mortality risk have reported, so far, conflicting results. Objective To investigate the association between resistin and both all-cause and cardiovascular (CV) mortality risk by 1) analyzing data from the Gargano Heart Study (GHS) prospective design (n=359 patients; 81 and 58 all-cause and CV deaths, respectively); 2) performing meta-analyses of all published studies addressing the above mentioned associations. Data Source and Study Selection MEDLINE and Web of Science search of studies reporting hazard ratios (HR) of circulating resistin for all-cause or CV mortality. Data Extraction Performed independently by two investigators, using a standardized data extraction sheet. Data Synthesis In GHS, adjusted HRs per one standard deviation (SD) increment in resistin concentration were 1.28 (95% CI: 1.07-1.54) and 1.32 (95% CI: 1.06-1.64) for all-cause and CV mortality, respectively. The meta-analyses included 7 studies (n=4016; 961 events) for all-cause mortality and 6 studies (n=4,187: 412 events) for CV mortality. Pooled HRs per one SD increment in resistin levels were 1.21 (95% CI: 1.03-1.42, Q-test p for heterogeneity more...
- Published
- 2015
26. Serum resistin and glomerular filtration rate in patients with type 2 diabetes
- Author
-
Concetta De Bonis, Alessandro Doria, Massimiliano Copetti, Lorena Ortega Moreno, Lucia Salvemini, Christine Mendonca, Vincenzo Trischitta, Salvatore De Cosmo, and Claudia Menzaghi
- Subjects
medicine.medical_specialty ,education.field_of_study ,Multidisciplinary ,business.industry ,Insulin ,medicine.medical_treatment ,lcsh:R ,Population ,lcsh:Medicine ,Adipokine ,Renal function ,Odds ratio ,Type 2 diabetes ,medicine.disease ,Endocrinology ,Diabetes mellitus ,Internal medicine ,medicine ,lcsh:Q ,Resistin ,lcsh:Science ,business ,education ,Research Article - Abstract
Background High serum levels of the pro-inflammatory adipokine resistin have been associated with decreased renal function in the general population. The goal of this study was to investigate whether such association is also present among diabetic subjects, who are at increased risk of renal function loss. Methods The cross-sectional association between serum resistin levels and estimated glomerular filtration rate (eGFR) was investigated in 1,560 type 2 diabetic (T2D) patients of European ancestry comprised in two different cohorts: 762 patients from San Giovanni Rotondo (SGR; Italy) and 798 patients from Boston (US). Results Serum resistin was inversely associated with eGFR in SGR [β (SE) for one SD of resistin increment = -1.01 (0.70) ml/min/1.73m2, p = 0.019] and in Boston [β (SE) = -5.31 (0.74) ml/min/1.73m2, p < 0.001] samples, as well as in the two studies combined [β (SE) = -3.42 (0.52) ml/min/1.73m2, p < 0.001]. The association was unaffected by adjustment for smoking habits, BMI, waist circumference, diabetes duration, HbA1c, insulin treatment, hypertension and lipid-lowering therapy: β (SE) for one SD of resistin increment = -1.07 (0.70), p = 0.02; -5.50 (0.88), p < 0.001; and -2.81 (0.55) ml/min/1.73m2, p < .001, in SGR, Boston and the two studies combined, respectively. The association was significantly stronger in men than in women (p for resistin-by-gender interaction = 0.003). For each resistin SD increment, the odds of having eGFR < 0 ml/min/1.73m2 increased by 22% (OR = 1.22; 95% CI 1.02–1.44; p = 0.025) in SGR sample, 69% (OR = 1.69; 95% CI 1.38–2.07; p < 0.001) in Boston sample, and 47% (OR = 1.47; 95% CI 1.29–1.68; p < 0.001) in the two studies considered together. Similar associations were observed in the adjusted model: OR 95% CI for each SD resistin increment being 1.23 (1.03–1.46), p = 0.021; 1.52 (1.20–1.92), p < 0.001; 1.33 (1.16–1.53), p < 0.001, in SGR, Boston and the two studies combined, respectively. Conclusions This is the first report of an association between high serum resistin and low eGFR in patients with T2D of European ancestry. more...
- Published
- 2015
27. Serum adiponectin and glomerular filtration rate in patients with type 2 diabetes
- Author
-
Claudia Menzaghi, Lorena Ortega Moreno, Olga Lamacchia, Massimiliano Copetti, Mauro Cignarelli, Lucia Salvemini, Salvatore De Cosmo, Vincenzo Trischitta, and Concetta De Bonis
- Subjects
Male ,Genetics and Molecular Biology (all) ,medicine.medical_specialty ,Adiponectin ,Aged ,Diabetes Mellitus, Type 2 ,Diabetic Nephropathies ,Female ,Humans ,Italy ,Middle Aged ,Risk Factors ,Glomerular Filtration Rate ,Biochemistry, Genetics and Molecular Biology (all) ,Agricultural and Biological Sciences (all) ,Renal function ,lcsh:Medicine ,Type 2 diabetes ,Biochemistry ,chemistry.chemical_compound ,Internal medicine ,Diabetes mellitus ,medicine ,Diabetes Mellitus ,lcsh:Science ,Creatinine ,Multidisciplinary ,business.industry ,lcsh:R ,Odds ratio ,medicine.disease ,Endocrinology ,chemistry ,lcsh:Q ,Glycated hemoglobin ,business ,Type 2 ,Kidney disease ,Research Article - Abstract
High serum adiponectin has been increased in several conditions of kidney disease. Only sparse and conflicting results have been reported in patients with type 2 diabetes (T2D), a subgroup of individuals who are at high risk for renal dysfunction. The aim of this study was to fill up this gap of knowledge by investigating such association in a large sample of Italian diabetic patients. The association between serum adiponectin levels and estimated glomerular filtration rate (eGFR by Chronic Kidney Disease-Epidemiology Collaboration CKD-EPI equation) was investigated in 1,243 patients with T2D from two cross-sectional Italian studies: 878 from San Giovanni Rotondo (SGR) and 365 from Foggia (FG). Serum adiponectin was inversely associated with eGFR in SGR [β (standard error, SE) for 1 standard deviation (SD) of adiponectin = -3.26 (0.64)] and in FG [β(SE)=-5.70(1.28)] sample, as well as in the two studies combined [β(SE)=-3.99(0.59)];(p more...
