Raffaele Napoli - Academia.edu (original) (raw)
Papers by Raffaele Napoli
International Journal of Obesity
Over the last few years, the complexity and diversity of gut microbiota within and across individ... more Over the last few years, the complexity and diversity of gut microbiota within and across individuals has been detailed in relation to human health. Further, understanding of the bidirectional association between gut microbiota and metabolic disorders has highlighted a complimentary, yet crucial role for microbiota in the onset and progression of obesity-related cancers. While strategies for cancer prevention and cure are known to work efficiently when supported by healthy diet and lifestyle choices and physical activity, emerging evidence suggests that the complex interplay relating microbiota both to neoplastic and metabolic diseases could aid strategies for cancer treatment and outcomes. This review will explore the experimental and clinical grounds supporting the functional role of gut microbiota in the pathophysiology and progression of cancers in relation to obesity and its metabolic correlates. Therapeutic approaches aiding microbiota restoration in connection with cancer treatments will be discussed.
Angiology, 2020
Vascular function in dilated cardiomyopathy of different etiology has been poorly investigated. M... more Vascular function in dilated cardiomyopathy of different etiology has been poorly investigated. Moreover, reference values of flow-mediated dilation (FMD) in chronic heart failure (CHF) need to be updated according to the new standardized protocols. We characterized the vascular impairment in different stages of post-ischemic dilated cardiomyopathy (PI-DC) or idiopathic dilated cardiomyopathy (I-DC). Eighty consecutive outpatients with CHF in different New York Heart Association (NYHA) classes (45 PI-DC, 35 I-DC) and 50 control subjects underwent FMD and brachial distensibility coefficient measurement. Patients with CHF showed a marked impairment in FMD compared with controls that worsened from classes NYHA I-II to III-IV, independently of etiology ( P < .05). New York Heart Association I-II PI-DC patients showed a worse FMD compared with NYHA I-II I-DC patients ( P < .05). Brachial distensibility coefficient values were significantly lower in patients with CHF compared with c...
Background Findings from the T.O.S.CA. Registry recently reported that patients with concomitant ... more Background Findings from the T.O.S.CA. Registry recently reported that patients with concomitant chronic heart failure (CHF) and impairment of insulin axis (either insulin resistance- IR or diabetes mellitus- T2D) display increased morbidity and mortality. However, little information is available on the relative impact of IR and T2D on cardiac structure and function, cardiopulmonary performance, and their longitudinal changes in CHF. Methods Patients enrolled in the T.O.S.CA. Registry performed echocardiography and cardiopulmonary exercise test at baseline and at a patient-average follow-up of 36 months. Patients were divided into three groups based on the degree of insulin impairment: euglycemic without IR (EU), euglycemic with IR (IR), and T2D. Results Compared with EU and IR, T2D was associated with increased filling pressures ( E/e’ ratio : 15.9 ± 8.9, 12.0 ± 6.5, and 14.5 ± 8.1 respectively, p
Cells, 2022
Along with insulin resistance and increased risk of type 2 diabetes (T2D), lean first-degree rela... more Along with insulin resistance and increased risk of type 2 diabetes (T2D), lean first-degree relatives of T2D subjects (FDR) feature impaired adipogenesis in subcutaneous adipose tissue (SAT) and subcutaneous adipocyte hypertrophy well before diabetes onset. The molecular mechanisms linking these events have only partially been clarified. In the present report, we show that silencing of the transcription factor Homeobox A5 (HOXA5) in human preadipocytes impaired differentiation in mature adipose cells in vitro. The reduced adipogenesis was accompanied by inappropriate WNT-signaling activation. Importantly, in preadipocytes from FDR individuals, HOXA5 expression was attenuated, with hypermethylation of the HOXA5 promoter region found responsible for its downregulation, as revealed by luciferase assay. Both HOXA5 gene expression and DNA methylation were significantly correlated with SAT adipose cell hypertrophy in FDR, whose increased adipocyte size marks impaired adipogenesis. In pre...
