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ABSTRACT: Eur J Clin Invest 2012 ABSTRACT: Background In normoglucose-tolerant subjects (NGT), 1-h post-load plasma glucose value ≥155 mg/dL, during an oral glucose tolerance test (OGTT), is associated with an increased risk of type-2 diabetes (T2D) and subclinical organ damage. Insulin-like growth factor-1 (IGF-1) is involved in the pathogenesis of insulin resistance (IR) and T2D. Moreover, hypertensives have different degrees of IR and different levels of IGF-1. Actually, there are no data supporting the association between post-load glucose and IGF-1; thus, the aim of the study was to investigate this relationship. Materials and methods We enrolled 1126 never-treated hypertensive subjects who underwent an OGTT and clinical characterization. Insulin sensitivity was assessed by the Matsuda index. IGF-1 was measured by a sensitive immunoradiometric assay. Results Among participants, 764 had NGT, 263 had impaired glucose tolerance (IGT) and 99 had T2D. According to the 1-h post-load plasma glucose cut-off point of 155 mg/dL, we divided NGT subjects into NGT < 155 mg/dL and NGT ≥ 155 mg/dL. NGT ≥ 155 in comparison with NGT < 155 had significantly reduced insulin sensitivity and IGF-1 levels. At multiple regression analysis, IGF-1 was the major determinant of 1-h post-load glucose in NGT ≥ 155 subjects, IGT and diabetics, accounting for 20·9%, 17·7% and 15·5% of its variation in the respective models. Conclusions In hypertensive NGT ≥ 155 subjects, IGF-1 results strongly associated with 1-h post-load glucose, similarly to that observed in IGT and diabetics. This finding has clinical relevance because both low IGF-1 levels and 1-h post-load glucose in NGT subjects are associated with subclinical organ damage, an independent predictor of cardiovascular events.
European Journal of Clinical Investigation 09/2012; · 3.02 Impact Factor
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ABSTRACT: We evaluated whether cardiometabolic risk profiles differ for subjects identified as having prediabetes by A1C, fasting glucose (FPG), or 2-h postchallenge glucose (2-PG) criteria.
Atherosclerosis risk factors, oral glucose tolerance test, and ultrasound measurement of carotid intima-media thickness (IMT) were analyzed in 780 nondiabetic individuals.
Poor agreement existed for A1C and FPG criteria for identification of subjects with prediabetes (κ coefficient = 0.332). No differences in cardiometabolic risk profiles were observed among the three groups of individuals with prediabetes by A1C only, FPG only, and both A1C and FPG. Poor agreement also existed for A1C and 2-PG criteria for identification of individuals with prediabetes (κ coefficient = 0.299). No significant differences in cardiometabolic risk factors were observed between IGT-only and individuals with prediabetes by A1C and 2-PG. Compared with subjects with prediabetes identified by A1C only, IGT-only individuals exhibited a worse cardiometabolic risk profile, with significantly higher systolic blood pressure, pulse pressure, 2-h postchallenge insulin, triglycerides, high-sensitivity C-reactive protein, and carotid IMT, and lower HDL cholesterol levels and insulin sensitivity.
These results suggest that considerable discordance between A1C, FPG, and 2-PG exists for the identification of individuals with prediabetes and that the cardiometabolic risk profile of these individuals varies by metabolic parameter, with 2-PG showing the stronger association with cardiometabolic risk factors and subclinical atherosclerosis than FPG or A1C.
Diabetes care 03/2012; 35(5):1144-9. · 8.09 Impact Factor
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ABSTRACT: Individuals with normal glucose tolerance (NGT), whose 1-h postload plasma glucose is ≥155 mg/dL (NGT 1h-high), have an increased risk of type 2 diabetes. The purpose of this study was to characterize their metabolic phenotype.
A total of 305 nondiabetic offspring of type 2 diabetic patients was consecutively recruited. Insulin secretion was assessed using both indexes derived from oral glucose tolerance test (OGTT) and intravenous glucose tolerance test (IVGTT). Insulin sensitivity was measured by hyperinsulinemic-euglycemic clamp.
Compared with individuals with a 1-h postload plasma glucose <155 mg/dL (NGT 1h-low), NGT 1h-high individuals exhibited lower insulin sensitivity after adjustment for age, sex, and BMI. Insulin secretion estimated from the OGTT did not differ between the two groups of individuals. By contrast, compared with NGT 1h-low individuals, the acute insulin response during an IVGTT and the disposition index were significantly reduced in NGT 1h-high individuals after adjustment for age, sex, and BMI. Incretin effect, estimated as the ratio between total insulin responses during OGTT and IVGTT, was higher in NGT 1h-high individuals compared with NGT 1h-low individuals.