- Published
- 2015
28. COMMENT: Genetic Variability in Insulin Action Inhibitor Ikkβ (IKBKB) Does Not Play a Major Role in the Development of Type 2 Diabetes
- Author
-
Xiaowei Ma, Steven E. Shoelson, Alessandro Doria, Nattachet Plengvidhya, James H. Warram, and Claudia Menzaghi
- Subjects
medicine.medical_specialty ,Genetic Linkage ,Endocrinology, Diabetes and Metabolism ,IKBKB Gene ,Clinical Biochemistry ,5' flanking region ,Locus (genetics) ,Protein Serine-Threonine Kinases ,Biology ,Biochemistry ,Exon ,Endocrinology ,Gene Frequency ,Reference Values ,Genetic linkage ,Internal medicine ,Genetic variation ,medicine ,Humans ,Genetic Testing ,Genetic variability ,Age of Onset ,Allele frequency ,Genes, Dominant ,Genetics ,Polymorphism, Genetic ,Biochemistry (medical) ,Genetic Variation ,I-kappa B Kinase ,Diabetes Mellitus, Type 2 - Abstract
Recent evidence indicates that IB kinase (Ikk) may be a mediator of acquired forms of insulin-resistance. In this study, we examined whether genetic variability at the Ikk locus (IKBKB) contributes to the development of genetic forms of early-onset type 2 diabetes transmitted with an autosomal dominant mode of inheritance. Linkage with four markers flanking the IKBKB gene was evaluated in 32 multigenerational families. Included in the study were 233 diabetic (mean age at Dx 37 18) and 152 nondiabetic subjects. The overall LOD scores were negative (54.9 and 46.2 on the centromeric and telomeric sides, respectively) indicating that variability in IKBKB was not a major determinant of diabetes in these families. Positive values, however, were observed for selected pedigrees. All 17 families for which linkage with the IKBKB locus could not be excluded were screened for sequence differences in the 22 exons and 1.6 kb of the 5 flanking region by dideoxyfingerprinting or direct sequencing. Polymorphisms were identified in the 5 flanking region (1775del/insC and 1547T > A), exon 11 (c.1083A > G, L361L) and in intron 12 (IVS1214t > a). However, no mutations segregating with diabetes could be found in these families. Furthermore, all four polymorphisms had similar allele frequencies in the 32 family probands, 171 individuals with common, later-onset type 2 diabetes, and 182 nondiabetic controls. We conclude that sequence differences in the IKBKB gene do not play a major role in either early-onset, autosomal dominant type 2 diabetes, or common forms with a later-onset. (J Clin Endocrinol Metab 87: 1894 –1897, 2002) more...
- Published
- 2002
- Full Text
- View/download PDF
29. Low prevalence of HNF1A mutations after molecular screening of multiple MODY genes in 58 Italian families recruited in the pediatric or adult diabetes clinic from a single Italian hospital
- Author
-
Maurizio, Delvecchio, Ornella, Ludovico, Claudia, Menzaghi, Rosa, Di Paola, Leopoldo, Zelante, Antonella, Marucci, Valeria, Grasso, Vincenzo, Trischitta, Massimo, Carella, Fabrizio, Barbetti, Francesco, Gallo, Maria Susanna, Coccioli, Clara, Zecchino, Maria Felicia, Faienza, Giuliana, Cardinale, Adriana, Franzese, Enza, Mozzillo, Dario, Iafusco, Angela, Zanfardino, Delvecchio, M, Ludovico, O, Menzaghi, C, Di Paola, R, Zelante, L, Marucci, A, Grasso, V, Trischitta, V, Carella, M, Barbetti, F, Gallo, F, Coccioli, M, Zecchino, C, Faienza, Mf, Cardinale, G, Franzese, A, Mozzillo, E, Iafusco, Dario, Zanfardino, A., Delvecchio, M., Ludovico, O., Menzaghi, C., Di Paola, R., Zelante, L., Marucci, A., Grasso, V., Trischitta, V., Carella, M., Barbetti, F., Gallo, F., Coccioli, Ms., Zecchino, C., Faienza, Mf., Cardinale, G., Franzese, A., Mozzillo, E., and Iafusco, D. more...
- Subjects
Adult ,Pediatrics ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Basic Helix-Loop-Helix Transcription Factor ,DNA Mutational Analysis ,Polymorphism, Single Nucleotide ,Settore MED/13 - Endocrinologia ,DNA Mutational Analysi ,Hospital ,Gene Frequency ,Polymorphism (computer science) ,Diabetes mellitus ,Glucokinase ,Internal Medicine ,medicine ,Basic Helix-Loop-Helix Transcription Factors ,Prevalence ,Humans ,Hepatocyte Nuclear Factor 1-alpha ,Child ,Gene ,Allele frequency ,Hepatocyte Nuclear Factor 1-beta ,Advanced and Specialized Nursing ,Homeodomain Proteins ,Type 1 diabetes ,Molecular screening ,business.industry ,Medicine (all) ,Homeodomain Protein ,medicine.disease ,Hospitals ,HNF1A ,Pedigree ,Diabetes Mellitus, Type 2 ,Hepatocyte Nuclear Factor 4 ,Italy ,Trans-Activator ,Mutation ,Trans-Activators ,business ,Human - Abstract
Maturity-onset diabetes of the young (MODY; MIM# 606391) is a genetically and clinically heterogeneous form of diabetes, accounting for 1–2% of all diabetes cases (1). MODY is characterized by mild hyperglycemia or overt diabetes usually detected in three consecutive generations, with onset before the age of 25 years and absence of type 1 diabetes autoantibodies. Among the thirteen MODY genes identified, two subtypes, GCK -MODY and HNF1A -MODY, account for most of cases (1). The prevalence of GCK -MODY has been reported higher in Southern Europe (2), while HNF1A -MODY is the most common MODY subtype in Northern Europe (3). This difference might be attributable to the clinical setting in which genetic screening is performed, especially when pediatric and adult diabetes clinics are distinct entities. We addressed this issue by investigating MODY patients identified in the pediatric or in the adult diabetes clinics of the same research-based … more...
