Association between higher duodenal levels of the fructose carrier glucose transporter-5 and nonalcoholic fatty liver disease and liver fibrosis.

BACKGROUND: An increased dietary fructose intake has been shown to exert several detrimental metabolic effects and contribute to the pathogenesis of nonalcoholic fatty liver disease (NAFLD). An augmented intestinal abundance of the fructose carriers glucose transporter-5 (GLUT-5) and glucose transporter-2 (GLUT-2) has been found in subjects with obesity and type 2 diabetes. Herein, we investigated whether elevated intestinal levels of GLUT-5 and GLUT-2, resulting in a higher dietary fructose uptake, are associated with NAFLD and its severity. METHODS: GLUT-5 and GLUT-2 protein levels were assessed on duodenal mucosa biopsies of 31 subjects divided into 2 groups based on ultrasound-defined NAFLD presence who underwent an upper gastrointestinal endoscopy. RESULTS: Individuals with NAFLD exhibited increased duodenal GLUT-5 protein levels in comparison to those without NAFLD, independently of demographic and anthropometric confounders. Conversely, no difference in duodenal GLUT-2 abundance was observed amongst the two groups. Univariate correlation analyses showed that GLUT-5 protein levels were positively related with body mass index, waist circumference, fasting and 2 h post-load insulin concentrations, and insulin resistance (IR) degree estimated by homeostatic model assessment of IR (r = 0.44; p = 0.02) and liver IR (r = 0.46; p = 0.03) indexes. Furthermore, a positive relationship was observed between duodenal GLUT-5 abundance and serum uric acid concentrations (r = 0.40; p = 0.05), a product of fructose metabolism implicated in NAFLD progression. Importantly, duodenal levels of GLUT-5 were positively associated with liver fibrosis risk estimated by NAFLD fibrosis score. CONCLUSION: Increased duodenal GLUT-5 levels are associated with NAFLD and liver fibrosis. Inhibition of intestinal GLUT-5-mediated fructose uptake may represent a strategy for prevention and treatment of NAFLD.

Mean platelet volume (MPV) as new marker of diabetic macrovascular complications in patients with different glucose homeostasis : Platelets in cardiovascular risk.

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.

Sex-specific differences in myocardial glucose metabolic rate in non-diabetic, pre-diabetic and type 2 diabetic subjects.

BACKGROUND: Evidence has shown that women with type 2 diabetes (T2DM) have a higher excess risk for cardiovascular disease (CVD) than men with T2DM. Subjects with either T2DM or prediabetes exhibit myocardial insulin resistance, but it is still unsettled whether sex-related differences in myocardial insulin resistance occur in diabetic and prediabetic subjects. METHODS: We aimed to evaluate sex-related differences in myocardial glucose metabolic rate (MRGlu), assessed using dynamic PET with 18F-FDG combined with euglycemic-hyperinsulinemic clamp, in subjects with normal glucose tolerance (NGT; n = 20), prediabetes (n = 11), and T2DM (n = 26). RESULTS: Women with prediabetes or T2DM exhibited greater relative differences in myocardial MRGlu than men with prediabetes or T2DM when compared with their NGT counterparts. As compared with women with NGT, those with prediabetes exhibited an age-adjusted 35% lower myocardial MRGlu value (P = 0.04) and women with T2DM a 74% lower value (P = 0.006), respectively. Conversely, as compared with men with NGT, men with T2DM exhibited a 40% lower myocardial MRGlu value (P = 0.004), while no significant difference was observed between men with NGT and prediabetes. The statistical test for interaction between sex and glucose tolerance on myocardial MRGlu (P < 0.0001) was significant suggesting a sex-specific association. CONCLUSIONS: Our data suggest that deterioration of glucose homeostasis in women is associated with a greater impairment in myocardial glucose metabolism as compared with men. The sex-specific myocardial insulin resistance could be an important factor responsible for the greater effect of T2DM on the excess risk of cardiovascular disease in women than in men.

Whole blood viscosity is associated with reduced myocardial mechano-energetic efficiency in nondiabetic individuals.

