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Background: Platelets play an important role in the development of cardiovascular disease (CVD). Mean platelet volume (MPV) is considered as biological marker of platelets activity and function. The aim of the present study was to evaluate MPV values and its possible correlation with arterial stiffness and subclinical myocardial damage, in normal glucose tolerance patients (NGT), in newly diagnosed type 2 diabetic (T2DM) patients and in individuals with pre-diabetes., Methods: We enrolled 400 newly diagnosed hypertensive patients. All patients underwent an Oral Glucose Tolerance test (OGTT). Arterial stiffness (AS) was evaluated with the measurement of carotid-femoral pulse wave velocity (PWV), augmentation pressure (AP) and augmentation index (AI). Echocardiographic recordings were performed using an E-95 Pro ultrasound system., Results: Among groups there was an increase in fasting plasma glucose (FPG) (p < 0.0001), fasting plasma insulin (FPI) (p < 0.0001), high sensitivity c reactive protein (hs-CRP) levels (p < 0.0001) and a decrease in renal function as demonstrated by e-GFR values (p < 0.0001). From the NGT group to the T2DM group there was a rise in MPV value (p < 0.0001). Moreover, in the evaluation of arterial stiffness and subclinical myocardial damage, MPV showed a positive correlation with these parameters., Conclusions: In the present study we highlighted that MPV is significantly increased, not only in newly diagnosed T2DM patients, but also in early stage of diabetes, indicating that subjects with pre-diabetes present increased platelets reactivity. Moreover, our results suggest that MPV is associated with increased arterial stiffness and subclinical myocardial damage, indicating MPV as new marker of CV risk., (© 2024. The Author(s).)

Context: Metabolic syndrome and elevated high-sensitivity C-reactive protein (hsCRP) levels are associated with risk of cardiovascular diseases. A reduced myocardial mechano-energetic efficiency (MEE) has been found to be an independent predictor of cardiovascular disease., Objective: To evaluate the association between metabolic syndrome and hsCRP levels with impaired MEE., Methods: Myocardial MEE was assessed by a validated echocardiography-derived measure in 1975 nondiabetic and prediabetic individuals subdivided into 2 groups according to the presence of metabolic syndrome., Results: Individuals with metabolic syndrome exhibited increased stroke work and myocardial oxygen consumption estimated by rate pressure product, and a reduced MEE per gram of left ventricular mass (MEEi) compared with subjects without metabolic syndrome, after adjusting for age and sex. Myocardial MEEi progressively decreased in parallel with the increase in the number of metabolic syndrome components. In a multivariable regression analysis, both metabolic syndrome and hsCRP contributed to reduced myocardial MEEi independently of sex, total cholesterol, high-density lipoprotein, triglycerides, fasting, and 2-hour postload glucose levels. When the study population was divided into 4 groups by the presence or absence of metabolic syndrome and by hsCRP levels above and below 3 mg/L, hsCRP levels ≥3 mg/L were associated with reduced myocardial MEEi both in subjects with metabolic syndrome and in those without the syndrome., Conclusion: Nondiabetic and prediabetic individuals with metabolic syndrome exhibit increased stroke work and myocardial oxygen consumption, and an impaired MEEi, an established predictor of adverse cardiovascular events, and elevated hsCRP levels in combination with metabolic syndrome aggravate the myocardial MEEi impairment., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Aim: Individuals with high 1-hour post-load glucose (1-h PG > 155 mg/dl; 8.6 mmol/l) during an oral glucose tolerance test are at increased risk of type 2 diabetes (T2D) and cardiovascular complications, hepatic steatosis, and mortality. However,the clinical relevance of 1-h PG for the severity of hepatic fibrosis risk remains undefined., Methods: Cross-sectional data of the CATAMERI study (n = 2335) were analyzed. Participants underwent anthropometric measurements, liver enzyme determinations, cardiometabolic profiling, and a75-gram oral glucose tolerance test, including fasting, 1-h and 2-h PG determinations and measurement of FIB-4 score to assess degree of hepatic fibrosis. Multivariable logistic regression analysis was performed to evaluate risk of advanced hepatic fibrosis with worsening glycemic status., Results: We stratifiedthe study group into 6 categories based on glycemic status: normal glucose tolerance (NGT) 1h-PG Low, NGT 1h-PG High, iIFG 1h-PG Low, iIFG 1h-PG High, IGT, and newly detected T2D. Anthropometric and cardiometabolic profiles worsened gradually with glycemic status. Moreover, compared to NGT-1h-PG Low group, worsening glycemic status was significantly associated with the severity of fibrosis, independent of other significant clinical risk factors., Conclusions: 1-PG is a valuable tool for stratifying subjects with NGT or IFG at heightened risk of hepatic fibrosis requiring further evaluation with elastography., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Prior studies in animal models showed that increased cardiac expression of TRIB3 has a pathogenic role in inducing left ventricular mass (LVM). Whether alterations in TRIB3 expression or function have a pathogenic role in inducing LVM increase also in humans is still unsettled. In order to address this issue, we took advantage of a nonsynonymous TRIB3 Q84R polymorphism (rs2295490), a gain-of-function amino acid substitution impairing insulin signalling, and action in primary human endothelial cells which has been associated with insulin resistance, and early vascular atherosclerosis., Methods: SNP rs2295490 was genotyped in 2426 White adults in whom LVM index (LVMI) was assessed by validated echocardiography-derived measures., Results: After adjusting for age and sex, LVMI progressively and significantly increased from 108 to 113, to 125 g/m 2 in Q84Q, Q84R, and R84R individuals, respectively (Q84R vs. Q84Q, P = 0.03; R84R vs. Q84Q, P < 0.0001). The association between LVMI and the Q84R and R84R genotype remained significant after adjusting for blood pressure, smoking habit, fasting glucose levels, glucose tolerance status, anti-hypertensive treatments, and lipid-lowering therapy (Q84R vs. Q84Q, P = 0.01; R84R vs. Q84Q, P < 0.0001)., Conclusions: We found that the gain-of-function TRIB3 Q84R variant is significantly associated with left ventricular mass in a large sample of White nondiabetic individual of European ancestry.