Aging Cell, 2022
Senescence of adipose precursor cells (APC) impairs adipogenesis, contributes to the age‐related ... more Senescence of adipose precursor cells (APC) impairs adipogenesis, contributes to the age‐related subcutaneous adipose tissue (SAT) dysfunction, and increases risk of type 2 diabetes (T2D). First‐degree relatives of T2D individuals (FDR) feature restricted adipogenesis, reflecting the detrimental effects of APC senescence earlier in life and rendering FDR more vulnerable to T2D. Epigenetics may contribute to these abnormalities but the underlying mechanisms remain unclear. In previous methylome comparison in APC from FDR and individuals with no diabetes familiarity (CTRL), ZMAT3 emerged as one of the top‐ranked senescence‐related genes featuring hypomethylation in FDR and associated with T2D risk. Here, we investigated whether and how DNA methylation changes at ZMAT3 promote early APC senescence. APC from FDR individuals revealed increases in multiple senescence markers compared to CTRL. Senescence in these cells was accompanied by ZMAT3 hypomethylation, which caused ZMAT3 upregulation. Demethylation at this gene in CTRL APC led to increased ZMAT3 expression and premature senescence, which were reverted by ZMAT3 siRNA. Furthermore, ZMAT3 overexpression in APC determined senescence and activation of the p53/p21 pathway, as observed in FDR APC. Adipogenesis was also inhibited in ZMAT3‐overexpressing APC. In FDR APC, rescue of ZMAT3 methylation through senolytic exposure simultaneously downregulated ZMAT3 expression and improved adipogenesis. Interestingly, in human SAT, aging and T2D were associated with significantly increased expression of both ZMAT3 and the P53 senescence marker. Thus, DNA hypomethylation causes ZMAT3 upregulation in FDR APC accompanied by acquisition of the senescence phenotype and impaired adipogenesis, which may contribute to FDR predisposition for T2D.
Nutrition, Metabolism and Cardiovascular Diseases, 2020
Background and aims: To evaluate the economic impact of using 2nd generation basal insulin analog... more Background and aims: To evaluate the economic impact of using 2nd generation basal insulin analogs, Glargine 300 Units/ml (Gla-300) vs Degludec 100 Units/ml (IDeg-100), in patients with type 2 diabetes (T2D). Methods and results: An economic analysis was conducted using findings from the BRIGHT study (the first controlled, head-to-head study comparing Gla-300 vs IDeg-100), and costs for the Italian National Healthcare Service (NHS). A cost-minimization analysis (CMA) and a budget impact analysis (BIA) were conducted. Only pharmacological costs were included in the analysis. The CMA estimated patient treatment costs at 24 weeks and 1 year; the BIA assessed the economic impact of treating the overall Italian population of T2D insulin-naïve patients, who initiated insulin treatment during the period September 2017eAugust 2018 (N Z 55 318). In the BIA, four different scenarios were compared: i) all patients receive IDeg-100 (Scenario A); ii) 61% of patients receive Gla-300, 39% IDeg-100 (Scenario B); iii) 80% of patients receive Gla-300, 20% IDeg-100 (Scenario C); iv) all patients treated with Gla-300 (Scenario D). The average treatment costs per patient were lower with Gla-300 vs IDeg-100 (at 24 weeks: V129 vs V161; at 1 year: V324 vs V409, respectively). Results of the BIA showed that comparing Scenario D vs Scenario A, total savings would amount to V1.76 million at 24 weeks, V4.73 million at 1 year, V5.53 million at 2 years. Conclusion: A larger use of Gla-300 vs IDeg-100 for the treatment of T2D patients would lead to a relevant reduction of therapy costs in Italy.
International Journal of Molecular Sciences, 2021
Diabetes mellitus (DM) is a chronic metabolic disorder characterized by hyperglycemia, responsibl... more Diabetes mellitus (DM) is a chronic metabolic disorder characterized by hyperglycemia, responsible for the onset of several long-term complications. Recent evidence suggests that cognitive dysfunction represents an emerging complication of DM, but the underlying molecular mechanisms are still obscure. Dopamine (DA), a neurotransmitter essentially known for its relevance in the regulation of behavior and movement, modulates cognitive function, too. Interestingly, alterations of the dopaminergic system have been observed in DM. This review aims to offer a comprehensive overview of the most relevant experimental results assessing DA’s role in cognitive function, highlighting the presence of dopaminergic dysfunction in DM and supporting a role for glucotoxicity in DM-associated dopaminergic dysfunction and cognitive impairment. Several studies confirm a role for DA in cognition both in animal models and in humans. Similarly, significant alterations of the dopaminergic system have been o...
Minerva Endocrinology, 2018
INTRODUCTION Hypoglycemia is the major limiting factor in the glycemic management of diabetes. Ai... more INTRODUCTION Hypoglycemia is the major limiting factor in the glycemic management of diabetes. Aim of this study was to produce a risk stratification tool to support the medical decision making, by facilitating the identification of patients at higher risk of hypoglycemia. EVIDENCE ACQUISITION A multistep approach was adopted, including a systematic review of observational studies investigating risk factors for severe hypoglycemia in type 2 diabetes (T2DM), followed by an expert input forum to identify factors perceived as relevant and at the same time reliably detectable, to be used for the development of a risk score. EVIDENCE SYNTHESIS The systematic review led to the identification of 41 studies. Many factors have been seldom investigated, and their association with the risk of hypoglycemia is still unclear. Factors more frequently associated with a high risk of hypoglycemia were: low level of education, ethnicity, irregular meals/malnutrition, insulin and sulfonylurea therapy, polypharmacy, previous hypoglycemia, impaired renal function, cognitive impairment, depression and frailty. The expert input forum involved 35 diabetologists. Following the ranking of the relevance of the factors identified, a parsimonious yet comprehensive set of risk factors was identified. CONCLUSIONS The process led to the identification of relevant factors, to be used for the development of a hypoglycemia risk score. An ad-hoc study will be performed to assess the contribution of these risk factors and their relative weight. If the risk score will confirm its ability to correctly stratify patients according to their risk of hypoglycemia, it will represent a useful support to optimize the care of people with T2DM.