- Published
- 2014
30. Circulating adiponectin and cardiovascular mortality in patients with type 2 diabetes mellitus: evidence of sexual dimorphism
- Author
-
Tao Huang, Yanping Li, Massimiliano Copetti, Lu Qi, Grazia Fini, Giuseppe Palladino, Yan Zheng, Concetta De Bonis, Simonetta Bacci, Lucia Salvemini, Claudia Menzaghi, Frank B. Hu, Min Xu, and Vincenzo Trischitta more...
- Subjects
Adult ,Male ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Population ,Adipokine ,Type 2 diabetes ,Adipokines ,Risk Factors ,Diabetes mellitus ,Internal medicine ,Humans ,Medicine ,Prospective Studies ,education ,Prospective cohort study ,Original Investigation ,Aged ,Aged, 80 and over ,Sex Characteristics ,education.field_of_study ,Adiponectin ,business.industry ,Paradoxical effect ,Incidence ,Hazard ratio ,Type 2 Diabetes Mellitus ,Middle Aged ,medicine.disease ,3. Good health ,Sex-linked genes ,Diabetes Mellitus, Type 2 ,Cardiovascular Diseases ,Female ,Cardiology and Cardiovascular Medicine ,business ,Follow-Up Studies - Abstract
Background The pathogenesis of cardiovascular (CV) mortality, whose rate is increased in type 2 diabetes, is poorly understood. While high serum adiponectin is associated with increased CV mortality in the general population, no data are available in type 2 diabetes. We here investigated whether this counterintuitive association was observable also in diabetic patients and whether it was sex-specific. Methods Three prospective cohorts were analyzed: 1) Gargano Heart Study (GHS; 359 patients, 58 events/1,934 person-years; py); 2) Health Professional Follow-up Study (HPFS; 833 men, 146 events/10,024 py); 3) Nurses’ Health Study (NHS; 902 women, 144 events/15,074 py). Results In GHS serum adiponectin predicted CV mortality in men (hazard ratio, HR, and 95% CI per standard deviation, SD, increment = 1.54, 1.19-2.01), but not women (HR = 0.98, 0.48-2.01). Circulating adiponectin predicted CV mortality in men from HPFS (HR = 1.44, 1.21-1.72), but not in women from NHS (HR = 1.08, 0.86-1.35), used as replication samples. In a pooled analysis, HRs were 1.47 (1.27-1.70) in 1,075 men and 1.07 (0.86-1.33) in 1,019 women (p for HRs heterogeneity across sexes = 0.018). Conclusions This is the first report showing that high circulating adiponectin predicts increased CV mortality in men, but not in women with type 2 diabetes. Further studies are necessary to unravel the mechanisms through which adiponectin influences CV mortality in a sex-specific manner. Electronic supplementary material The online version of this article (doi:10.1186/s12933-014-0130-y) contains supplementary material, which is available to authorized users. more...
- Published
- 2014
- Full Text
- View/download PDF
31. Clinical heterogeneity of abnormal glucose homeostasis associated with the HNF4A R311H mutation
- Author
-
Rosa Di Paola, Michele Sacco, Vincenzo Trischitta, Claudia Menzaghi, Davide Mangiacotti, and Maurizio Delvecchio
- Subjects
Blood Glucose ,Proband ,endocrine system ,medicine.medical_specialty ,endocrine system diseases ,Type 2 diabetes ,Impaired glucose tolerance ,Diabetes mellitus ,Monogenic diabetes ,Internal medicine ,Adults ,Homeostasis ,Humans ,Medicine ,HNF4A-MODY ,Child ,Letter to the Editor ,Children ,Gestational diabetes ,Genetic testing ,medicine.diagnostic_test ,business.industry ,Diabetes Mellitus, Type 2 ,Female ,Hepatocyte Nuclear Factor 4 ,Exons ,Mutation ,medicine.disease ,Abnormal glucose homeostasis ,Endocrinology ,Mutation (genetic algorithm) ,business ,Type 2 - Abstract
We describe a diabetic child and her relatives carrying the HNF4A R311H mutation. The proband was diagnosed with insulin-dependent diabetes when 9.1 year-old. Three weeks later, a complete remission occurred. She underwent genetic testing showing the HNF4A-R311H mutation, which was found also in the brother (with impaired glucose tolerance), the mother (with gestational diabetes), and the maternal uncle (with type 2 diabetes). This case suggests that the HNF4A R311H mutation may play a role on hyperglycaemia since childhood and may be associated with clinical heterogeneity of abnormal glucose homeostasis. Transient diabetes might warrant the screening for MODY when indicated. more...