INTRODUCTION: This cross-sectional study aimed to investigate the association between myocardial mechano-energetic efficiency (MEE) and whole blood viscosity (WBV) in nondiabetic adults participating in the CATAnzaro MEtabolic RIsk factors (CATAMERI) study. METHODS: 1143 participants underwent an oral glucose tolerance test and an echocardiogram for myocardial MEE per gram of left ventricular mass (MEEi) measurement. WBV was measured as: [0.12 × h] + [0.17 × (p-2.07)], where h is haematocrit and p is plasma protein levels. RESULTS: Study population includes 595 males and 548 females with a mean age of 46 ± 12 years and a mean BMI of 30.0 ± 6.2 kg/m2 . Individuals with normal glucose tolerance were 63%, while those with impaired fasting glucose, impaired glucose tolerance and or the combination of both were 14.3%, 13% and 9.7%, respectively. A univariate analysis showed that MEEi was significantly associated with sex, age, smoking, BMI, waist circumference, total cholesterol, HDL, triglycerides, fasting glucose, fasting insulin, HOMA-IR index, glucose tolerance, C-reactive protein, haematocrit, haemoglobin, plasma protein and WBV. In a multivariable regression model including variables that were significantly associated with MEEi in univariate analysis, MEEi was associated with HOMA-IR (ß = -0.144, p < .001), age (ß = -0.140, p < .001), WBV (ß = -0.129, p < .001) and glucose tolerance (ß = -0.064, p = .04). The independent association between WBV and MEEi remained statistically significant (ß = -0.122, p < .001) when antihypertensive therapy and lipid-lowering therapy were included in the model. CONCLUSION: WBV is associated with decreased myocardial MEE independently of other cardiovascular risk factors.

Frequency of prediabetes in individuals with increased adiposity and metabolically healthy or unhealthy phenotypes.

AIMS: To utilize the estimated glucose disposal rate (eGDR) index of insulin sensitivity, which is based on readily available clinical variables, namely, waist circumference, hypertension and glycated haemoglobin, to discriminate between metabolically healthy and unhealthy phenotypes, and to determine the prevalence of prediabetic conditions. METHODS: Non-diabetic individuals (n = 2201) were stratified into quartiles of insulin sensitivity based on eGDR index. Individuals in the upper quartiles of eGDR were defined as having metabolically healthy normal weight (MHNW), metabolically healthy overweight (MHOW) or metabolically healthy obesity (MHO) according to their body mass index, while those in the lower quartiles were classified as having metabolically unhealthy normal weight (MUNW), metabolically unhealthy overweight (MUOW) and metabolically unhealthy obesity (MUO), respectively. RESULTS: The frequency of impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and IFG + IGT status was comparable among the MHNW, MHOW and MHO groups, while it increased from those with MUNW status towards those with MUOW and MUO status. As compared with participants with MHNW, the odds ratio of having IFG, IGT, or IFG + IGT was significantly higher in participants with MUOW and MUO but not in those with MUNW, MHOW and MHO, respectively. CONCLUSIONS: A metabolically healthy phenotype is associated with lower frequency of IFG, IGT, and IFG + IGT status across all body weight categories.

One-hour post-load glucose levels are associated with hepatic steatosis assessed by transient elastography.

AIM: To examine the association between 1-hour plasma glucose (PG) concentration and markers of non-alcoholic fatty liver disease (NAFLD) assessed by transient elastography (TE). METHODS: We performed TE in 107 metabolically well-characterized non-diabetic White individuals. Controlled attenuation parameter (CAP) was used to quantify liver steatosis, while liver stiffness marker (LS) was used to evaluate fibrosis. RESULTS: Controlled attenuation parameter correlated significantly with 1-hour PG (r = 0.301, P < 0.01), fasting insulin (r = 0.285, P < 0.01), 2-hour insulin (r = 0.257, P < 0.02), homeostasis model assessment index of insulin resistance (r = 0.252, P < 0.01), high-density lipoprotein cholesterol (r = -0.252, P < 0.02), body mass index (BMI; r = 0.248, P < 0.02) and age (r = 0.212, P < 0.03), after correction for age, sex and BMI. In a multivariable linear regression analysis, 1-hour PG (ß = 0.274, P = 0.008) and fasting insulin levels (ß = 0.225, P = 0.029) were found to be independent predictors of CAP. After excluding subjects with prediabetes, 1-hour PG was the sole predictor of CAP variation (ß = 0.442, P < 0.001). In a logistic regression model, we observed that the group with 1-hour PG ≥ 8.6 mmol/L (155 mg/dL) had a significantly higher risk of steatosis (odds ratio 3.98, 95% confidence interval 1.43-11.13; P = 0.008) than individuals with 1-hour PG < 8.6 mmol/L, after correction for potential confounders. No association was observed between 1-hour PG and LS. CONCLUSION: Our data confirm that 1-hour PG ≥ 8.6 mmol/L is associated with higher signs of NAFLD, even among individuals with normal glucose tolerance, categorized as low risk by canonical diagnostic standards. TE is a safe low-impact approach that could be employed for stratifying the risk profile in these patients, with a high level of accuracy.