Background: Nonalcoholic fatty liver disease (NAFLD) is linked to a raised risk of cardiovascular diseases (CVD), although the underlying mechanisms are not completely known. A reduced myocardial mechano-energetic efficiency (MEE) has been found to be an independent predictor of CVD., Objective: To evaluate the association between NAFLD and a compromised MEE., Methods: Myocardial MEE was assessed by a validated echocardiography-derived measure in 699 nondiabetic individuals subdivided into two groups according to ultrasonography defined presence of NAFLD., Results: Subjects with NAFLD displayed higher levels of systolic (SBP) and diastolic blood pressure (DBP), triglycerides, fasting and postload glucose, high-sensitivity C-reactive protein (hsCRP), insulin resistance (IR) estimated by HOMA-IR and liver IR index, and lower values of high-density lipoprotein (HDL) in comparison with those without NAFLD. Presence of NAFLD was associated with increased levels of myocardial oxygen demand and reduced values of MEE. MEE was negatively correlated with male sex, age, BMI, waist circumference, SBP, DBP, total cholesterol, triglycerides, fasting and postload glucose, HOMA-IR and liver IR index, hsCRP and positively with HDL levels. In a multivariable regression analysis, presence of NAFLD was associated with MEE regardless of several cardio-metabolic risk factors such as age, gender, waist circumference, SBP, DBP, total and HDL cholesterol, triglycerides, glucose tolerance and hsCRP (β = -0.09, P = 0.04), but not independently of IR estimates., Conclusion: Ultrasound-defined presence of NAFLD is associated with a decreased MEE, a predictor of adverse cardiovascular events. The relationship between NAFLD and a compromised MEE is dependent of IR., (© 2020 The Association for the Publication of the Journal of Internal Medicine.)