- Published
- 2014
- Full Text
- View/download PDF
32. Genetics of serum resistin: a paradigm of population-specific regulation?
- Author
-
Vincenzo Trischitta and Claudia Menzaghi
- Subjects
medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Adipokine ,Adipose tissue ,Type 2 diabetes ,Biology ,Polymorphism, Single Nucleotide ,White People ,Insulin Antagonists ,Insulin resistance ,insulin resistance ,Diabetes mellitus ,Internal medicine ,Internal Medicine ,medicine ,Humans ,Resistin ,Obesity ,population-specific effect ,resistin circulating levels ,retn ,Allele ,3' Untranslated Regions ,Triglycerides ,Genetics ,Insulin ,Cholesterol, HDL ,Chromosome Mapping ,medicine.disease ,Endocrinology ,Adipose Tissue ,Diabetes Mellitus, Type 2 ,Gene Expression Regulation ,5' Untranslated Regions - Abstract
Keywords Insulinresistance.Population-specificeffect.Resistincirculatinglevels.RETNAdipocytes release a number of peptide hormones, collec-tively known as adipokines, which are essential inregulation of intermediate metabolism, and which maycontribute to the pathogenesis of insulin resistance andrelated disorders [1].Among these is resistin, a 12.5 kDa cysteine-rich proteinthat is secreted also by macrophages [2–4]. Several piecesof evidence suggest that this molecule antagonises insulinaction and fosters inflammation [2–4]. In humans, mostcross-sectional studies have reported that elevated resistinlevels are associated with insulin resistance [5–7] and type2 diabetes [8]. In most [9–11], although not all [12],prospective studies, resistin turned out to be a predictor oftype 2 diabetes and cardiovascular disease. Taken together,these findings highlight the role of serum resistin as anemerging pathogenic factor and a potential therapeutictarget for insulin resistance-related disorders. This latterpossibility is reinforced by the observation that resistinexpression in human adipose tissue is inhibited bythiazolidinediones [13], insulin-sensitising molecules thatare used as oral hypoglycaemic agents in the treatment ofpatients with type 2 diabetes.The mechanisms regulating resistin expression, secretionand circulating levels are still poorly understood. Recentdata clearly indicate that resistin serum levels are undergenetic control [6, 14]. Several single-nucleotide poly-morphisms (SNPs) in the RETN gene coding for resistin,have been associated with serum resistin levels and insulinresistance traits [6 ,8 14–18].Among others, rs1862513 at position g.−420 in theRETN 5′ flanking region has attracted much attention. ThisSNP has been associated with high resistin levels [8, 16],insulin resistance [ 17], obesity [15 , 18] and type 2diabetes [8, 19]. A recent meta-analysis, including morethan 3,500 individuals, has shown that those homozygousfor the G allele at rs1862513 have a 30% increase in theodds of being affected by type 2 diabetes [8]. Along thesame lines, the G allele was predictive of glycaemicdeterioration in a Chinese population followed for 5 years[20]. These associations are supported by functional datademonstrating a stronger activation of the RETN promoterby Sp1 and Sp3 transcription factors in the presence of theG allele [8]. In agreement with these data, the same allelehas been reported to be associated with higher abdominal-fat resistin mRNA levels [21]. Thus, so far, so good forSNP rs1862513.Recently, a fine-mapping analysis of the RETN gene hasbeen carried out in a sample of more than 2,500 individualsof European ancestry [14]. The authors found that alleles at more...
- Published
- 2009
- Full Text
- View/download PDF
33. Graves’ Immunoglobulins Activate Phospholipase A2by Recognizing Specific Epitopes on Thyrotropin Receptor1
- Author
-
Leonard D. Kohn, Rosa Di Paola, Daniela Corda, Vito De Filippis, Kazuo Tahara, Alfredo Di Cerbo, and Claudia Menzaghi
- Subjects
endocrine system ,medicine.medical_specialty ,endocrine system diseases ,Endocrinology, Diabetes and Metabolism ,Chinese hamster ovary cell ,Graves' disease ,Biochemistry (medical) ,Clinical Biochemistry ,Biology ,medicine.disease ,Biochemistry ,Epitope ,Thyrotropin receptor ,Adenylyl cyclase ,chemistry.chemical_compound ,Endocrinology ,Phospholipase A2 ,chemistry ,Internal medicine ,medicine ,biology.protein ,Thyroid Stimulating Immunoglobulin ,Receptor - Abstract
Thyroid-stimulating IgG from Graves’ patients bind to the TSH receptor and activate both adenylyl cyclase (AC) and phospholipase A2 (PLA2) in FRTL5 thyroid cells. Both activities have been associated with increased thyroid cell growth and function; evidence exists that subpopulations of Graves’ IgG can stimulate either AC or PLA2 cascades and that the activation of both is associated with the largest goiters in patients. Studies using chimeras of the human TSHR receptor (hTSHR) and the LH-CG receptor show that most patients with Graves’ disease have cAMP-stimulating IgG that require epitopes on the N-terminal portion of the TSHR extracellular domain; epitopes associated with PLA2 activation are not clear. To address this question we used stably transfected Chinese hamster ovary (CHO) cells containing the wild-type hTSHR and the hTSHR chimera with residues 8–165 (Mc1+2) substituted by equivalent residues of the LH-CG receptor. PLA2 activity, measured as arachidonic acid (AA) release, was determined in 32 p... more...
- Published
- 1999
- Full Text
- View/download PDF
34. Association Between an R338L Mutation in the Thyroid Hormone Receptor-β Gene and Thyrotoxic Features in Two Unrelated Kindreds with Resistance to Thyroid Hormone
- Author
-
A. Balsamo, Claudia Menzaghi, Gabriella Gallone, Rosa Di Paola, Vito De Filippis, Claudio Rossi, Vittorio Tassi, and Domenico Fonzo
- Subjects
Male ,Thyroid Hormone Resistance Syndrome ,medicine.medical_specialty ,Adolescent ,Endocrinology, Diabetes and Metabolism ,Restriction Mapping ,Thyrotropin ,Biology ,Gene mutation ,Arginine ,Hyperthyroidism ,Thyroid hormone receptor beta ,Endocrinology ,Leucine ,Internal medicine ,medicine ,Humans ,Point Mutation ,Alleles ,Polymorphism, Single-Stranded Conformational ,Aged ,Heat intolerance ,Receptors, Thyroid Hormone ,Triiodothyronine ,Thyroid hormone receptor ,Point mutation ,Thyroid ,Middle Aged ,Pedigree ,Thyroxine ,Phenotype ,Thyrotoxicosis ,medicine.anatomical_structure ,Amino Acid Substitution ,Haplotypes ,Italy ,Female ,medicine.symptom ,Follow-Up Studies ,Hormone - Abstract
Resistance to thyroid hormone (RTH) is a rare syndrome characterized by reduced sensitivity to thyroid hormone due to thyroid hormone receptor-beta (TRbeta) gene mutations or deletion. RTH has been classified on the basis of clinical features into generalized (GRTH) and pituitary (PRTH) resistance. There is, however, overlap of clinical and biochemical findings in patients with the two forms of resistance, and similar TRbeta gene mutations have been identified in both. The 2 subtypes of RTH, therefore, are considered to be different manifestations of a single genetic entity. We report a mutation of the TRbeta gene, an arginine to leucine substitution at codon 338 (R338L), in 2 unrelated RTH kindreds of northern Italian ancestry. The same mutation was already reported in a single unrelated kindred affected by PRTH. Five individuals, 3 in the first and 2 in the second family, were clinically evaluated and followed for 3-11 years. During the long-term follow-up, the patients manifested symptoms and signs of hyperthyroidism including palpitations, fine tremors, heat intolerance, increased sweating, increased deep tendon reflexes, moist and warm skin, cardiac rhythm abnormalities, reduced body weight, and reduced bone mineral density. The clinical features of these kindreds are consistent with a predominant PRTH phenotype. more...