Asymmetric dimethylarginine (ADMA) is associated with reduced myocardial mechano-energetic efficiency in hypertensive subjects.

BACKGROUND AND AIMS: Our prior study showed that endothelial dysfunction contributed to reduced myocardial mechano-energetics efficiency (MEEi) independently of several confounders. Reduced activity of endothelial nitric oxide synthase may be due to increased levels of the endogenous inhibitor asymmetric dimethylarginine (ADMA). The impact of ADMA on myocardial MEEi has not been determined yet. This study aims to investigate the association between plasma ADMA levels and MEEi in drug-naïve hypertensive individuals. METHODS AND RESULTS: 63 hypertensive individuals participating in the CATAnzaro MEtabolic RIsk factors (CATAMERI) study were included. All participants underwent to an echocardiogram for myocardial MEEi measurement. ADMA plasma concentrations were measured by high-performance liquid chromatography. A multivariate linear regression analysis was conducted to investigate the independent association between ADMA levels and MEEi. In a univariate analysis, ADMA levels were significantly associated with myocardial MEEi (r = 0.438; P < 0.001). In a multivariate regression analysis, plasma ADMA levels were associated to decreased myocardial MEEi (ß = 0.458, P < 0.001) independently of well-established cardiovascular risk factors including age, sex, BMI, waist circumference, smoking status, total cholesterol and HDL, triglycerides, glucose tolerance status, and HOMA-IR index of insulin resistance. CONCLUSIONS: ADMA may contribute to reduced myocardial MEEi by reducing nitric oxide bioavailability.

Higher circulating levels of proneurotensin are associated with increased risk of incident NAFLD.

BACKGROUND: Neurotensin (NT), an intestinal peptide able to promote fat absorption, is implicated in the pathogenesis of obesity. Increased levels of proneurotensin (pro-NT), a stable NT precursor fragment, have been found in subjects with nonalcoholic fatty liver disease (NAFLD); however, whether higher pro-NT levels are associated with an increased NAFLD risk independently of other metabolic risk factors is unsettled. METHODS: Ultrasound-defined presence of NAFLD was assessed on 303 subjects stratified into tertiles according to fasting pro-NT levels. The longitudinal association between pro-NT levels and NAFLD was explored on the study participants without NAFLD at baseline reexamined after 5 years of follow-up (n = 124). RESULTS: Individuals with higher pro-NT levels exhibited increased adiposity, a worse lipid profile, and insulin sensitivity as compared to the lowest tertile of pro-NT. Prevalence of NAFLD was progressively increased in the intermediate and highest pro-NT tertile as compared to the lowest tertile. In a logistic regression analysis adjusted for several confounders, individuals with higher pro-NT levels displayed a raised risk of having NAFLD (OR = 3.43, 95%CI = 1.48-7.97, p = 0.004) than those in the lowest pro-NT tertile. Within the study cohort without NAFLD at baseline, subjects with newly diagnosed NAFLD at follow-up exhibited higher baseline pro-NT levels than those without incident NAFLD. In a cox hazard regression analysis model adjusted for anthropometric and metabolic parameters collected at baseline and follow-up visit, higher baseline pro-NT levels were associated with an increased risk of incident NAFLD (HR = 1.52, 95%CI = 1.017-2.282, p = 0.04). CONCLUSION: Higher pro-NT levels are a predictor of NAFLD independent of other metabolic risk factors.

Sex-related differences for uric acid in the prediction of cardiovascular events in essential hypertension. A population prospective study.