Heart Failure Clinics, 2020
Many patients with chronic heart failure show some hormonal deficiency that might worsen morbidit... more Many patients with chronic heart failure show some hormonal deficiency that might worsen morbidity and mortality. Chronic heart failure development might be explained by the imbalance between catabolic and anabolic pathways present in the disease. Multiple hormonal deficiency is associated with a relevant worsening of prognosis in patients with chronic heart failure and patients should be screened for it. Replacement hormonal therapy in patients with chronic heart failure has shown promising beneficial results.
Internal and Emergency Medicine, 2018
Background: Multiple hormonal deficiency syndrome (MHDS) is common in heart failure (HF). To date... more Background: Multiple hormonal deficiency syndrome (MHDS) is common in heart failure (HF). To date, no large observational study has unequivocally demonstrated that MHDS impacts on HF progression. Aim of the T.O.S.CA. Registry (NCT02335801) was to test whether MHDS affects morbidity and mortality in a large cohort of HF patients. Methods: The T.O.S.CA. Registry is a prospective, observational study involving 19 Italian centers. Thyroid hormones, insulin-like growth factor-1, testosterone, dehydropianoandrosterone, and insulin were measured at baseline and every year for a patient-average follow-up of 3 years. MHDS was defined as the presence of 2 or more hormonal deficiency (HD). Primary endpoint was a composite of all-cause mortality and cardiovascular hospitalizations. Results: A total of 526 consecutive patients was enrolled with a median follow-up of 36 months. MHDS was diagnosed in 405 patients (75%). A total of 276 events (98 death and 176 cardiovascular hospitalizations) were recorded; respectively 42.7% in MHDS-and 62.2 % in MHDS (p:0.001). MHDS was independently associated with the occurrence of the primary endpoint [HR 95% (CI), p-value: 1.58 (1.16-2.15), p:0.001] (Panel A). Further, MHDS identified a group of patients with higher mortality (χ2=9.2, p=0.03). Moreover a graded relation between HD and cumulative events were found (p:0.01) (Panel B). Conclusion: MHDS is a common finding in CHF and is independently associated with increased all-cause mortality and CV hospitalization.
Diabetes, Obesity and Metabolism, 2018
The Journal of Clinical Endocrinology & Metabolism, 1994
To determine the role of insulin and free fatty acid (FFA) concentration in the regulation of FFA... more To determine the role of insulin and free fatty acid (FFA) concentration in the regulation of FFA metabolism, forearm FFA fluxes were quantified in 16 healthy volunteers by combining the forearm perfusion technique with the infusion of [3H]palmitate. Three groups of studies were performed. In study 1 (n = 6), a systemic insulin infusion (1.2 mU/kg.min) was performed for 120 min while euglycemia was maintained by a variable glucose infusion. In Study 2 (n = 5), insulin (0.05 mU/kg.min) was infused into the brachial artery to expose the forearm tissues to the same insulin level as in study 1. In study 3 (n = 5), heparin was infused to raise plasma FFA concentration to 1-1.5 mmol/L. At 60 min, an intrabrachial insulin infusion was added as in study 2 and maintained for 60 min. During systemic insulin infusion, plasma FFA concentration fell to 0.09 +/- 0.02 mmol/L. Forearm FFA uptake (FFA-U) decreased from the basal value of 2.54 +/- 0.52 to 0.95 +/- 0.10 mumol/L.min (P &amp;lt; 0.05). Likewise, forearm FFA release (FFA-R) fell to 1.0 +/- 0.31 mumol/L.min (P &amp;lt; 0.05). With local insulin administration, both FFA levels and FFA-U remained unchanged, whereas FFA-R was markedly inhibited (from 1.78 +/- 0.23 to 1.04 +/- 0.24 mumol/L.min; P &amp;lt; 0.05). In study 3 (heparin infusion), FFA levels rose to 1.17 +/- 0.12 mmol/L due to a 4-fold increase in FFA-R (from 1.18 +/- 0.36 to 6.92 +/- 2.40 mumol/L.min; P &amp;lt; 0.05). FFA-U rose from the basal value of 2.50 +/- 0.82 to 6.92 +/- 1.95 mumol/L.min (P &amp;lt; 0.05). Addition of intrabrachial insulin did not modify FFA-U, whereas heparin activation of FFA-R was only partially antagonized (4.53 +/- 2.40 mumol/L.min; 0.01 &amp;lt; P &amp;lt; 0.05 vs. heparin alone). The data demonstrate that plasma FFA concentration is the main determinant of forearm FFA transport. Insulin exerts a direct inhibitory effect on FFA release and affects tissue FFA transport only indirectly through the fall in circulating FFA.