- Published
- 1999
- Full Text
- View/download PDF
35. Cyclooxygenase-Dependent Thyroid Cell Proliferation Induced by Immunoglobulins from Patients with Graves’ Disease1
- Author
-
Claudia Menzaghi, Daniela Corda, Vito De Filippis, Alfredo Di Cerbo, and Rosa Di Paola
- Subjects
endocrine system ,medicine.medical_specialty ,endocrine system diseases ,Phospholipase C ,biology ,Cell growth ,Endocrinology, Diabetes and Metabolism ,Graves' disease ,Biochemistry (medical) ,Clinical Biochemistry ,medicine.disease ,Biochemistry ,Adenylyl cyclase ,chemistry.chemical_compound ,Endocrinology ,Phospholipase A2 ,chemistry ,Internal medicine ,biology.protein ,medicine ,Arachidonic acid ,Cyclooxygenase ,Receptor - Abstract
IgG associated with Graves' disease bind to the TSH receptor and alter thyroid growth and function, mainly through the stimulation of adenylyl cyclase. In addition, Graves' IgG are able to interact with the phospholipase C (PLC)/Ca2+ and phospholipase A2 (PLA2)/arachidonic acid (AA) cascades. The activation of this latter pathway leads to thyroid cell growth in vitro. The elucidation of additional mechanisms of action of Graves' IgG has made possible the identification of four subgroups of patients, characterized by IgG with different biochemical activities (extent of cAMP and AA release stimulation in in vitro assays). On the basis of these results, a novel therapeutic approach could be proposed based on the inhibition of PLA2 and AA metabolism. To test this hypothesis, the ability of IgG from 56 Graves' patients to stimulate [3H]thymidine incorporation in FRTL5 thyroid cells in the presence and absence of the cyclooxygenase inhibitor indomethacin (2.5 x 10(-6) mol/L) was measured. A significant reduction in [3H]thymidine incorporation was found (33% inhibition; P < 0.0001) upon pretreatment with indomethacin, suggesting that in vitro thyroid cell growth is regulated by cyclooxygenase metabolites. This strengthens the argument for involvement of the PLA2/AA cascade in the pathophysiology of Graves' disease and the proposal for novel selective pharmacological treatments of these patients. more...
- Published
- 1997
- Full Text
- View/download PDF
36. GALNT2 expression is reduced in patients with Type 2 diabetes: possible role of hyperglycemia
- Author
-
Rosa Di Paola, Grazia Fini, Antonella Marucci, G. Lotti, Lazzaro Di Mauro, Davide Mangiacotti, Sabrina Prudente, Claudia Menzaghi, and Vincenzo Trischitta
- Subjects
Blood Glucose ,Male ,medicine.medical_treatment ,Type 2 diabetes ,chemistry.chemical_compound ,Endocrinology ,Molecular Cell Biology ,Whole blood ,Multidisciplinary ,biology ,Middle Aged ,N-Acetylgalactosaminyltransferases ,Medicine ,Female ,Research Article ,Signal Transduction ,Adult ,medicine.medical_specialty ,Clinical Research Design ,Science ,Signaling Pathways ,Gene Expression Regulation, Enzymologic ,Insulin resistance ,Internal medicine ,Diabetes mellitus ,Cell Line, Tumor ,medicine ,Genetics ,Humans ,Obesity ,RNA, Messenger ,Biology ,Genetic Association Studies ,Diabetic Endocrinology ,business.industry ,Insulin ,Human Genetics ,Diabetes Mellitus Type 2 ,medicine.disease ,Insulin receptor ,L-Glucose ,chemistry ,Diabetes Mellitus, Type 2 ,Hyperglycemia ,Case-Control Studies ,Metabolic Disorders ,biology.protein ,Gene Function ,business ,Insulin-Dependent Signal Transduction - Abstract
Impaired insulin action plays a major role in the pathogenesis of type 2 diabetes, a chronic metabolic disorder which imposes a tremendous burden to morbidity and mortality worldwide. Unraveling the molecular mechanisms underlying insulin resistance would improve setting up preventive and treatment strategies of type 2 diabetes. Down-regulation of GALNT2, an UDPN-acetyl-alpha-D-galactosamine polypeptideN-acetylgalactosaminyltransferase-2 (ppGalNAc-T2), causes impaired insulin signaling and action in cultured human liver cells. In addition, GALNT2 mRNA levels are down-regulated in liver of spontaneously insulin resistant, diabetic Goto-Kakizaki rats. To investigate the role of GALNT2 in human hyperglycemia, we measured GALNT2 mRNA expression levels in peripheral whole blood cells of 84 non-obese and 46 obese non-diabetic individuals as well as of 98 obese patients with type 2 diabetes. We also measured GALNT2 mRNA expression in human U937 cells cultured under different glucose concentrations. In vivo studies indicated that GALNT2 mRNA levels were significantly reduced from non obese control to obese non diabetic and to obese diabetic individuals (p more...
- Published
- 2012
37. Serum Resistin and Kidney Function: A Family-Based Study in Non-Diabetic, Untreated Individuals
- Author
-
Grazia Fini, Rosa Di Paola, Davide Mangiacotti, Salvatore De Cosmo, Concetta De Bonis, Maddalena Giorelli, Alessandro Doria, Claudia Menzaghi, Vincenzo Trischitta, Lucia Salvemini, Eleonora Morini, and Ryan Thompson more...