BACKGROUND: Uric acid (UA) is an independent prognostic factor for cardiovascular events, but there are no data demonstrating a different risk profile between women and men. Thus, we tested whether UA is associated with a possible sex-related difference in fatal and non-fatal cardiovascular events. METHODS: In this prospective population-based study we enrolled 1,650 never-treated Caucasian hypertensive outpatients referred to Catanzaro University Hospital (Italy). Inclusion criteria were newly diagnosed hypertensive patients, aged 20 years or more. Exclusion criteria were secondary form of hypertension, previous cardiovascular events, rheumatic and non-rheumatic valvular heart disease, prosthetic valves, cardiomyopathies, type-2 diabetes, chronic kidney disease, malignant diseases, gout arthritis and secondary forms of hyperuricemia, liver diseases, peripheral vascular diseases, and heart failure. Anthropometric, clinical, and biochemical parameters were measured. UA prognostic role was investigated by Cox regression analyses. Receiver-operating characteristic curve analyses and area under the curve were used to determine the predictive validity and the optimal cut-off point of UA. We investigated following endpoints: coronary events (fatal and nonfatal myocardial infarction, unstable angina, coronary revascularization procedures, coronary death); fatal and nonfatal stroke; all-cause mortality and major adverse cardiovascular events (MACE). RESULTS: We enrolled 830 males and 820 females aged 52.2 ± 11.3 years. During 9.5 ± 3.1 years follow-up, there were 424 new clinical events (2.71%): 250 coronary (1.59%), 118 (0.75%) cerebrovascular, and 56 (0.40%) deaths. Comparison between groups demonstrated a higher and significant difference in incidence rate in females for MACE (3.08 vs 2.33%, P = 0.001), coronary (1.82 vs 1.36%, P = 0.014) and cerebrovascular events (0.93 vs 0.57%, P = 0.006). UA at multiple Cox regression analysis resulted a strong and significant predictor of coronary events (HR = 1.493;95% CI 1.375-1.621), cerebrovascular events (HR = 1.256;95% CI 1.109-1.423), MACE (HR = 1.415;95% CI 1.328- 53 1.508), and all-cause mortality (HR = 1.469;95% CI 1.237-1.745) in the whole population and in both groups with a HR higher in females. The best estimated cut-off values of uric acid for males and females predicted these endpoints equally well, but it was always lower in females than males. CONCLUSIONS: We demonstrate, that UA operates with a sex-related impact and best cut-off value in predicting cardiovascular outcomes and all-cause mortality, reflecting a possible sex difference in disease pathophysiology.

Impaired insulin-stimulated myocardial glucose metabolic rate is associated with reduced estimated myocardial energetic efficiency in subjects with different degrees of glucose tolerance.

BACKGROUND: Alterations in myocardial mechano-energetic efficiency (MEEi), which represents the capability of the left ventricles to convert the chemical energy obtained by oxidative metabolism into mechanical work, have been associated with cardiovascular disease. Although whole-body insulin resistance has been related to impaired myocardial MEEi, it is unknown the relationship between cardiac insulin resistance and MEEi. Aim of this study was to evaluate the relationship between insulin-stimulated myocardial glucose metabolic rate (MrGlu) and myocardial MEEi in subjects having different degrees of glucose tolerance. METHODS: We evaluated insulin-stimulated myocardial MrGlu using cardiac dynamic positron emission tomography (PET) with 18F-Fluorodeoxyglucose (18F-FDG) combined with euglycemic-hyperinsulinemic clamp, and myocardial MEEi in 57 individuals without history of coronary heart disease having different degrees of glucose tolerance. The subjects were stratified into tertiles according to their myocardial MrGlu values. RESULTS: After adjusting for age, gender and BMI, subjects in I tertile showed a decrease in myocardial MEEi (0.31 ± 0.05 vs 0.42 ± 0.14 ml/s*g, P = 0.02), and an increase in myocardial oxygen consumption (MVO2) (10,153 ± 1375 vs 7816 ± 1229 mmHg*bpm, P < 0.0001) as compared with subjects in III tertile. Univariate correlations showed that insulin-stimulated myocardial MrGlu was positively correlated with MEEi and whole-body glucose disposal, and negatively correlated with waist circumference, fasting plasma glucose, HbA1c and MVO2. In a multivariate regression analysis running a model including several CV risk factors, the only variable that remained significantly associated with MEEi was myocardial MrGlu (ß 0.346; P = 0.01). CONCLUSIONS: These data suggest that an impairment in insulin-stimulated myocardial glucose metabolism is an independent contributor of depressed myocardial MEEi in subjects without history of CHD.

Association between right ventricular dysfunction and adverse cardiac events in mild COPD patients.