European Heart Journal, 2003
Diabetes Research and Clinical Practice, 1991
To investigate the effects of carnitine on insulin sensitivity in non-insulin-dependent diabetes,... more To investigate the effects of carnitine on insulin sensitivity in non-insulin-dependent diabetes, insulin-mediated glucose disposal was measured in nine diabetic patients (age 54 +/- 3 years, BMI 27 +/- 1 kg/mq) during a primed (3 mmol) constant (1.7 mumol/min) intravenous infusion of carnitine. In control experiments, the same patients received saline instead of carnitine. Plasma glucose concentration was maintained constant at the level of 100 mg/dl during both studies while plasma insulin was raised to a plateau of 60 microU/ml. Despite similar insulin levels, whole-body glucose utilization was higher with carnitine (4.05 +/- 0.37 mg/kg/min) than saline infusion (3.52 +/- 0.36). Blood lactate concentrations were similar in the basal state and decreased significantly during carnitine infusion (P less than 0.05-0.005), whereas it remained substantially unchanged during saline infusion. Plasma FFA decreased to a similar level (0.1 mmol/l) in both studies. We conclude that an acute carnitine administration is able to improve insulin sensitivity in NIDDM patients. The lactate data suggest that this effect may at least in part be mediated by carnitine activation of pyruvate dehydrogenase.
Nutrition, Metabolism and Cardiovascular Diseases, 2021
Patients with type 2 diabetes mellitus (T2DM) show an increased risk of cardiovascular diseases (... more Patients with type 2 diabetes mellitus (T2DM) show an increased risk of cardiovascular diseases (CVD) and mortality. Many factors are implicated in the pathogenesis of CVD in patients with T2DM. Among the factors involved, chronic hyperglycemia and the cluster of CVD risk factors, such as dyslipidemia, hypertension, and obesity, play a major role. For many years, the control of hyperglycemia has been complicated by the fact that the use of many available drugs was associated with an increased risk of hypoglycemia. Paradoxically, hypoglycemia per se represents a risk factor for CVD. Recently, new drugs for the control of hyperglycemia have become available: many of them can determine a good control of hyperglycemia with minor risks of hypoglycemia. Among these new classes of drugs, glucagon-like peptide-1 receptor agonists (GLP-1RAs) offer many advantages. In addition to a strong anti-hyperglycemic action, they possess the ability to act on body weight and other relevant risk factors for CVD. Consistently, some of the GLP-1RAs have demonstrated, in RCT designed to assess their safety, to reduce the risk of major adverse cardiovascular events. Furthermore, GLP-1RAs possess properties useful to treat additional conditions, as the capability of improving liver damage in patients with NAFLD or NASH, highly prevalent conditions in people with T2DM. In this document, written by experts of the Italian diabetes society (SID), we will focus our attention on the therapy with GLP-1RAs in patients with T2DM, particularly on the effects on hyperglycemia, cardiovascular disease risk factors, NAFLD/NASH and CVD prevention.
Nutrition, Metabolism and Cardiovascular Diseases, 2020
This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Metabolism, 1991
To determine the contribution of skeletal muscle to the insulin resistance of essential hypertens... more To determine the contribution of skeletal muscle to the insulin resistance of essential hypertension, insulin-stimulated forearm glucose uptake was quantitated in 12 control (age, 32 * 3 years) and 12 hypertensive subjects (age, 36 + 2 years) using the forearm perfusion technique. Peripheral insulin levels were raised acutely (-60 FU/mL), while blood glucose concentration was clamped at its basal value (90 mg/dL) by a variable glucose infusion. During insulin stimulation, whole body glucose uptake was lower in hypertensive (4.5 ? .3 mgkg-' * min-') than in normal subjects (5.6 "_ .4 mg. kg-'. min-', P < .05). Similarly, the amount of glucose taken up by the forearm was markedly reduced in the hypertensive (5.3 2 .91 mg. L-'. min-') compared with the control group (6.7 f 1.1 mg. L-'. min-'). No appreciable difference was observed as to forearm blood flow (39 +-4 mL. L-'min-' and 37-c 5 mL * L-' * min-') in hypertensive patients. These results indicate that skeletal muscle is a major site of insulin resistance in essential hypertension and that this defect is independent of muscle perfusion.