Objective: Most but not all studies suggest that women with type 2 diabetes have higher relative risk (RR) for cardiovascular disease (CVD) than men. More uncertainty exists on whether the RR for CVD is higher in women with prediabetes compared with men with prediabetes., Research Design and Methods: In a cross-sectional study, in 3,540 adults with normal glucose tolerance (NGT), prediabetes, and diabetes, we compared the RR for prevalent nonfatal CVD between men and women. In a longitudinal study including 1,658 adults with NGT, prediabetes, and diabetes, we compared the RR for incidences of major adverse outcomes, including all-cause death, coronary heart disease, and cerebrovascular disease events, after 5.6 years of follow-up., Results: Women with prediabetes and diabetes exhibited greater relative differences in BMI, waist circumference, blood pressure, total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, fasting glucose, hs-CRP, and white blood cell count than men with prediabetes and diabetes when compared with their NGT counterparts. We found a higher RR for prevalent CVD in women with diabetes (RR 9.29; 95% CI 4.73-18.25; P < 0.0001) than in men (RR 4.56; 95% CI 3.07-6.77; P < 0.0001), but no difference in RR for CVD was observed comparing women and men with prediabetes. In the longitudinal study, we found that women with diabetes, but not those with prediabetes, have higher RR (RR 5.25; 95% CI 3.22-8.56; P < 0.0001) of incident major adverse outcomes than their male counterparts (RR 2.72; 95% CI 1.81-4.08; P < 0.0001)., Conclusions: This study suggests that women with diabetes, but not those with prediabetes, have higher RR for prevalent and incident major adverse outcomes than men., (© 2020 by the American Diabetes Association.)

Introduction: Non-alcoholic fatty liver disease (NAFLD) is associated with cardiovascular disease (CVD) in patients with type 2 diabetes; nonetheless, it is unknown whether the relationship between NAFLD and CVD occurs also in subjects with prediabetes. Herein, we evaluated whether NAFLD is associated with prevalent CVD in subjects with different glucose tolerance states independently of cardiovascular risk factors., Materials and Methods: Presence of NALFD, defined by liver ultrasound, and its association with prevalent composite and individual CVD, including coronary artery disease (CAD) and cerebrovascular disease, was assessed in a cohort of 1254 Caucasian subjects classified as having normal glucose tolerance (NGT, n = 517), prediabetes (n = 397) or type 2 diabetes (n = 340)., Results: Prevalence of NAFLD in the study population was 47.9%. Presence of NAFLD was linked to an augmented prevalence of composite CVD and individual CAD in all the three glucose tolerance groups. In a logistic regression model adjusted for several cardio-metabolic risk factors, subjects with NGT and NAFLD exhibited a 3.2- and 3.4-fold increased risk of having CVD or CAD, respectively, as compared with those without NAFLD. Similarly, subjects with prediabetes and NAFLD showed an increased risk of having CVD or CAD by 2.3- and 2.0-fold, respectively, in comparison to their counterpart without NAFLD. Within the group with type 2 diabetes, subjects having NAFLD displayed a 2.3- and 2.0-fold higher risk of having CVD or CAD, respectively, in comparison to those without NAFLD., Conclusion: Ultrasonography-defined NAFLD is independently associated with an increased risk of having CVD in individuals with different glucose tolerance., (© 2020 John Wiley & Sons Ltd.)