BACKGROUND: Lung hyperinflation and systemic inflammation are currently believed to be the most important causes of right heart alterations in chronic obstructive pulmonary disease (COPD) patients. A multicentre observational study was performed to assess the morphological and functional parameters of right ventricle (RV) in COPD subjects, as well as to evaluate the potential prognostic impact on the development of major cardiovascular adverse events (MACEs). METHODS: For this retrospective study, from 1 January 2010 to 31 December 2021, we enrolled COPD patients on the basis of their airflow limitation. In particular, we selected subjects spanning across GOLD 1 and 2 functional stages. Clinical, laboratory and functional parameters were collected at baseline. Echocardiography was routinely performed in all COPD patients. RV dysfunction was defined on the basis of tricuspid annular plane systolic excursion (TAPSE) values. MACE occurrence (non-fatal ischemic stroke, non-fatal myocardial infarction, cardiac revascularization or coronary bypass surgery and cardiovascular death) was evaluated during a median follow-up of 55 (36-72) months. RESULTS: Among the 749 enrolled patients, 408 subjects had a TAPSE value ≥20 mm, while the remaining 341 had a TAPSE value <20 mm. In patients with TAPSE ≥20 mm the observed MACEs were 1.9 events/100 patient-year, while in the group with a worse right heart function there were 4.2 events/100 patient-year (p < .0001). The multivariate analysis model confirmed the association between RV dysfunction and MACE. Indeed, a 1-mm increase in TAPSE value and the intake of long-acting ß2 -receptor agonists (LABA)/long-acting muscarinic antagonist (LAMA) inhaled therapy were protective factors for the onset of MACE, while the presence of diabetes mellitus and high values of both uric acid (UA) and systolic pulmonary arterial pressure (S-PAP) enhanced the risk of MACE in study participants. CONCLUSIONS: The results of this study showed that in patients with mild COPD there is an association between right heart dysfunction and the risk of MACE during follow-up.

Liver fibrosis is associated with an increased risk of non-fatal myocardial infarction.

INTRODUCTION: Liver fibrosis is a risk factor for liver-related adverse outcomes and cardiovascular disease (CVD). Recently, the non-invasive Hepamet fibrosis score (HFS) has been validated as a tool capable to identify with good diagnostic accuracy subjects with advanced liver fibrosis. It is unsettled whether HFS is capable to identify individuals at higher risk of CVD. To investigate whether individuals with liver fibrosis measured with HFS have higher risk of myocardial infarction (MI) in adults participating in the CATAnzaro MEtabolic RIsk factors (CATAMERI) study. METHODS: Participants (n = 2948) were divided into three groups according to HFS: low risk of fibrosis (<0.12); intermediate risk of fibrosis (≥0.12 to <0.47); high risk of fibrosis (≥0.47). The association between the liver fibrosis risk and MI was analysed by a logistic regression analysis. RESULTS: As compared with those having the lowest risk (5.3%), a higher proportion of subjects with moderate or high risk of liver fibrosis had MI (12.9% and 24.4%, respectively; p < 0.001). In a logistic regression analysis, individuals at increased risk of liver fibrosis exhibited a threefold increased risk of having MI as compared to those with low risk (OR 3.18; 95% CI 1.31-7.70) independently of confounders including smoking, cholesterol, triglycerides, anti-hypertensive, lipid-lowering and glucose-lowering therapies. CONCLUSIONS: In this cross-sectional study, individuals with higher values of HFS show a higher risk of MI, suggesting that HFS may be a useful tool to identify not only individuals with liver fibrosis but also those at the increased risk of CVD.

Serum proprotein convertase subtilisin/Kexin type 9 and vascular disease in type 2 diabetic patients.