International Journal of Obesity
Over the last few years, the complexity and diversity of gut microbiota within and across individ... more Over the last few years, the complexity and diversity of gut microbiota within and across individuals has been detailed in relation to human health. Further, understanding of the bidirectional association between gut microbiota and metabolic disorders has highlighted a complimentary, yet crucial role for microbiota in the onset and progression of obesity-related cancers. While strategies for cancer prevention and cure are known to work efficiently when supported by healthy diet and lifestyle choices and physical activity, emerging evidence suggests that the complex interplay relating microbiota both to neoplastic and metabolic diseases could aid strategies for cancer treatment and outcomes. This review will explore the experimental and clinical grounds supporting the functional role of gut microbiota in the pathophysiology and progression of cancers in relation to obesity and its metabolic correlates. Therapeutic approaches aiding microbiota restoration in connection with cancer treatments will be discussed.
Angiology, 2020
Vascular function in dilated cardiomyopathy of different etiology has been poorly investigated. M... more Vascular function in dilated cardiomyopathy of different etiology has been poorly investigated. Moreover, reference values of flow-mediated dilation (FMD) in chronic heart failure (CHF) need to be updated according to the new standardized protocols. We characterized the vascular impairment in different stages of post-ischemic dilated cardiomyopathy (PI-DC) or idiopathic dilated cardiomyopathy (I-DC). Eighty consecutive outpatients with CHF in different New York Heart Association (NYHA) classes (45 PI-DC, 35 I-DC) and 50 control subjects underwent FMD and brachial distensibility coefficient measurement. Patients with CHF showed a marked impairment in FMD compared with controls that worsened from classes NYHA I-II to III-IV, independently of etiology ( P < .05). New York Heart Association I-II PI-DC patients showed a worse FMD compared with NYHA I-II I-DC patients ( P < .05). Brachial distensibility coefficient values were significantly lower in patients with CHF compared with c...
Background Findings from the T.O.S.CA. Registry recently reported that patients with concomitant ... more Background Findings from the T.O.S.CA. Registry recently reported that patients with concomitant chronic heart failure (CHF) and impairment of insulin axis (either insulin resistance- IR or diabetes mellitus- T2D) display increased morbidity and mortality. However, little information is available on the relative impact of IR and T2D on cardiac structure and function, cardiopulmonary performance, and their longitudinal changes in CHF. Methods Patients enrolled in the T.O.S.CA. Registry performed echocardiography and cardiopulmonary exercise test at baseline and at a patient-average follow-up of 36 months. Patients were divided into three groups based on the degree of insulin impairment: euglycemic without IR (EU), euglycemic with IR (IR), and T2D. Results Compared with EU and IR, T2D was associated with increased filling pressures ( E/e’ ratio : 15.9 ± 8.9, 12.0 ± 6.5, and 14.5 ± 8.1 respectively, p
Cells, 2022
Along with insulin resistance and increased risk of type 2 diabetes (T2D), lean first-degree rela... more Along with insulin resistance and increased risk of type 2 diabetes (T2D), lean first-degree relatives of T2D subjects (FDR) feature impaired adipogenesis in subcutaneous adipose tissue (SAT) and subcutaneous adipocyte hypertrophy well before diabetes onset. The molecular mechanisms linking these events have only partially been clarified. In the present report, we show that silencing of the transcription factor Homeobox A5 (HOXA5) in human preadipocytes impaired differentiation in mature adipose cells in vitro. The reduced adipogenesis was accompanied by inappropriate WNT-signaling activation. Importantly, in preadipocytes from FDR individuals, HOXA5 expression was attenuated, with hypermethylation of the HOXA5 promoter region found responsible for its downregulation, as revealed by luciferase assay. Both HOXA5 gene expression and DNA methylation were significantly correlated with SAT adipose cell hypertrophy in FDR, whose increased adipocyte size marks impaired adipogenesis. In pre...