NGT 1h-high individuals may represent an intermediate state of glucose intolerance between NGT and type 2 diabetes characterized by insulin resistance and reduced β-cell function, the two main pathophysiological defects responsible for the development of type 2 diabetes. Postload hyperglycemia is the result of an intrinsic β-cell defect rather than impaired incretin effect.
Diabetes care 02/2012; 35(4):868-72. · 8.09 Impact Factor
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ABSTRACT: Subjects who are normal glucose tolerant (NGT) are considered at low risk, even if a plasma glucose value ≥155 mg/dL for the 1-h postload plasma glucose during an oral glucose tolerance test (OGTT) is able to identify NGT subjects at high risk for type 2 diabetes and subclinical organ damage. Hyperuricemia is associated with several risk factors for cardiovascular diseases such as hypertension, insulin resistance, and diabetes. However, it is unknown whether uric acid (UA) is able to affect 1-h postload plasma glucose in hypertensive NGT subjects.
From a cohort of ∼1,200 uncomplicated hypertensive outpatients who underwent OGTT, we selected 955 subjects (548 men and 407 women) aged 45.6 ± 10.1 years. Laboratory evaluations were performed, and estimated glomerular filtration rate was assessed by using the new equation proposed by investigators in the Chronic Kidney Disease Epidemiology Collaboration.
Considering different stepwise multivariate linear regression models, UA was the major predictor of 1-h postload glucose in the entire population, with NGT ≥155 subjects, impaired glucose tolerant, and type 2 diabetic patients accounting for 26.0% (P < 0.0001), 25.3% (P < 0.0001), 13.5% (P < 0.0001), and 13.5% (P = 0.003) of its variation in the respective models.
We documented that in hypertensive NGT ≥155 subjects, UA is strongly associated with 1-h postload glucose, similarly to what is observed in impaired glucose tolerant and diabetic patients.
Diabetes care 01/2012; 35(1):153-7. · 8.09 Impact Factor
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ABSTRACT: Pulse wave velocity (PWV) is a surrogate end-point for cardiovascular morbidity and mortality. A plasma glucose value ≥155 mg/dl for the 1-hour post-load plasma glucose during an oral glucose tolerance test (OGTT) is able to identify subjects with normal glucose tolerance (NGT) at high-risk for type-2 diabetes (T2D) and for subclinical organ damage. Thus, we addressed the question if 1-hour post-load plasma glucose levels, affects PWV and its central hemodynamic correlates, as augmentation pressure (AP) and augmentation index (AI).
We enrolled 584 newly diagnosed hypertensives. All patients underwent OGTT and measurements of PWV, AP and AI. Insulin sensitivity was assessed by Matsuda-index.
Among participants, 424 were NGT and 160 had impaired glucose tolerance (IGT). Of 424 NGT, 278 had 1-h post-load plasma glucose <155 mg/dl (NGT<155) and 146 had 1-h post-load plasma glucose ≥155 mg/dl (NGT≥155). NGT≥155 had a worse insulin sensitivity and higher hs-CRP than NGT<155, similar to IGT subjects. In addition, NGT ≥155 in comparison with NGT<155 had higher central systolic blood pressure (134±12 vs 131±10 mmHg), as well as PWV (8.4±3.7 vs 6.7±1.7 m/s), AP (12.5±7.1 vs 9.8±5.7 mmHg) and AI (29.4±11.9 vs 25.1±12.4%), and similar to IGT. At multiple regression analysis, 1-h post-load plasma glucose resulted the major determinant of all indices of vascular stiffness.
Hypertensive NGT≥155 subjects, compared with NGT<155, have higher PWV and its hemodynamic correlates that increase their cardiovascular risk profile.