BACKGROUND: Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) levels have been suggested as novel atherosclerotic biomarker. PCSK9 plays important roles in the pathogenesis of atherosclerosis by regulating the degradation of low-density lipoprotein receptor as well as different inflammatory pathways. Considering the important prognostic role of arterial stiffness in cardiovascular disease (CVD), the aim of the study is to investigate the correlation between PCSK9 levels and arterial stiffness in a cohort of diabetic patients, without previous CV events. METHODS: This cross-sectional analysis enrolled 401 Caucasian patients with type II diabetes mellitus (T2DM). PCSK9 levels were measured by ELISA test, arterial stiffness was estimated by measuring carotid-femoral pulse wave velocity (PWV). RESULTS: Patients were divided in three tertiles according to increasing value of PCSK9. From the I to the III tertiles, there was a significant increase in high sensitivity C-reactive protein (hs-CRP), fibrinogen and white blood cells (WBC) and a reduction in estimated glomerular filtration rate (e-GFR). Patients with higher levels of PCSK9 presented increased systolic, diastolic blood pressure, pulse pressure and PWV. PWV was significantly and directly correlated with PCSK9, fibrinogen, age, BMI and PP, and indirectly correlated with diet, lifestyle and e-GFR. Serum PCSK9 was the major predictor of PWV, justifying a 16.9% of its variation. CONCLUSION: Our study demonstrates a close association between circulating PCSK9 levels and PWV in T2DM subjects without previous CV events even after adjusting for well-known CV risk factor and pharmacological medications. Serum PCSK9 could be a useful biomarker for CV risk stratification in diabetic subjects.

One-hour post-load glucose and subclinical left atrial myocardial dysfunction in hypertensive patients.

BACKGROUND: Recently, studies demonstrated that normal glucose-tolerant subjects (NGT) with 1-h post-load plasma glucose value ≥155 mg/dL during oral glucose tolerance test (OGTT) (NGT ≥ 155) present an impaired cardio-metabolic profile, with subclinical myocardial damage. Atrial morphological and functional alterations, closely related to diastolic dysfunction, are important predictors of atrial fibrillation (AF), cardiovascular (CV) events and mortality in the entire population as well as in diabetic patients. The aim of our study was to evaluate subclinical atrial myocardial damage, assessed with speckle tracking echocardiography, in NGT≥155 mg/dL patients, comparing to NGT < 155 mg/dL subjects, impaired glucose tolerant (IGT) individuals and patients with newly diagnosed type 2 diabetes (T2DM). METHODS: We enrolled 229 Caucasian patients. All subjects underwent anthropometrical and haemodynamic parameters evaluation, OGTT, advanced Colour-Doppler echocardiography with evaluation of main atrial and ventricular parameters. RESULTS: As expected, from first to the fourth group there was a worsening of the metabolic profile as attested by fasting, 1- and 2-h post-load plasma glucose levels, during OGTT. Moreover, from NGT < 155 to T2DM group there was an impairment in reservoir and pump atrial function (PALS and PACS, respectively) (p < .0001). CONCLUSION: Present data demonstrated for the first time that NGT≥155 subjects present subclinical atrial dysfunction. These results may be clinically relevant because they highlight how atrial myopathy occurs early in pre-diabetes stage regardless of fibrotic and morphological alterations of the ventricular myocardium.

Glucagon induces the hepatic expression of inflammatory markers in vitro and in vivo.

Glucagon exerts multiple hepatic actions, including stimulation of glycogenolysis/gluconeogenesis. The liver plays a crucial role in chronic inflammation by synthesizing proinflammatory molecules, which are thought to contribute to insulin resistance and hyperglycaemia. Whether glucagon affects hepatic expression of proinflammatory cytokines and acute-phase reactants is unknown. Herein, we report a positive relationship between fasting glucagon levels and circulating interleukin (IL)-1ß (r = 0.252, p = .042), IL-6 (r = 0.230, p = .026), fibrinogen (r = 0.193, p = .031), complement component 3 (r = 0.227, p = .024) and high sensitivity C-reactive protein (r = 0.230, p = .012) in individuals without diabetes. In CD1 mice, 4-week continuous treatment with glucagon induced a significant increase in circulating IL-1ß (p = .02), and IL-6 (p = .001), which was countered by the contingent administration of the glucagon receptor antagonist, GRA-II. Consistent with these results, we detected a significant increase in the hepatic activation of inflammatory pathways, such as expression of NLRP3 (p < .02), and the phosphorylation of nuclear factor kappaB (NF-κB; p < .02) and STAT3 (p < .01). In HepG2 cells, we found that glucagon dose-dependently stimulated the expression of IL-1ß (p < .002), IL-6 (p < .002), fibrinogen (p < .01), complement component 3 (p < .01) and C-reactive protein (p < .01), stimulated the activation of NLRP3 inflammasome (p < .01) and caspase-1 (p < .05), induced the phosphorylation of TRAF2 (p < .01), NF-κB (p < .01) and STAT3 (p < .01). Preincubating cells with GRA-II inhibited the ability of glucagon to induce an inflammatory response. Using HepaRG cells, we confirmed the dose-dependent ability of glucagon to stimulate the expression of NLRP3, the phosphorylation of NF-κB and STAT3, in the absence of GRA-II. These results suggest that glucagon has proinflammatory effects that may participate in the pathogenesis of hyperglycaemia and unfavourable cardiometabolic risk profile.