Aging Cell, 2022
Senescence of adipose precursor cells (APC) impairs adipogenesis, contributes to the age‐related ... more Senescence of adipose precursor cells (APC) impairs adipogenesis, contributes to the age‐related subcutaneous adipose tissue (SAT) dysfunction, and increases risk of type 2 diabetes (T2D). First‐degree relatives of T2D individuals (FDR) feature restricted adipogenesis, reflecting the detrimental effects of APC senescence earlier in life and rendering FDR more vulnerable to T2D. Epigenetics may contribute to these abnormalities but the underlying mechanisms remain unclear. In previous methylome comparison in APC from FDR and individuals with no diabetes familiarity (CTRL), ZMAT3 emerged as one of the top‐ranked senescence‐related genes featuring hypomethylation in FDR and associated with T2D risk. Here, we investigated whether and how DNA methylation changes at ZMAT3 promote early APC senescence. APC from FDR individuals revealed increases in multiple senescence markers compared to CTRL. Senescence in these cells was accompanied by ZMAT3 hypomethylation, which caused ZMAT3 upregulation. Demethylation at this gene in CTRL APC led to increased ZMAT3 expression and premature senescence, which were reverted by ZMAT3 siRNA. Furthermore, ZMAT3 overexpression in APC determined senescence and activation of the p53/p21 pathway, as observed in FDR APC. Adipogenesis was also inhibited in ZMAT3‐overexpressing APC. In FDR APC, rescue of ZMAT3 methylation through senolytic exposure simultaneously downregulated ZMAT3 expression and improved adipogenesis. Interestingly, in human SAT, aging and T2D were associated with significantly increased expression of both ZMAT3 and the P53 senescence marker. Thus, DNA hypomethylation causes ZMAT3 upregulation in FDR APC accompanied by acquisition of the senescence phenotype and impaired adipogenesis, which may contribute to FDR predisposition for T2D.
Nutrition, Metabolism and Cardiovascular Diseases, 2020
Background and aims: To evaluate the economic impact of using 2nd generation basal insulin analog... more Background and aims: To evaluate the economic impact of using 2nd generation basal insulin analogs, Glargine 300 Units/ml (Gla-300) vs Degludec 100 Units/ml (IDeg-100), in patients with type 2 diabetes (T2D). Methods and results: An economic analysis was conducted using findings from the BRIGHT study (the first controlled, head-to-head study comparing Gla-300 vs IDeg-100), and costs for the Italian National Healthcare Service (NHS). A cost-minimization analysis (CMA) and a budget impact analysis (BIA) were conducted. Only pharmacological costs were included in the analysis. The CMA estimated patient treatment costs at 24 weeks and 1 year; the BIA assessed the economic impact of treating the overall Italian population of T2D insulin-naïve patients, who initiated insulin treatment during the period September 2017eAugust 2018 (N Z 55 318). In the BIA, four different scenarios were compared: i) all patients receive IDeg-100 (Scenario A); ii) 61% of patients receive Gla-300, 39% IDeg-100 (Scenario B); iii) 80% of patients receive Gla-300, 20% IDeg-100 (Scenario C); iv) all patients treated with Gla-300 (Scenario D). The average treatment costs per patient were lower with Gla-300 vs IDeg-100 (at 24 weeks: V129 vs V161; at 1 year: V324 vs V409, respectively). Results of the BIA showed that comparing Scenario D vs Scenario A, total savings would amount to V1.76 million at 24 weeks, V4.73 million at 1 year, V5.53 million at 2 years. Conclusion: A larger use of Gla-300 vs IDeg-100 for the treatment of T2D patients would lead to a relevant reduction of therapy costs in Italy.
International Journal of Molecular Sciences, 2021
Diabetes mellitus (DM) is a chronic metabolic disorder characterized by hyperglycemia, responsibl... more Diabetes mellitus (DM) is a chronic metabolic disorder characterized by hyperglycemia, responsible for the onset of several long-term complications. Recent evidence suggests that cognitive dysfunction represents an emerging complication of DM, but the underlying molecular mechanisms are still obscure. Dopamine (DA), a neurotransmitter essentially known for its relevance in the regulation of behavior and movement, modulates cognitive function, too. Interestingly, alterations of the dopaminergic system have been observed in DM. This review aims to offer a comprehensive overview of the most relevant experimental results assessing DA’s role in cognitive function, highlighting the presence of dopaminergic dysfunction in DM and supporting a role for glucotoxicity in DM-associated dopaminergic dysfunction and cognitive impairment. Several studies confirm a role for DA in cognition both in animal models and in humans. Similarly, significant alterations of the dopaminergic system have been o...
Minerva Endocrinology, 2018
INTRODUCTION Hypoglycemia is the major limiting factor in the glycemic management of diabetes. Ai... more INTRODUCTION Hypoglycemia is the major limiting factor in the glycemic management of diabetes. Aim of this study was to produce a risk stratification tool to support the medical decision making, by facilitating the identification of patients at higher risk of hypoglycemia. EVIDENCE ACQUISITION A multistep approach was adopted, including a systematic review of observational studies investigating risk factors for severe hypoglycemia in type 2 diabetes (T2DM), followed by an expert input forum to identify factors perceived as relevant and at the same time reliably detectable, to be used for the development of a risk score. EVIDENCE SYNTHESIS The systematic review led to the identification of 41 studies. Many factors have been seldom investigated, and their association with the risk of hypoglycemia is still unclear. Factors more frequently associated with a high risk of hypoglycemia were: low level of education, ethnicity, irregular meals/malnutrition, insulin and sulfonylurea therapy, polypharmacy, previous hypoglycemia, impaired renal function, cognitive impairment, depression and frailty. The expert input forum involved 35 diabetologists. Following the ranking of the relevance of the factors identified, a parsimonious yet comprehensive set of risk factors was identified. CONCLUSIONS The process led to the identification of relevant factors, to be used for the development of a hypoglycemia risk score. An ad-hoc study will be performed to assess the contribution of these risk factors and their relative weight. If the risk score will confirm its ability to correctly stratify patients according to their risk of hypoglycemia, it will represent a useful support to optimize the care of people with T2DM.