PLoS ONE 01/2012; 7(9):e44470. · 4.09 Impact Factor
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ABSTRACT: BACKGROUND: Normotolerant subjects (NGT) are considered at low risk, even if a plasma glucose value ≥155mg/dl for the 1-hour post-load plasma glucose during an oral glucose tolerance test (OGTT) is able to identify NGT at high-risk for type-2 diabetes and subclinical organ damage. Insulin resistance (IR) contributes to the pathogenesis of impaired glucose tolerance and participates to the development of subclinical organ damage. However, it is unknown whether NGT<155 subjects are at low risk for the development of subclinical organ damage independently from other metabolic variables, such as IR/hyperinsulinemia. METHODS: From a large cohort of about 1200 uncomplicated hypertensive outpatients underwent to OGTT, we selected 645 NGT subjects, 319 men and 326 women aged 47.6±10.6. All subjects underwent standard echocardiography for measurement of left ventricular mass (LVM), and carotid ultrasonography for evaluation of intima media thickness (IMT). Finally, we estimated glomerular filtration rate (e-GFR) by using the new equation proposed by investigators in the chronic kidney disease epidemiology (CKD-EPI) collaboration. RESULTS: NGT<155 subjects into upper tertile of 1-h post-load insulin had a worse lipemic profile, a higher hs-CRP, creatinine, LVM, e-GFR and IMT. Comparing the NGT groups, we observed that metabolic and hemodynamic parameters of NGT<155 subjects into upper tertile of 1-h post-load insulin were similar to that observed in NGT≥155 subjects. Similarly, fasting and both 1-h and 2-h post-load insulin values were similar to that observed in NGT≥155. CONCLUSIONS: We documented that hypertensive NGT subjects have different phenotypic patterns, particularly in their metabolic profile and in presence of subclinical organ damage.
International journal of cardiology 09/2011; · 7.08 Impact Factor
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Angela Sciacqua,
Sofia Miceli,
Laura Greco, Franco Arturi,
Paola Naccarato,
Deborah Mazzaferro,
Eliezer J Tassone,
Laura Turano,
Francesco Martino,
Giorgio Sesti,
Francesco Perticone
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ABSTRACT: To address whether glucose tolerance status, and in particular 1-h postload plasma glucose levels, may affect diastolic function in 161 never-treated hypertensive white subjects. Impaired left ventricular relaxation, an early sign of diastolic dysfunction, represents the first manifestation of myocardial involvement in diabetic cardiomyopathy. A plasma glucose value ≥155 mg/dL for the 1-h postload plasma glucose during an oral glucose tolerance test (OGTT) is able to identify subjects with normal glucose tolerance (NGT) at high risk for type 2 diabetes and with subclinical organ damage.
Subjects underwent OGTT and standard echocardiography. Diastolic function was assessed by pulsed Doppler transmitral flow velocity and tissue Doppler imaging. Insulin sensitivity was assessed by Matsuda index.
Among the participants, 120 had NGT, 26 had impaired glucose tolerance (IGT), and 15 had type 2 diabetes. According to the 1-h postload plasma glucose cutoff point of 155 mg/dL, we divided NGT subjects as follows: NGT <155 mg/dL (n = 90) and NGT ≥155 mg/dL (n = 30). Those with NGT ≥155 mg/dL had higher left atrium dimensions (P < 0.0001) and isovolumetric relaxation time (IVRT) (P = 0.037) than those with NGT <155 mg/dL. By contrast, early/late transmitral flow velocity and all tissue Doppler parameters were significantly lower in those with NGT ≥155 mg/dL than in those with NGT<155 mg/dL. At multiple regression analysis, 1-h glucose was the major determinant of left atrium area, IVRT, septal e', septal e'-to-a' ratio, lateral e', and lateral e'-to-a' ratio.
The main finding of this study is that 1-h postload plasma glucose is associated with left ventricular diastolic dysfunction. Subjects with NGT ≥155 mg/dL had significantly worse diastolic function than those with NGT<155 mg/dL.
Diabetes care 09/2011; 34(10):2291-6. · 8.09 Impact Factor
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Franco Arturi,
Elena Succurro,
Cristina Procopio,
Elisabetta Pedace,
Gaia Chiara Mannino,
Marina Lugarà,
Teresa Procopio,
Francesco Andreozzi,
Angela Sciacqua,
Marta Letizia Hribal,
Francesco Perticone,
Giorgio Sesti
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ABSTRACT: Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease and is associated with insulin resistance and cardiovascular disease. Among the potential factors that may account for the increased cardiometabolic risk, IGF-I is a plausible candidate because the liver is the main site of its production.