Magnesium (Mg 2+ ) levels are associated with insulin resistance, hypertension, atherosclerosis, and type 2 diabetes (T2DM). We evaluated the clinical utility of physiological Mg 2+ in assessing subclinical cardiovascular organ damage including increased carotid artery intima- media thickness (c-IMT) and left ventricular mass index (LVMI) in a cohort of well-characterized adult non-diabetic individuals. Age- and gender-adjusted correlations between Mg 2+ and metabolic parameters showed that Mg 2+ circulating levels were correlated negatively with body mass index (BMI), fasting glucose, and 2h-oral glucose tolerance test (OGTT) glucose. Similarly, Mg 2+ levels were significantly and negatively related to c-IMT and LVMI. A multivariate regression analysis revealed that age (β = 0.440; p < 0.0001), BMI (β = 0.225; p < 0.0001), and Mg 2+ concentration (β = -0.122; p < 0.01) were independently associated with c-IMT. Age (β = 0.244; p = 0.012), Mg 2+ (β = -0.177; p = 0.019), and diastolic blood pressure (β = 0.184; p = 0.038) were significantly associated with LVMI in women, while age (β = 0.211; p = 0.019), Mg 2+ (β = -0.171; p = 0.038) and the homeostasis model assessment index of insulin resistance (HOMA-IR) (β = -0.211; p = 0.041) were the sole variables associated with LVMI in men. In conclusion, our data support the hypothesis that the assessment of Mg 2+ as part of the initial work-up might help unravel the presence of subclinical organ damage in subjects at increased risk of cardiovascular complications., Competing Interests: The authors declare no conflict of interest.

Aims: A value of 1-hour post-load plasma glucose (PG) ≥155 mg/dL combined with the recently established HbA1c diagnostic thresholds for prediabetes increases the ability to predict diabetes and to detect subclinical cardiovascular organ damage. Herein, we evaluated whether a value of 1-hour PG ≥155 mg/dL may recognize non-diabetic individuals with an increased risk of cardiovascular diseases (CVD) within HbA1c-defined glycemic categories., Materials and Methods: The prevalence of composite and individual CVD, including coronary artery disease (CAD) and cerebrovascular disease, was assessed in 1010 non-diabetic individuals., Results: Within the group with HbA1c <5.7%, a higher proportion of subjects with 1-hour PG ≥ 155 mg/dL had composite CVD and individual CAD in comparison to those having 1-hour PG˂155 mg/dL. Similarly, within the group with HbA1c-defined prediabetes (5.7%-6.4%), the prevalence of composite CVD and individual CAD in subjects with 1-hour PG ≥155 mg/dL was higher than in the group with individuals having 1-hour PG < 155 mg/dL. In a logistic regression analysis adjusted for several CVD risk factors individuals with HbA1c <5.7% and 1-hour PG ≥ 155 mg/dL and those with HbA1c 5.7% to 6.4% and 1-hour PG ≥ 155 mg/dL had a 4.5- (95%CI: 1.02-20.44) and 6.2- (95%CI: 1.29-29.74) fold increased risk of composite CVD and 6.2- (95%CI: 1.05-36.32) and 8.0- (95%CI: 1.25-51.70) fold increased risk of having CAD, respectively, in comparison to individuals with HbA1c <5.7% and 1-hour PG < 155 mg/dL., Conclusions: 1-hour post-load hyperglycemia may identify a subset of individuals within HbA1c-defined glycemic categories at higher risk of having CVD., (© 2018 John Wiley & Sons, Ltd.)

Background and Aims: A link between increased blood viscosity and type 2 diabetes has been previously reported. Herein, we investigated the association of blood viscosity with prediabetes, identified by glycated hemoglobin A1c (HbA1c) according to the new American Diabetes Association criteria, and subclinical atherosclerosis., Methods and Results: The study cohort includes 1136 non-diabetic adults submitted to anthropometrical evaluation, an oral glucose tolerance test and ultrasound measurement of carotid intima-media thickness (IMT). Whole blood viscosity was estimated using a validated formula based on hematocrit and total plasma proteins. After adjusting for age, and gender, individuals with HbA1c-defined prediabetes (HbA1c 5.7-6.4% [39-47 mmol/mol]) exhibited significantly higher values of hematocrit, and predicted blood viscosity as compared with controls. Increased levels of IMT were observed in subjects with HbA1c-defined prediabetes in comparison to controls. Predicted blood viscosity was positively correlated with age, waist circumference, blood pressure, cholesterol, triglycerides, fibrinogen, white blood cell, HbA1c, fasting and 2-h post-load glucose levels, fasting insulin, IMT and inversely correlated with HDL and Matsuda index of insulin sensitivity. Of the three glycemic parameters, i.e. HbA1c, fasting and 2-h post-load glucose, only HbA1c showed a significant correlation with predicted blood viscosity (β = 0.054, P = 0.04) in a multivariate regression analysis model including multiple atherosclerosis risk factors., Conclusion: The study shows that individuals with HbA1c-defined prediabetes have increased predicted blood viscosity and IMT. The HbA1c criterion may be helpful to capture individuals with an increased risk of diabetes and cardiovascular disease who may benefit from an intensive lifestyle intervention., (Copyright © 2017 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