Heart Failure Clinics, 2020
Many patients with chronic heart failure show some hormonal deficiency that might worsen morbidit... more Many patients with chronic heart failure show some hormonal deficiency that might worsen morbidity and mortality. Chronic heart failure development might be explained by the imbalance between catabolic and anabolic pathways present in the disease. Multiple hormonal deficiency is associated with a relevant worsening of prognosis in patients with chronic heart failure and patients should be screened for it. Replacement hormonal therapy in patients with chronic heart failure has shown promising beneficial results.
Internal and Emergency Medicine, 2018
Background: Multiple hormonal deficiency syndrome (MHDS) is common in heart failure (HF). To date... more Background: Multiple hormonal deficiency syndrome (MHDS) is common in heart failure (HF). To date, no large observational study has unequivocally demonstrated that MHDS impacts on HF progression. Aim of the T.O.S.CA. Registry (NCT02335801) was to test whether MHDS affects morbidity and mortality in a large cohort of HF patients. Methods: The T.O.S.CA. Registry is a prospective, observational study involving 19 Italian centers. Thyroid hormones, insulin-like growth factor-1, testosterone, dehydropianoandrosterone, and insulin were measured at baseline and every year for a patient-average follow-up of 3 years. MHDS was defined as the presence of 2 or more hormonal deficiency (HD). Primary endpoint was a composite of all-cause mortality and cardiovascular hospitalizations. Results: A total of 526 consecutive patients was enrolled with a median follow-up of 36 months. MHDS was diagnosed in 405 patients (75%). A total of 276 events (98 death and 176 cardiovascular hospitalizations) were recorded; respectively 42.7% in MHDS-and 62.2 % in MHDS (p:0.001). MHDS was independently associated with the occurrence of the primary endpoint [HR 95% (CI), p-value: 1.58 (1.16-2.15), p:0.001] (Panel A). Further, MHDS identified a group of patients with higher mortality (χ2=9.2, p=0.03). Moreover a graded relation between HD and cumulative events were found (p:0.01) (Panel B). Conclusion: MHDS is a common finding in CHF and is independently associated with increased all-cause mortality and CV hospitalization.
Diabetes, Obesity and Metabolism, 2018
The Journal of Clinical Endocrinology & Metabolism, 1994
To determine the role of insulin and free fatty acid (FFA) concentration in the regulation of FFA... more To determine the role of insulin and free fatty acid (FFA) concentration in the regulation of FFA metabolism, forearm FFA fluxes were quantified in 16 healthy volunteers by combining the forearm perfusion technique with the infusion of [3H]palmitate. Three groups of studies were performed. In study 1 (n = 6), a systemic insulin infusion (1.2 mU/kg.min) was performed for 120 min while euglycemia was maintained by a variable glucose infusion. In Study 2 (n = 5), insulin (0.05 mU/kg.min) was infused into the brachial artery to expose the forearm tissues to the same insulin level as in study 1. In study 3 (n = 5), heparin was infused to raise plasma FFA concentration to 1-1.5 mmol/L. At 60 min, an intrabrachial insulin infusion was added as in study 2 and maintained for 60 min. During systemic insulin infusion, plasma FFA concentration fell to 0.09 +/- 0.02 mmol/L. Forearm FFA uptake (FFA-U) decreased from the basal value of 2.54 +/- 0.52 to 0.95 +/- 0.10 mumol/L.min (P &amp;lt; 0.05). Likewise, forearm FFA release (FFA-R) fell to 1.0 +/- 0.31 mumol/L.min (P &amp;lt; 0.05). With local insulin administration, both FFA levels and FFA-U remained unchanged, whereas FFA-R was markedly inhibited (from 1.78 +/- 0.23 to 1.04 +/- 0.24 mumol/L.min; P &amp;lt; 0.05). In study 3 (heparin infusion), FFA levels rose to 1.17 +/- 0.12 mmol/L due to a 4-fold increase in FFA-R (from 1.18 +/- 0.36 to 6.92 +/- 2.40 mumol/L.min; P &amp;lt; 0.05). FFA-U rose from the basal value of 2.50 +/- 0.82 to 6.92 +/- 1.95 mumol/L.min (P &amp;lt; 0.05). Addition of intrabrachial insulin did not modify FFA-U, whereas heparin activation of FFA-R was only partially antagonized (4.53 +/- 2.40 mumol/L.min; 0.01 &amp;lt; P &amp;lt; 0.05 vs. heparin alone). The data demonstrate that plasma FFA concentration is the main determinant of forearm FFA transport. Insulin exerts a direct inhibitory effect on FFA release and affects tissue FFA transport only indirectly through the fall in circulating FFA.