Our objective was to examine the relationship between NAFLD and IGF-I levels and to test the hypothesis that free fatty acids-induced insulin resistance might impair insulin-induced increase of GH receptor (GHR) expression in human hepatoma cells. SUBJECTS, DESIGN, AND SETTING: Five hundred three nondiabetic Caucasians participated in this ambulatory-care cross-sectional study.
Cardiometabolic risk factors and liver ultrasound scanning were assessed. Insulin-induced expression of GHR in HuH7 human hepatoma cells exposed for 24 h to palmitate was determined by Western blotting and real-time PCR.
After adjustment for age and gender, individuals with NAFLD had significantly higher body mass index, waist circumference, fasting insulin, triglycerides, homeostasis model assessment index, liver enzymes, and lower high-density lipoprotein cholesterol compared with control subjects. IGF-I levels were significantly lower in individuals with NAFLD (P = 0.001). Exposure of HuH7 hepatoma cells to palmitate caused a dose-dependent reduction in the insulin-induced increase of GHR expression.
These data show that IGF-I levels are reduced in subjects with NAFLD and suggest that hepatic insulin resistance may affect IGF-I levels by modulating GH-stimulated synthesis of hepatic IGF-I.
The Journal of clinical endocrinology and metabolism 08/2011; 96(10):E1640-4. · 6.50 Impact Factor
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ABSTRACT: Left ventricular hypertrophy (LVH), an independent risk factor for cardiovascular (CV) morbidity and mortality, recognizes a multifactorial pathogenesis. A plasma glucose value ≥155 mg/dL for the 1-h postload plasma glucose during an oral glucose tolerance test (OGTT) identifies subjects with normal glucose tolerance (NGT) at high risk for type 2 diabetes. We addressed the question if glucose tolerance status, particularly 1-h postload plasma glucose levels, affects left ventricular mass (LVM) and cardiac geometry in essential hypertension.
We enrolled 767 never-treated hypertensive subjects, 393 women and 374 men (mean age 49.6 ± 8.5 years). All patients underwent an OGTT for the evaluation of glucose tolerance and standard echocardiography. LVM was calculated using the Devereux formula and normalized by body surface area (LVM index [LVMI]). Insulin sensitivity was assessed by the Matsuda index. Among all participants, 514 had NGT, 168 had impaired glucose tolerance (IGT), and 85 had type 2 diabetes. According to the 1-h postload plasma glucose cutoff point of 155 mg/dL, we divided normotolerant subjects into two groups: NGT <155 mg/dL (n = 356) and NGT ≥155 mg/dL (n = 158).
Subjects in the NGT ≥155 mg/dL group had worse insulin sensitivity than subjects in the NGT <155 mg/dL group (Matsuda index 63.9 vs. 88.8; P < 0.0001). Men with NGT ≥155 mg/dL had a higher LVMI than men with NGT <155 mg/dL (126.6 vs. 114.3 g/m(2); P = 0.002) and a different LVH prevalence (41.1 vs. 25.8%; P < 0.0001). At multiple regression analysis, 1-h glucose resulted in the major determinant of LVMI in normotolerant, IGT, and diabetic groups.
These data show that NGT ≥155 mg/dL subjects, compared with NGT <155 mg/dL subjects, have a higher LVMI and a greater prevalence of LVH similar to that of IGT and diabetic patients.
Diabetes care 06/2011; 34(6):1406-11. · 8.09 Impact Factor
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Elena Succurro,
Maria Adelaide Marini, Franco Arturi,
Alessandro Grembiale,
Teresa Vanessa Fiorentino,
Francesco Andreozzi,
Angela Sciacqua,
Renato Lauro,
Marta Letizia Hribal,
Francesco Perticone,
Giorgio Sesti
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ABSTRACT: We compared the performance of hemoglobin A1c (HbA1c) versus the fasting plasma glucose (FPG) in diagnosing the metabolic syndrome and assessed the diagnostic accuracy of the metabolic syndrome definition using HbA1c in identifying insulin-resistant subjects. The cardiometabolic risk factors, HbA1c, and glucose tolerance were analyzed in 774 nondiabetic white subjects. Insulin sensitivity was estimated with an oral glucose tolerance test-derived insulin sensitivity index. Insulin resistance was defined as the lower quartile of insulin sensitivity index. A 90.9% agreement existed between the use of HbA1c and the FPG for diagnosis of the metabolic syndrome (κ coefficient = 0.813); however, the proportion of subjects who met the metabolic syndrome criteria using the HbA1c was greater (42.1% vs 39.7%). Compared to the subjects who met the metabolic syndrome criteria using the FPG alone, those with the metabolic syndrome using the HbA1c-alone criterion were younger, had greater visceral adiposity, greater levels of inflammatory markers and liver enzymes, and lower blood pressure. In a logistic regression analysis with adjustment for age and gender, the subjects with the metabolic syndrome using the HbA1c criterion only had a 3.6-fold increase risk of having insulin resistance, defined as the lowest quartile of the insulin sensitivity index. A similar risk (3.8-fold) was observed in those who met the metabolic syndrome criteria using FPG alone. Insulin-resistant subjects who did not meet the criteria for the metabolic syndrome using the HbA1c had an unfavorable cardiovascular disease risk profile. In conclusion, although a good agreement existed between the HbA1c and FPG criteria for the diagnosis of the metabolic syndrome, appreciably different groups of subjects were classified using each method.