- Subjects
Nephrology ,Genetic Screens ,Heredity ,Gene Expression ,lcsh:Medicine ,Blood Pressure ,030204 cardiovascular system & hematology ,Kidney ,Body Mass Index ,chemistry.chemical_compound ,0302 clinical medicine ,Chronic Kidney Disease ,Resistin ,lcsh:Science ,0303 health sciences ,Multidisciplinary ,Smoking ,Age Factors ,3. Good health ,Phenotypes ,Creatinine ,Medicine ,medicine.symptom ,Research Article ,Glomerular Filtration Rate ,medicine.medical_specialty ,Renal function ,White People ,03 medical and health sciences ,Insulin resistance ,Sex Factors ,Internal medicine ,Diabetes mellitus ,medicine ,Genetics ,Albuminuria ,Humans ,Family ,Biology ,Exercise ,030304 developmental biology ,Clinical Genetics ,business.industry ,Complex Traits ,lcsh:R ,nutritional and metabolic diseases ,medicine.disease ,Endocrinology ,chemistry ,Immunology ,Genetics of Disease ,Linear Models ,lcsh:Q ,business ,Body mass index - Abstract
Background 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. Methods 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. Results 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. Conclusion 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. more...
- Published
- 2012
38. Novel Locus FER Is Associated With Serum HMW Adiponectin Levels
- Author
-
Frank B. Hu, Claudia Menzaghi, Vincenzo Trischitta, Lu Qi, Concetta De Bonis, and Lucia Salvemini
- Subjects
Adult ,Male ,medicine.medical_specialty ,Diabetes risk ,Endocrinology, Diabetes and Metabolism ,Single-nucleotide polymorphism ,Genome-wide association study ,Type 2 diabetes ,030204 cardiovascular system & hematology ,Biology ,Polymorphism, Single Nucleotide ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Internal Medicine ,medicine ,Genetics ,SNP ,Humans ,030304 developmental biology ,Metabolic Syndrome ,0303 health sciences ,Adiponectin ,Case-control study ,nutritional and metabolic diseases ,Middle Aged ,medicine.disease ,3. Good health ,Molecular Weight ,Endocrinology ,Diabetes Mellitus, Type 2 ,Case-Control Studies ,Female ,Metabolic syndrome ,Genome-Wide Association Study - Abstract
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 × 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. more...
- Published
- 2011
39. The SH2B1 obesity locus is associated with myocardial infarction in diabetic patients and with NO synthase activity in endothelial cells
- Author
-
Gaia Chiara Mannino, Angela Nigro, Thomas H. Hauser, Lucia Frittitta, Alessandro Doria, Eleonora Morini, Ernest V. Gervino, Emanuele Bellacchio, Vittoria Proto, Simonetta Bacci, Natalia Di Pietro, Sabrina Prudente, Assunta Pandolfi, Giorgio Sesti, Claudia Menzaghi, Gloria Formoso, Fabio Pellegrini, Vincenzo Trischitta, Francesco Andreozzi, and Jay Larmon more...
- Subjects
Male ,medicine.medical_specialty ,Nitric Oxide Synthase Type III ,Myocardial Infarction ,Single-nucleotide polymorphism ,Coronary Artery Disease ,Polymorphism, Single Nucleotide ,Risk Assessment ,Linkage Disequilibrium ,Article ,Coronary artery disease ,Diabetes Complications ,Insulin resistance ,SH2B1 ,Gene Frequency ,Risk Factors ,Internal medicine ,medicine ,Human Umbilical Vein Endothelial Cells ,Odds Ratio ,SNP ,Humans ,Insulin ,Genetic Predisposition to Disease ,Myocardial infarction ,Obesity ,Allele frequency ,Genetic Association Studies ,Adaptor Proteins, Signal Transducing ,Aged ,business.industry ,Case-control study ,Computational Biology ,Middle Aged ,medicine.disease ,Endocrinology ,Logistic Models ,Phenotype ,Diabetes Mellitus, Type 2 ,Italy ,Case-Control Studies ,Female ,Cardiology and Cardiovascular Medicine ,business ,type 2 diabetes mellitus ,genetic risk factors ,myocardial infarction ,coronary artery disease ,polymorphisms ,insulin resistance ,Boston - Abstract
Objective 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). Design and setting 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)]. Results 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. Conclusions 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. more...
- Published
- 2011
40. ENPP1 Q121 variant, increased pulse pressure and reduced insulin signaling, and nitric oxide synthase activity in endothelial cells
- Author
-
Sandra Mastroianno, Simonetta Bacci, Francesco Perticone, Fabio Pellegrini, Claudia Menzaghi, Grazia Fini, Rosa Di Paola, Sara Di Silvestre, Roberto Baratta, Gloria Formoso, Patrizia Di Fulvio, Assunta Pandolfi, Vincenzo Trischitta, Agostino Consoli, Antonella Marucci, and Lucia Frittitta more...
- Subjects
Adult ,Male ,medicine.medical_specialty ,Systole ,medicine.medical_treatment ,Blood Pressure ,endothelial dysfunction ,White People ,Nitric oxide ,chemistry.chemical_compound ,arterial stiffness ,cardiovascular disease ,enpp-1 gene ,insulin resistance ,Insulin resistance ,Polymorphism (computer science) ,Internal medicine ,medicine ,Humans ,Insulin ,Endothelial dysfunction ,Phosphorylation ,Pyrophosphatases ,Cells, Cultured ,Polymorphism, Genetic ,biology ,Phosphoric Diester Hydrolases ,Endothelial Cells ,Middle Aged ,medicine.disease ,Receptor, Insulin ,Nitric oxide synthase ,Endothelial stem cell ,Insulin receptor ,Endocrinology ,chemistry ,Hypertension ,biology.protein ,Female ,Insulin Resistance ,Nitric Oxide Synthase ,Cardiology and Cardiovascular Medicine ,Proto-Oncogene Proteins c-akt ,Signal Transduction - Abstract
Objective— Insulin resistance induces increased pulse pressure (PP), endothelial dysfunction (ED), and reduced bioavailability of endothelium-derived nitric oxide (NO). The genetic background of these 3 cardiovascular risk factors might be partly common. The ENPP1 K121Q polymorphism is associated with insulin resistance and cardiovascular risk. Methods and Results— We investigated whether the K121Q polymorphism is associated with increased PP in white Caucasians and with ED in vitro. In 985 individuals, (390 unrelated and 595 from 248 families), the K121Q polymorphism was associated with PP ( P =8.0×10 −4 ). In the families, the Q121 variant accounted for 0.08 of PP heritability ( P =9.4×10 −4 ). This association was formally replicated in a second sample of 475 individuals ( P =2.6×10 −2 ) but not in 2 smaller samples of 289 and 236 individuals ( P =0.49 and 0.21, respectively). In the individual patients’ data meta-analysis, comprising 1985 individuals, PP was associated with the Q121 variant ( P =1.2×10 −3 ). Human endothelial cells carrying the KQ genotype showed, as compared to KK cells, reduced insulin-mediated insulin receptor autophosphorylation ( P =0.03), Ser 473 -Akt phosphorylation ( P =0.03), and NO synthase activity ( P =0.003). Conclusions— Our data suggest that the ENPP1 Q121 variant is associated with increased PP in vivo and reduced insulin signaling and ED in vitro, thus indicating a possible pathogenic mechanism for the increased cardiovascular risk observed in ENPP1 Q121 carriers. more...