The results of the cardiovascular outcome trials comparing the SGLT2 inhibitor empagliflozin and the glucagon-like peptide-1 receptor agonist liraglutide to placebo have been recently published. Interestingly, empagliflozin and liraglutide treatments significantly reduce cardiovascular events in subjects with type 2 diabetes. The mechanisms underlying the observed cardioprotective effects of empagliflozin and liraglutide are speculative and future studies are needed to better understand these results. However, since reduction in the primary outcome was evident 3 months after starting empagliflozin and 24 months after starting liraglutide, it is tempting to hypothesize that the cardiovascular benefits observed in diabetic patients treated with empagliflozin are due to its hemodynamic effects and to metabolic substrate shift induced by the mild and persistent hyperketonemia, while the positive effects of liraglutide treatment may be attributable to biologic changes of atherosclerotic lesions.

Aim: Endoplasmic reticulum (ER) stress is implicated in the pathogenesis of several human disorders, including cardiovascular disease (CVD). CVD recognizes endothelial dysfunction (ED) as its pathogenetic primum movens; interestingly a large body of evidence has identified the unchecked ER stress response as a main actor in vascular damage elicited by various cardio-metabolic risk factors. In the present Review, we summarize findings from experimental studies on the ER stress-related ED, focusing on the mechanisms underlying this association., Data Synthesis: Different noxious agents, such as hyperhomocysteinemia, hyperlipidemia, hyperglycemia and chronic inflammation, induce ED promoting an amplified ER stress response as demonstrated by several studies in animal models, as well as in human primary and immortalized endothelial cells. ER stress represents therefore a key mediator of vascular damage, operating in a setting of increased inflammatory burden and oxidative stress, thus contributing to foster a vicious pathogenic cycle., Conclusions: Experimental studies summarized in this Review strongly suggest that an unchecked ER stress response plays a central role in the pathogenesis of ED and, consequently, CVD. Counteracting ER stress may thus represent a promising, even if largely unexplored as-yet, therapeutic approach aimed to prevent vascular damage, slowing the progression from ED to cardiovascular events., (Copyright © 2016 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Previous trials of glucose-lowering strategies in subjects with type 2 diabetes have demonstrated a beneficial effect of intensive glycemic control on microvascular complications but failed to show a clear benefit on cardiovascular complications. The findings of meta-analyses of rosiglitazone trials suggesting that rosiglitazone might increase the risk of myocardial infarction have cast doubt on the cardiovascular safety of glucose-lowering drugs. In 2008, the US Food and Drug Administration has implemented rigorous criteria to approve new glucose-lowering drugs, requiring proof of cardiovascular safety. These regulatory requirements have led to a considerable increase in the number of cardiovascular outcome trials in type 2 diabetes to ensure that newer glucose-lowering drugs are not associated with increased cardiovascular risk. Incretin-based therapies including dipeptidyl peptidase 4 (DPP-4) inhibitors, and injectable glucagon-like peptide 1 (GLP-1) receptor agonists are novel treatment options for patients with inadequate glucose control. Although DPP-4 inhibitors have shown neutral effects on risk factors for cardiovascular diseases, it remains unclear whether treatment with these new glucose-lowering agents might be associated with a reduction in cardiovascular events. The results of the three cardiovascular outcome trials comparing DPP-4 inhibitors treatment to placebo in addition to other glucose-lowering drugs have been published. All the three DPP-4 inhibitor cardiovascular outcome trials have shown non-inferiority with regard to cardiovascular safety, compared with placebo, when added to usual care. In this review, we summarize cardiovascular outcome trials of DPP-4 inhibitors, and provide an overview of these trials and their limitations.