Persistent Pancytopenia as a Long-COVID Manifestation in a Patient with Adult-Onset Still's Disease: A Case Report.

Background: Adult-onset Still's disease (AOSD) is a rare rheumatic inflammatory condition with an extremely heterogeneous clinical presentation and systemic impairment. Uncommon manifestations may be challenging to manage, especially in patients with previous severe acute SARS-CoV-2 infection. For the first time, we report the case of a patient affected by refractory AOSD presenting with severe pancytopenia as a long-COVID manifestation. The purpose of this case report is to illustrate the clinical presentation, diagnostic and therapeutic management of this unusual manifestation. Moreover, we examine the mechanisms that are potentially responsible for the onset of the pancytopenia observed in our patient. Case presentation: We describe the case of a 40-year-old male who presented with a history of fever for 2 years, arthralgia, maculopapular salmon-pink rash and a previous SARS-CoV-2 infection which required admission to intensive care. The patient's laboratory results revealed elevated inflammatory markers levels (erythrocyte sedimentation rate and C-reactive protein), hyperferritinemia and severe pancytopenia that needed multiple transfusions. A diagnosis of AOSD was made based on clinical and laboratory presentation after excluding neoplastic, infectious and other rheumatic diseases. The previous empirical treatment was not adequate to control the condition; therefore, treatment with high-dose steroids, canakinumab and epoetin alfa was started and led to the resolution of the man's symptoms and a reduction in inflammatory marker levels, whereas blood cell count remained stable without a need for further blood transfusions. The patient is currently under rheumatologic and hematologic follow-up every month. Conclusions: Neither AOSD nor SARS-CoV-2 infection usually manifests with pancytopenia, except in hemophagocytic syndrome or immunodeficient patients, respectively. Identifying the underlying etiology of pancytopenia is mandatory to establish a prompt treatment that generally resolves the disorder. However, in our case, all common causes of pancytopenia were excluded, suggesting a potential manifestation of the long-COVID syndrome. Despite the resolution of the acute infection and the remarkable treatment of AOSD, pancytopenia persists. Herein, we propose for refractory AOSD patients with previous SARS-CoV-2 infection a novel approach to the diagnosis and treatment of pancytopenia.

Effects of 26 weeks of treatment with empagliflozin versus glimepiride on the myocardial glucose metabolic rate in patients with type 2 diabetes: The randomized, open-label, crossover, active-comparator FIORE trial.

AIM: To determine whether treatment with empagliflozin was able to affect the myocardial glucose metabolic rate, as assessed by cardiac dynamic 18 F-fluorodeoxyglucose-positron emission tomography (18 F-FDG-PET) combined with euglycaemic-hyperinsulinaemic clamp compared with glimepiride in patients with type 2 diabetes. MATERIALS AND METHODS: To further investigate the cardioprotective mechanism of sodium-glucose co-transporter-2 inhibitors, we performed a 26-week, randomized, open-label, crossover, active-comparator study to determine the effects of empagliflozin 10 mg versus glimepiride 2 mg daily on the myocardial glucose metabolic rate assessed by cardiac dynamic 18 F-FDG-PET combined with euglycaemic-hyperinsulinaemic clamp in 23 patients with type 2 diabetes. We also measured cardiac geometry and myocardial mechano-energetic efficiency, as well as systolic and diastolic function by echocardiography. RESULTS: Compared with glimepiride, treatment with empagliflozin resulted in a greater reduction in the myocardial glucose metabolic rate from baseline to 26 weeks (adjusted difference -6.07 [-8.59, -3.55] µmol/min/100 g; P < .0001). Moreover, compared with glimepiride, empagliflozin led to significant reductions in left atrial diameter, left ventricular end-systolic and end-diastolic volumes, N-terminal pro b-type natriuretic peptide levels, blood pressure, heart rate, stroke work, and myocardial oxygen consumption estimated by the rate pressure product, and increases in ejection fraction, myocardial mechano-energetic efficiency, red blood cells, and haematocrit and haemoglobin levels. CONCLUSIONS: The present study provides evidence that empagliflozin treatment in subjects with type 2 diabetes without coronary artery disease leads to a significant reduction in the myocardial glucose metabolic rate.