The American journal of cardiology 03/2011; 107(11):1650-5. · 3.58 Impact Factor
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Elena Succurro, Franco Arturi,
Marina Lugarà,
Alessandro Grembiale,
Teresa Vanessa Fiorentino,
Vittoria Caruso,
Francesco Andreozzi,
Angela Sciacqua,
Marta Letizia Hribal,
Francesco Perticone,
Giorgio Sesti
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ABSTRACT: A cutoff of 155 mg/dl for 1-hour postload plasma glucose (1hPG) during the oral glucose tolerance test (OGTT) is able to identify patients who are at high risk for type 2 diabetes and vascular atherosclerosis. We aimed to examine whether individuals with 1hPG ≥155 mg/dl are also at increased risk for chronic kidney disease (CKD).
Atherosclerosis risk factors, OGTT, and estimated GFR by Chronic Kidney Disease Epidemiology Collaboration equation were analyzed in 1075 white individuals without diabetes.
The area under the receiver operating characteristic curve for 1hPG was the highest (0.700) compared with the areas under the receiver operating characteristic curve of 0, 30-minute, and 2-hour glucose concentrations. Individuals with 1hPG ≥155 mg/dl had a worse cardiometabolic risk profile, exhibiting significantly higher body mass index, BP, triglycerides, and fasting insulin levels and lower HDL, IGF-1 levels, and insulin sensitivity, than individuals with 1hPG <155 mg/dl. Estimated GFR was significantly lower in individuals with 1hPG ≥155 mg/dl. In a logistic regression model adjusted for age and gender, individuals with 1hPG ≥155 mg/dl showed an increased risk for CKD compared with individuals with 1hPG <155 mg/dl. When the logistic regression analysis was restricted to individuals who had normal glucose tolerance, those with 1hPG ≥155 mg/dl showed a higher risk for CKD compared with individuals with 1hPG <155 mg/dl.
These data suggest that a cutoff point of 155 mg/dl for the 1hPG during OGTT may be helpful in the identification of individuals who are at increased risk for CKD.
Clinical Journal of the American Society of Nephrology 11/2010; 5(11):1922-7. · 5.23 Impact Factor
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ABSTRACT: Low IGF1 levels have been associated with an increased cardiovascular risk. It is unknown however whether IGF1 mediates the atherosclerotic process by modulating high-density lipoprotein cholesterol (HDL-C) independently from confounders. To address this issue, we evaluated the association between IGF1 levels and HDL-C in nondiabetic subjects.
A cross-sectional analysis was used in the context of the CAtanzaro MEtabolic RIsk factors Study. One thousand and four participants (aged 20-69 years), for whom HDL-C and IGF1 measurements were available, were eligible for the study.
After adjusting for gender and age, IGF1 levels were positively correlated with HDL-C, and negatively correlated with body mass index (BMI), waist circumference, blood pressure (BP), triglyceride, fasting insulin, and homeostasis model assessment (HOMA). In a logistic regression model adjusted for age and gender, IGF1 in the lowest tertile (<125 ng/ml) was associated with an increased risk of having low HDL-C (odds ratio (OR) 2.14, 95% confidence interval (CI) 1.4-3.0; P=4x10(-5)) compared with the highest tertile (>186 ng/ml). When BMI, waist circumference, total cholesterol, triglyceride, and HOMA index were added to the model, IGF1 remained significantly associated with increased risk of low HDL-C (OR 1.52, 95% CI 1.01-2.31; P=0.04). A stepwise multivariate regression analysis in a model including age, gender, BMI, total cholesterol, triglycerides, IGF1, HOMA, and BP showed that the variables significantly associated with HDL-C were gender (P<0.0001), triglycerides (P<0.0001), total cholesterol (P<0.0001), BMI (P<0.0001), IGF1 levels (P<0.0001), and HOMA (P=0.001), accounting for 32.6% of its variation.