- Published
- 2009
41. The protein tyrosine phosphatase receptor type f (PTPRF) locus is associated with coronary artery disease in type 2 diabetes
- Author
-
C. De Bonis, Claudia Menzaghi, P. Lanna, Vincenzo Trischitta, Angelo Coco, Vittorio Tassi, Giulia Paroni, Giuseppe Miscio, Carlo Vigna, and Simonetta Bacci
- Subjects
Male ,medicine.medical_specialty ,Locus (genetics) ,Protein tyrosine phosphatase ,Type 2 diabetes ,Coronary Artery Disease ,PTPRF ,Receptor type ,Coronary artery disease ,Text mining ,Internal medicine ,Internal Medicine ,Medicine ,Humans ,Genetic Predisposition to Disease ,Aged ,Polymorphism, Genetic ,business.industry ,Receptor-Like Protein Tyrosine Phosphatases, Class 2 ,Middle Aged ,medicine.disease ,PTPN11 ,Endocrinology ,Diabetes Mellitus, Type 2 ,Female ,business ,Diabetic Angiopathies - Published
- 2008
42. The K121Q polymorphism of the ENPP1/PC-1 gene is associated with insulin resistance/atherogenic phenotypes, including earlier onset of type 2 diabetes and myocardial infarction
- Author
-
Grazia Fini, Sabrina Prudente, Claudia Menzaghi, Ornella Ludovico, Lucia Salvemini, Simonetta Bacci, Yuan Yuan Zhang, Davide Mangiacotti, Anna Rauseo, Cesare Amico, Fabio Pellegrini, Jill Duffy, Vincenzo Trischitta, David S. Nolan, Carlo Vigna, Alessandro Doria, and Rosa Di Paola more...
- Subjects
Adult ,Male ,medicine.medical_specialty ,Aging ,Heart disease ,Endocrinology, Diabetes and Metabolism ,Myocardial Infarction ,Type 2 diabetes ,Gastroenterology ,Coronary artery disease ,Insulin resistance ,Internal medicine ,Internal Medicine ,medicine ,Odds Ratio ,Humans ,Myocardial infarction ,Pyrophosphatases ,Gene ,Aged ,Polymorphism, Genetic ,business.industry ,Phosphoric Diester Hydrolases ,Odds ratio ,Middle Aged ,medicine.disease ,Atherosclerosis ,Phenotype ,Endocrinology ,Diabetes Mellitus, Type 2 ,Female ,Insulin Resistance ,business - Abstract
Insulin resistance (IR) is pathogenic for type 2 diabetes and coronary artery disease (CAD). The K121Q polymorphism of the ENPP1/PC-1 gene is associated with IR. Our aim was to investigate the role of the 121Q variant on the risk of type 2 diabetes and CAD. Nondiabetic control subjects (n = 638), type 2 diabetic patients without CAD (n = 535), and type 2 diabetic patients with CAD (n = 434) from Italy and the U.S. were studied. The proportion of 121Q carriers progressively increased in the three groups (27.4, 28.8, and 33.2%, respectively; adjusted P value = 0.027). Among diabetic patients (n = 969), 121Q carriers had an increased risk of developing type 2 diabetes before the age of 65 years (adjusted odds ratio [OR] 2.26, 95% CI 1.26–4.03; P = 0.006) and having a myocardial infarction (MI) (n = 156) by 50 years of age (3.17, 1.46–6.88, P = 0.007). The 121Q variant was also associated with an increased risk for CAD (1.47, 1.01–2.18; P = 0.049) in diabetic patients who did not smoke (n = 546). In conclusion, the ENPP1/PC-1 121Q variant is associated with a progressive deterioration of the IR-atherogenic phenotype; among diabetic individuals, it is also associated with earlier onset of type 2 diabetes and MI. more...