Clinical trials of glucose-lowering strategies in patients with type 2 diabetes mellitus (T2DM) have shown a favorable effect of intensive glycemic control on microvascular complications but failed to show a clear benefit on cardiovascular events. In 2008, the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) have required stringent criteria to approve new glucose-lowering drugs, demanding proof of cardiovascular safety. As a result of these regulatory requirements, a number of cardiovascular outcome trials in T2DM have been conducted examining the cardiovascular safety of novel glucose-lowering drugs. Dipeptidyl peptidase 4 (DPP4) inhibitors, analogs of glucagon-like peptide 1 (GLP-1), and inhibitors of the renal sodium-glucose linked transporter-2 (SGLT2) are new classes of glucose-lowering drugs for subjects with T2DM. The results of the cardiovascular outcome trials comparing the DPP4 inhibitors saxagliptin, alogliptin, and sitagliptin or the GLP-1 analog lixisenatide to placebo have demonstrated that these drugs are safe. The results of a cardiovascular outcome trial comparing the SGLT2 inhibitor empagliflozin to placebo have been published. Notably, empagliflozin treatment has been associated with a significant reduction in the primary composite cardiovascular outcome. Although the question regarding the positive effect of glycemic control on cardiovascular risk is still unanswered, current evidence suggests that a multifactorial approach aimed at treating not only hyperglycemia but also classical cardiovascular risk factors is necessary in order to reduce the risk of cardiovascular events in patients with T2DM.

Tight glycemic control represents one of the major goals of the therapeutic management of diabetes mellitus. However, several clinical studies have reported that an intensive glucose-lowering treatment, especially when insulin or sulfonylureas are used, is associated with an increased risk of hypoglycemia and may exert negative effects on the cardiovascular risk. Hypoglycemia is the major side effect of antidiabetic therapy and it has also been associated with adverse cardiovascular events. The surge of sympathetic activity during hypoglycemic episodes may induce cardiac and cerebral ischemia and promote potentially fatal arrhythmias. In addition, hypoglycemic episodes have a negative effect on patient compliance to the antidiabetic treatment and consequently may worsen glycemic control, thus increasing the risk of micro- and macroangiopathic complications of diabetes. Therefore, in order to counteract the cardiovascular risk it is necessary achieving a good glycemic control through therapeutic strategies associated with a lower risk of hypoglycemia. Unlike treatment with sulfonylureas, glucagon-like peptide-1 analogs and dipeptidyl peptidase-4 inhibitors have been demonstrated to improve metabolic control without inducing hypoglycemia and, therefore, represent a new therapeutic option for type 2 diabetes, which offer the advantage of combining glucose-lowering activity with a low risk of hypoglycemia, thus providing a greater cardiovascular protection.