These data provide evidence that IGF1 may be an independent modulator for HDL-C in nondiabetic individuals.
European Journal of Endocrinology 03/2010; 163(1):75-80. · 3.42 Impact Factor
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European Journal of Clinical Pharmacology 12/2009; 66(3):321-2. · 2.85 Impact Factor
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ABSTRACT: The AMP-activated protein kinase (AMPK) lies upstream of Akt in the pathway leading to endothelial NO synthase (eNOS) activation. Whether leptin promotes eNOS activation via AMPK-dependent activation of Akt, and which of the two AMPKalpha catalytic subunits is involved, remains unknown. Leptin resistance may be partly attributed to interaction between leptin and C-reactive protein (CRP). We hypothesized that leptin effect on eNOS activation in human aortic endothelial cells might be blunted by direct interaction with human recombinant CRP. Small interfering RNAs (siRNAs) were used to knock down expression of alpha1- or alpha2-AMPK in transient transfection assay to evaluate which is involved in this pathway and whether leptin effect on eNOS activation in human aortic endothelial cells might be blunted by direct interaction with human CRP. siRNA-mediated down-regulation of AMPKalpha1, but not AMPKalpha2, abolished leptin-induced Akt-Ser(473) phosphorylation, eNOS-Ser(1177) phosphorylation, eNOS activation, and cGMP accumulation. By contrast, siRNA-mediated knockdown of Akt1 did not affect AMPKalpha1 phosphorylation, but it abolished leptin-induced phosphorylation of Akt-Ser(473) and eNOS-Ser(1177), suggesting that Akt functions downstream of AMPKalpha1. Preincubation of leptin with human recombinant CRP impaired leptin-induced AMPK activation, eNOS-Ser(1177) phosphorylation, eNOS activity, and intracellular cGMP accumulation. The data are consistent with a model implicating an AMPKalpha1-->Akt-->eNOS pathway leading to NO production in response to leptin supporting the idea that interaction between leptin and CRP may have a role in impairing leptin effect on eNOS activation, suggesting a link between leptin resistance, low-grade inflammation, and endothelial dysfunction.
Endocrinology 05/2009; 150(8):3584-93. · 4.46 Impact Factor
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Angela Scipioni,
Elisabetta Ferretti,
Giuseppe Soda,
Emanuele Tosi,
Rocco Bruno,
Giuseppe Costante,
Domenico Meringolo, Franco Arturi,
Cosimo Durante,
Andrea Amorosi,
Maria Pia Foschini,
Francesco Nardi,
Diego Russo,
Sebastiano Filetti
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ABSTRACT: Nonfunctioning thyroid nodules (NFTNs) display a diminished iodide-concentrating ability, owing to defective expression and cell membrane targeting of the sodium-iodide symporter (NIS). Since NIS expression is primarily modulated by thyroid iodine content in vitro and in animal models, we attempted to determine whether iodine supply influences the expression and localization of human NIS (hNIS) in NFTNs.
Using immunohistochemistry, we analyzed cold hyperplastic nodules and nonnodular thyroid samples (controls) from patients living in iodine-sufficient (n = 19) or severely iodine-deficient (n = 15) areas.
Nodules from the iodine-sufficient area exhibited weak or absent hNIS immunostaining whereas almost all nodules from the iodine-deficient area were hNIS positive. Heterogeneous hNIS staining was common among the iodine-deficient samples (p = 0.028). hNIS was localized on membrane in all nodular samples from the iodine-deficient area and in less than 40% in the iodine-sufficient area.
hNIS is adequately expressed and appropriately localized in NFTNs cell membrane from iodine-deficient areas and its expression in vivo is modulated by iodine supply.
Thyroid 08/2007; 17(7):613-8. · 4.79 Impact Factor
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ABSTRACT: Benign and malignant thyroid tumours are characterized by alterations of the expression level of thyroid-specific genes involved in the iodide metabolism. Imbalance in the levels of transcription factors has been recognized as a critical molecular event in the development of neoplasm. The delineation of eventual correlations existing between the expression of transcription factors and of putative target genes in physiological and pathological conditions could be relevant to better understand tumorigenesis.