- Published
- 2005
43. Lack of evidence for interaction between APM1 and PPARgamma2 genes in modulating insulin sensitivity in nondiabetic Caucasians from Italy
- Author
-
Tonino Ercolino, Vincenzo Trischitta, Grazia Fini, Claudia Menzaghi, R. Di Paola, Alessandro Doria, Lucia Salvemini, and Angelo Coco
- Subjects
Adult ,Male ,medicine.medical_specialty ,Polymorphism, Genetic ,business.industry ,Insulin sensitivity ,PPAR gamma ,Endocrinology ,Haplotypes ,Internal medicine ,Internal Medicine ,medicine ,Humans ,Insulin ,Intercellular Signaling Peptides and Proteins ,Female ,Adiponectin ,Insulin Resistance ,business ,Gene - Published
- 2005
44. Multigenic control of serum adiponectin levels: evidence for a role of the APM1 gene and a locus on 14q13
- Author
-
Grazia Fini, Vincenzo Trischitta, Claudia Menzaghi, S. H. Kim, Angelo Coco, Alessandro Doria, Tonino Ercolino, and Lucia Salvemini
- Subjects
Adult ,Blood Glucose ,Male ,medicine.medical_specialty ,Adolescent ,Genotype ,Physiology ,Genetic Linkage ,medicine.medical_treatment ,Adipokine ,Adipose tissue ,Locus (genetics) ,Type 2 diabetes ,Biology ,Insulin resistance ,Internal medicine ,Genetics ,medicine ,Humans ,Enhancer ,Aged ,Aged, 80 and over ,Chromosomes, Human, Pair 14 ,Adiponectin ,Insulin ,Fasting ,Middle Aged ,medicine.disease ,Endocrinology ,Haplotypes ,Italy ,Multigene Family ,Intercellular Signaling Peptides and Proteins ,Female - Abstract
Adiponectin is a circulating enhancer of insulin action that is secreted by the adipose tissue. In epidemiological studies, serum levels of this protein predict the risk of type 2 diabetes and cardiovascular events. Serum adiponectin levels have been associated with variants at the adiponectin (APM1) and PPARγ2 loci and have also been linked to markers on 5p15 and 14q13. We investigated the role of these four loci in regulating serum adiponectin in a Caucasian population from Italy. Four haplotype-tagging single-nucleotide polymorphisms (ht-SNPs) (−11377 C>G, −4041 A>C, +45 T>G, and +276 G>T) at the APM1 locus and the PPARγ2 Pro12Ala polymorphism were examined for association with serum adiponectin in 413 unrelated, nondiabetic individuals. Of the five SNPs tested, +276G>T was the only one to be associated with serum adiponectin ( P = 0.032), with “TT” individuals having higher adiponectin levels than other subjects. In a variance-components analysis of 737 nondiabetic members of 264 nuclear families, adiponectin heritability was 30%, with a small but significant proportion explained by the +276 genotype ( P = 0.0034). Suggestive evidence of linkage with adiponectin levels was observed on chromosome 14q13, with a LOD of 2.92 ( P = 0.000057) after including the APM1 +276 genotype in the model. No linkage was observed at 5p15. Our data indicate a strong genetic control of serum adiponectin. A small proportion of this can be attributed in our population to variability at the APM1 locus, but an as yet unidentified gene on 14q13 appears to play a much bigger role. more...
- Published
- 2004
45. The +276 G/T single nucleotide polymorphism of the adiponectin gene is associated with coronary artery disease in type 2 diabetic patients
- Author
-
Claudia Menzaghi, Umberto Di Mario, Simonetta Bacci, Xiaowei Ma, Alessandro Doria, Raffaele Fanelli, Vincenzo Trischitta, Carlo Vigna, Tonino Ercolino, Lucia Salvemini, and Anna Rauseo
- Subjects
Male ,medicine.medical_specialty ,Genotype ,Endocrinology, Diabetes and Metabolism ,Coronary Disease ,Single-nucleotide polymorphism ,Type 2 diabetes ,Lower risk ,Polymorphism, Single Nucleotide ,Gastroenterology ,Coronary artery disease ,Electrocardiography ,Reference Values ,Diabetes mellitus ,Internal medicine ,Internal Medicine ,medicine ,Humans ,Myocardial infarction ,Advanced and Specialized Nursing ,Adiponectin ,business.industry ,Homozygote ,Coronary Stenosis ,Odds ratio ,Middle Aged ,medicine.disease ,Endocrinology ,Diabetes Mellitus, Type 2 ,Exercise Test ,Intercellular Signaling Peptides and Proteins ,Female ,business ,Diabetic Angiopathies - Abstract
OBJECTIVE—Two single nucleotide polymorphisms (SNPs) at the adiponectin locus (+45T>G and +276G>T) have been associated with low circulating adiponectin levels, insulin resistance, and type 2 diabetes. We investigated whether these genetic markers are determinants of coronary artery disease (CAD) in type 2 diabetic patients. RESEARCH DESIGN AND METHODS—A total of 376 consecutive type 2 diabetic patients were studied: 142 case subjects with coronary stenosis >50% or previous myocardial infarction and 234 control subjects with no symptoms, no electrocardiogram (ECG) signs of myocardial ischemia, and a normal ECG stress test (n = 189) and/or (n = 45) with coronary stenosis ≤50%. RESULTS—No association with CAD was observed for the +45 SNP (P = 0.48). By contrast, a significant association was observed for the +276 SNP, with T/T homozygotes having a lower risk of CAD than carriers of other genotypes (adjusted odds ratio [OR] 0.13 [95% CI 0.037–0.46], P = 0.002). A similarly protective effect of the +276 T/T genotype was observed in 110 case and 45 control subjects for whom the CAD status had been determined by angiography (0.04 [0.006–0.30], P = 0.002). Serum adiponectin, although clearly related to several features of the proatherogenic/insulin-resistant phenotype, was not different between control subjects and CAD patients (26 ± 17 vs. 25 ± 13 μg/ml). CONCLUSIONS—In conclusion, the +276 G>T polymorphism is a determinant of CAD risk in type 2 diabetic patients. This marker may assist in the identification of diabetic individuals at especially high risk of CAD, so that preventive programs can be targeted at these subjects. more...
- Published
- 2004
46. PO5-126 COMBINED EFFECT OF K121Q OF ENPP1 (PC-1) AND Q84R OF TRIB3 ON AGE AT MYOCARDIAL INFARCTION IN TYPE 2 DIABETIC PATIENTS
- Author
-
Lucia Salvemini, Watip Boonyasrisawat, Davide Mangiacotti, Vincenzo Trischitta, F. Turchi, S. Mastroianno, Eleonora Morini, J. Duffy, Alessandro Doria, Simonetta Bacci, D. Nolan, Yuemei Zhang, Sabrina Prudente, and Claudia Menzaghi more...
- Subjects
medicine.medical_specialty ,business.industry ,TRIB3 ,Internal medicine ,Internal Medicine ,medicine ,Cardiology ,General Medicine ,Myocardial infarction ,Cardiology and Cardiovascular Medicine ,medicine.disease ,business - Published
- 2007
- Full Text
- View/download PDF
47. Corrigenda
- Author
-
Claudia Menzaghi, C. De Bonis, Vincenzo Trischitta, and Giulia Paroni
- Subjects
medicine.medical_specialty ,business.industry ,Locus (genetics) ,Protein tyrosine phosphatase ,Type 2 diabetes ,PTPRF ,Receptor type ,medicine.disease ,Coronary artery disease ,Endocrinology ,Internal medicine ,Internal Medicine ,Medicine ,business - Published
- 2008
- Full Text
- View/download PDF
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.