Evidence suggests that advanced fibrosis, as determined by the noninvasive NAFLD fibrosis score (NFS), is a predictor of cardiovascular mortality in individuals with ultrasonography-diagnosed NAFLD. Whether the severity of histology (i.e., fibrosis stage) is associated with more pronounced cardiovascular organ damage is unsettled. In this study, we analyzed the clinical utility of NFS in assessing increased carotid intima-media thickness (cIMT), and left ventricular mass index (LVMI). In this cross-sectional study NFS, cIMT and LVMI were assessed in 400 individuals with ultrasonography-diagnosed steatosis. As compared with individuals at low probability of liver fibrosis, individuals both at high and at intermediate probability of fibrosis showed an unfavorable cardio-metabolic risk profile having significantly higher values of waist circumference, insulin resistance, high sensitivity C-reactive protein (hsCRP), fibrinogen, cIMT, and LVMI, and lower insulin-like growth factor-1 (IGF-1) levels. The differences in cIMT and LVMI remained significant after adjustment for smoking and metabolic syndrome. In a logistic regression model adjusted for age, gender, smoking, and diagnosis of metabolic syndrome, individuals at high probability of fibrosis had a 3.9-fold increased risk of vascular atherosclerosis, defined as cIMT>0.9 mm, (OR 3.95, 95% CI 1.12-13.87) as compared with individuals at low probability of fibrosis. Individuals at high probability of fibrosis had a 3.5-fold increased risk of left ventricular hypertrophy (LVH) (OR 3.55, 95% CI 1.22-10.34) as compared with individuals at low probability of fibrosis. In conclusion, advanced fibrosis, determined by noninvasive fibrosis markers, is associated with cardiovascular organ damage independent of other known factors.

Increased plasma levels of both leptin and C reactive protein (CRP) have been reported in a number of conditions, including obesity, and have been linked to cardiovascular pathophysiological processes and increased cardiovascular risk; interestingly these two biomarkers appear to be able to reciprocally regulate their bioavailability, through complex mechanisms that have not been completely clarified yet. Here we first review clinical evidence suggesting not only that the circulatory levels of CRP and leptin show an independent correlation, but also that assessing them in tandem may result in an increased ability to predict cardiovascular disease. We summarize also molecular studies showing that leptin is able to promote CRP production from hepatocytes and endothelial cells in vitro and discuss the studies addressing the possibility that in vivo leptin administration may be able to modulate plasma CRP levels. Furthermore, we describe two studies demonstrating that CRP directly binds leptin in extra-cellular settings, thus impairing its biological actions. Finally we report genetic evidence that common variations at the leptin receptor locus are associated with CRP blood levels. Overall, the data reviewed here show that the chronic elevation of CRP observed in obese subjects may worsen leptin resistance, contributing to the pathogenesis of cardiovascular disease, and highlight a potential link between conditions, such as leptin resistance and endothelial dysfunction, that may be amenable of pharmacological treatment targeted to the disruption of leptin-CRP interaction.

Diabetes mellitus is associated to an increased risk of cardiovascular diseases. Hyperglycemia is an important factor in cardiovascular damage, working through different mechanisms such as activation of protein kinase C, polyol and hexosamine pathways, advanced glycation end products production. All of these pathways, in association to hyperglycemia-induced mitochondrial dysfunction and endoplasmic reticulum stress, promote reactive oxygen species (ROS) accumulation that, in turn, promote cellular damage and contribute to the diabetic complications development and progression. ROS can directly damage lipids, proteins or DNA and modulate intracellular signaling pathways, such as mitogen activated protein kinases and redox sensitive transcription factors causing changes in protein expression and, therefore, irreversible oxidative modifications. Hyperglycemia-induced oxidative stress induces endothelial dysfunction that plays a central role in the pathogenesis of micro- and macro-vascular diseases. It may also increase pro-inflammatory and pro-coagulant factors expression, induce apoptosis and impair nitric oxide release. Oxidative stress induces several phenotypic alterations also in vascular smooth-muscle cell (VSMC). ROS is one of the factors that can promote both VSMC proliferation/migration in atherosclerotic lesions and VSMC apoptosis, which is potentially involved in atherosclerotic plaque instability and rupture. Currently, there are contrasting clinical evidences on the benefits of antioxidant therapies in the prevention/treatment of diabetic cardiovascular complications. Appropriate glycemic control, in which both hypoglycemic and hyperglycemic episodes are reduced, in association to the treatment of dyslipidemia, hypertension, kidney dysfunction and obesity, conditions which are also associated to ROS overproduction, can counteract oxidative stress and, therefore, both microvascular and macrovascular complications of diabetes mellitus.