We examined the expression levels of transcription factors involved in thyroid development [thyroid transcription factor 1 (TTF-1), paired box gene 8 (PAX-8) and haematopoietically expressed homeobox (HEX)] in 101 thyroid tissues, including 14 normal thyroid tissues, 13 hyperfunctioning tissues, 27 benign adenomas and 47 follicular or papillary carcinomas. Then, we compared their expression levels with those of thyroid-specific genes involved in iodide metabolism.
In benign tumours, PAX-8 and TTF-1 gene expression levels were not significantly different from the expression levels in normal tissues. However, a significant decrease was found in carcinomas. Interestingly, HEX gene expression was significantly decreased in both hyper- and hypofunctioning benign tissues and also in carcinomas. Expression levels of Pendred syndrome (PDS), natrium iodine symporter (NIS), thyroglobulin (Tg), thyroid peroxidase (TPO) and dual oxidase 1 or 2 (DUOX2) genes were significantly correlated with the expression of PAX-8 and with that of HEX. Expression level of TTF-1 was weakly correlated only with the expression levels of PDS and DUOX2.
Our findings suggest that alterations in the transcription factors PAX-8, TTF-1 and HEX gene expression, by acting individually or together, have a role in both thyroidal tumorigenesis and in the dedifferentiation process.
Clinical Endocrinology 05/2006; 64(4):398-404. · 3.17 Impact Factor
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Leonardo D'Aloiso,
Francesca Carlomagno,
Michele Bisceglia,
Suresh Anaganti,
Elisabetta Ferretti,
Antonella Verrienti, Franco Arturi,
Daniela Scarpelli,
Diego Russo,
Massimo Santoro,
Sebastiano Filetti
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ABSTRACT: RET mutation analysis provides useful information on the clinical outcome of medullary thyroid carcinomas (MTCs) and the risk of disease in the family members.
The objective of this study was to document genotype-phenotype relationships in an Italian family with a novel RET mutation.
RET gene alterations were investigated in a patient with unifocal MTC and her relatives. The identified mutation was subjected to in vitro functional testing.
Patients included a female proband who developed MTC at age 60, her five children, and three grandchildren.
DNA extracted from the blood and the proband's tumor were analyzed for RET alterations. The transforming potential and mitogenic properties of the identified mutation were investigated.
A novel heterozygous germline RET mutation at codon 777 (AAC-->AGC, N-->S) (RET/N777S) was identified in the proband and three of her relatives. Two of the latter presented thyroid nodules, but none had MTC or C cell hyperplasia. The proband's MTC was characterized by late onset and limited aggressiveness, with no evidence of regional lymph node or distant metastases 10 yr after total thyroidectomy. This phenotype is consistent with the RET/N777S mutant's low-grade transforming potential and limited activation of RET tyrosine kinase.
Our findings indicate that the newly identified RET/N777S mutation is a low-penetrant cause of MTC disease. This phenotype might be less aggressive than that associated with MEN2A of familial MTC, although close clinical follow-up of carriers is essential.
Journal of Clinical Endocrinology & Metabolism 03/2006; 91(3):754-9. · 6.50 Impact Factor
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Rocco Bruno,
Elisabetta Ferretti,
Emanuele Tosi, Franco Arturi,
Paolo Giannasio,
Tiziana Mattei,
Angela Scipioni,
Ivan Presta,
Roberta Morisi,
Alberto Gulino,
Sebastiano Filetti,
Diego Russo
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ABSTRACT: Evidence from in vitro studies or animal models has shown that TSH affects thyrocytes by thyroid-specific expression modulation.
The objective of our study was to analyze the role of TSH in human thyroid gene expression in vivo.
Thirty-nine normal thyroid tissues were collected at the same center.
Patients were divided into two groups based on serum TSH levels: 17 with normal TSH levels (1-4 mU/liter; group 1) and 22 with TSH levels below 0.5 mU/liter (group 2). Intervention: Group 2 underwent thyroidectomy after suppressive L-T4 therapy.
mRNA levels of thyroid genes such as sodium/iodide symporter (NIS), apical iodide transporter, pendrin, thyroglobulin, thyroperoxidase, TSH receptor, paired box transcription factor 8, and thyroid transcription factor-1 were evaluated by quantitative PCR.