European Heart Journal, 2003
Diabetes Research and Clinical Practice, 1991
To investigate the effects of carnitine on insulin sensitivity in non-insulin-dependent diabetes,... more To investigate the effects of carnitine on insulin sensitivity in non-insulin-dependent diabetes, insulin-mediated glucose disposal was measured in nine diabetic patients (age 54 +/- 3 years, BMI 27 +/- 1 kg/mq) during a primed (3 mmol) constant (1.7 mumol/min) intravenous infusion of carnitine. In control experiments, the same patients received saline instead of carnitine. Plasma glucose concentration was maintained constant at the level of 100 mg/dl during both studies while plasma insulin was raised to a plateau of 60 microU/ml. Despite similar insulin levels, whole-body glucose utilization was higher with carnitine (4.05 +/- 0.37 mg/kg/min) than saline infusion (3.52 +/- 0.36). Blood lactate concentrations were similar in the basal state and decreased significantly during carnitine infusion (P less than 0.05-0.005), whereas it remained substantially unchanged during saline infusion. Plasma FFA decreased to a similar level (0.1 mmol/l) in both studies. We conclude that an acute carnitine administration is able to improve insulin sensitivity in NIDDM patients. The lactate data suggest that this effect may at least in part be mediated by carnitine activation of pyruvate dehydrogenase.
Nutrition, Metabolism and Cardiovascular Diseases, 2021
Patients with type 2 diabetes mellitus (T2DM) show an increased risk of cardiovascular diseases (... more Patients with type 2 diabetes mellitus (T2DM) show an increased risk of cardiovascular diseases (CVD) and mortality. Many factors are implicated in the pathogenesis of CVD in patients with T2DM. Among the factors involved, chronic hyperglycemia and the cluster of CVD risk factors, such as dyslipidemia, hypertension, and obesity, play a major role. For many years, the control of hyperglycemia has been complicated by the fact that the use of many available drugs was associated with an increased risk of hypoglycemia. Paradoxically, hypoglycemia per se represents a risk factor for CVD. Recently, new drugs for the control of hyperglycemia have become available: many of them can determine a good control of hyperglycemia with minor risks of hypoglycemia. Among these new classes of drugs, glucagon-like peptide-1 receptor agonists (GLP-1RAs) offer many advantages. In addition to a strong anti-hyperglycemic action, they possess the ability to act on body weight and other relevant risk factors for CVD. Consistently, some of the GLP-1RAs have demonstrated, in RCT designed to assess their safety, to reduce the risk of major adverse cardiovascular events. Furthermore, GLP-1RAs possess properties useful to treat additional conditions, as the capability of improving liver damage in patients with NAFLD or NASH, highly prevalent conditions in people with T2DM. In this document, written by experts of the Italian diabetes society (SID), we will focus our attention on the therapy with GLP-1RAs in patients with T2DM, particularly on the effects on hyperglycemia, cardiovascular disease risk factors, NAFLD/NASH and CVD prevention.
Nutrition, Metabolism and Cardiovascular Diseases, 2020
This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Metabolism, 1991
To determine the contribution of skeletal muscle to the insulin resistance of essential hypertens... more To determine the contribution of skeletal muscle to the insulin resistance of essential hypertension, insulin-stimulated forearm glucose uptake was quantitated in 12 control (age, 32 * 3 years) and 12 hypertensive subjects (age, 36 + 2 years) using the forearm perfusion technique. Peripheral insulin levels were raised acutely (-60 FU/mL), while blood glucose concentration was clamped at its basal value (90 mg/dL) by a variable glucose infusion. During insulin stimulation, whole body glucose uptake was lower in hypertensive (4.5 ? .3 mgkg-' * min-') than in normal subjects (5.6 "_ .4 mg. kg-'. min-', P < .05). Similarly, the amount of glucose taken up by the forearm was markedly reduced in the hypertensive (5.3 2 .91 mg. L-'. min-') compared with the control group (6.7 f 1.1 mg. L-'. min-'). No appreciable difference was observed as to forearm blood flow (39 +-4 mL. L-'min-' and 37-c 5 mL * L-' * min-') in hypertensive patients. These results indicate that skeletal muscle is a major site of insulin resistance in essential hypertension and that this defect is independent of muscle perfusion.