The reduction of TSH stimulation causes decreases in NIS and apical iodide transporter gene expression in normal tissues and more limited reductions in thyroglobulin, thyroperoxidase, and paired box transcription factor 8, but it has no significant effect on TSH receptor, pendrin, or thyroid transcription factor-1. Comparison of NIS levels in normal and nodular tissues from the same patient confirmed that it is differentially expressed in nodules only in the presence of normal TSH (P < 0.01). In patients with suppressed TSH, nodular NIS levels were similar to those in normal tissues.
Our data represent the first demonstration in human thyroid tissues that TSH contributes to the regulation of thyrocyte differentiation by modulating thyroid gene levels. It exerts a particularly important effect on the transcription of NIS, which becomes very low after prolonged TSH suppression.
Journal of Clinical Endocrinology & Metabolism 11/2005; 90(10):5692-7. · 6.50 Impact Factor
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Elisabetta Ferretti, Franco Arturi,
Tiziana Mattei,
Angela Scipioni,
Gianluca Tell,
Emanuele Tosi,
Ivan Presta,
Roberta Morisi,
Ludovic Lacroix,
Alberto Gulino,
Diego Russo,
Giuseppe Damante,
Sebastiano Filetti
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ABSTRACT: Pax proteins are transcriptional regulators that control a variety of developmental decisions in vertebrates. During development, the paired-box gene 8 (PAX8) is expressed in the thyroid, kidney, and several areas of the central nervous system. It is also expressed in the adult thyroid gland, in which it mediates TSH-induced modulation of the expression of important genes, such as those encoding thyroglobulin, thyroperoxidase, and the sodium/iodide symporter (NIS). Thus far, placental expression of PAX8 has been described only in mice. In the present study, we show that PAX8 is also expressed in the human placenta at term. In an in vitro model of placental cancer, the JAR choriocarcinoma cell line, human chorionic gonadotropin (hCG) increased levels of PAX8 mRNA and protein, and gel retardation assays indicated that the up-regulation of PAX8 protein expression is associated with an increase in its DNA-binding activity. The effects of hCG were mimicked by forskolin, indicating that they are cAMP dependent. Levels of mRNA for the Wilms' tumor 1 (WT1) and NIS genes were increased in JAR cells by hCG treatment, whereas overexpression of PAX8 increased only levels of WT1 mRNA. In cells transfected with PAX8-specific small interfering RNA, the stimulatory effects of hCG on WT1 mRNA levels were abolished, but hormonal enhancement of NIS mRNA levels was unchanged. These findings indicate that, in JAR cells, hCG activates a cAMP-dependent pathway that can up-regulate WT1 expression through PAX8.
Endocrinology 10/2005; 146(9):4009-15. · 4.46 Impact Factor
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Franco Arturi,
Elisabetta Ferretti,
Ivan Presta,
Tiziana Mattei,
Angela Scipioni,
Daniela Scarpelli,
Rocco Bruno,
Ludovic Lacroix,
Emanuele Tosi,
Alberto Gulino,
Diego Russo,
Sebastiano Filetti
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ABSTRACT: Sodium/iodide symporter (NIS) expression has recently been described in human breast cancer, with emphasis on its potential exploitation for the treatment of these tumors with radioiodine. In this study, we analyzed the regulation of NIS expression and function in the MCF-7 human breast cancer cell line. Cell exposure to insulin, IGF-I, IGF-II, or prolactin induced significant increases in 125I uptake and the expression of both NIS mRNA and NIS protein. The latter increases were evident after 6 and 12 h of hormonal stimulation, respectively. In immunocytochemistry studies, NIS was detected mainly in the plasma membrane of MCF-7 cells. A low but significant increase in iodide uptake was produced by treatment with activators of the adenylyl cyclase (cAMP) or protein kinase C pathways. Our study demonstrates that: 1) MCF-7 breast cancer cells are capable of active iodide transport that can be stimulated by insulin, IGF-I, IGF-II, or prolactin; 2) both NIS transcript and protein are expressed in these cells, and this expression is also hormonally stimulated; and 3) MCF-7 iodide transport and NIS expression may be influenced by the activation of cAMP or protein kinase C-dependent signaling. These findings increase our understanding of the molecular mechanisms that regulate NIS expression in breast cancer cells, information that is fundamental for future research aimed at the development of targeted radioiodide treatment for this type of cancer.
Journal of Clinical Endocrinology & Metabolism 05/2005; 90(4):2321-6. · 6.50 Impact Factor