Immuno-Mediated Inflammation in Hypertensive Patients with 1-h Post-Load Hyperglycemia.

Inflammation plays a key role in the pathogenesis/progression of atherosclerosis, and inflammatory molecules contribute to the progression of cardiovascular disease. Subjects with normal post-load glucose tolerance and 1-h post-load plasma glucose >155 mg/dL have an increased risk of subclinical target organ damage and incident diabetes. We aimed to test possible differences in immune-mediated inflammatory parameters in newly-diagnosed hypertensives with or without 1-h post-load hyperglycemia. We enrolled 25 normotensives (NGT) and 50 hypertensives normotolerant on oral glucose tolerance test, further divided into two groups based on 1-h post-load plasma glucose: NGT 1-h ≥ 155 (n = 25) and NGT 1-h < 155 (n = 25). We measured toll-like receptor (TLR) 2, TLR4, nuclear factor kß (NF-kß), interleukin (IL)-1ß, IL-6, IL-8, IL-10, and tumor necrosis factor (TNF)-α. Hypertensives showed significantly worse metabolic and lipid profiles, and higher values of body mass ass index (BMI), creatinine, and inflammatory parameters, compared to controls. NGT 1-h ≥ 155 had a worse glycometabolic profile and higher values of TLR2 (9.4 ± 4.2 vs. 5.9 ± 2.6 MFI), TLR4 (13.1 ± 3.9 vs. 7.8 ± 2.3 MFI), NF-kß (0.21 ± 0.07 vs. 0.14 ± 0.04), IL-1ß (6.9 ± 3.4 vs. 3.2 ± 2.1 pg/mL), IL-6 (10.8 ± 2.6 vs. 4.1 ± 1.6 pg/mL), IL-8 (27.6 ± 9.3 vs. 13.3 ± 5.6 pg/mL), TNF-α (6.4 ± 2.9 vs. 3.3 ± 1.4 pg/mL), and high-sensitivity C-reactive protein (hs-CRP) (4.8 ± 1.5 vs. 2.7 ± 1.0 mg/dL) in comparison with NGT 1-h < 155. Matsuda-index and 1-h post-load glycemia were retained as major predictors of TLRs and NF-kß. These results contribute to better characterizing cardiovascular risk in hypertensives.

Sex-specific differences in left ventricular mass and myocardial energetic efficiency in non-diabetic, pre-diabetic and newly diagnosed type 2 diabetic subjects.

BACKGROUND: Women with type 2 diabetes (T2DM) have a higher excess risk for cardiovascular disease (CVD) than their male counterparts. However, whether the risk for CVD is higher in prediabetic women than men is still debated. We aimed to determine whether sex-related differences exist in left ventricular mass index (LVMI), and myocardial mechano-energetic efficiency (MEEi) in with normal glucose tolerant (NGT), pre-diabetic and newly diagnosed type 2 diabetic subjects. METHODS: Sex-related differences in LVMI and myocardial MEEi, assessed by validated echocardiography-derived measures, were examined among 1562 adults with NGT, prediabetes, and newly diagnosed T2DM, defined according to fasting glucose, 2-h post-load glucose, or HbA1c. RESULTS: Worsening of glucose tolerance in both men and women was associated with an increase in age-adjusted LVMI and myocardial MEEi. Women with newly diagnosed T2DM exhibited greater relative differences in LVMI and myocardial MEEi than diabetic men when compared with their NGT counterparts. Prediabetic women exhibited greater relative differences in myocardial MEEi, but not in LVMI, than prediabetic men when compared with their NGT counterparts. The statistical test for interaction between sex and glucose tolerance on both LVMI (P < 0.0001), and myocardial MEEi (P < 0.0001) was significant suggesting a sex-specific association. CONCLUSIONS: Left ventricle is subject to maladaptive changes with worsening of glucose tolerance, especially in women with newly diagnosed T2DM. The sex-specific increase in LVM and decrease in MEEi, both being predictors of CVD, may have a role in explaining the stronger impact of T2DM on the excess risk of CVD in women than in men.

The TRIB3 R84 variant is associated with increased left ventricular mass in a sample of 2426 White individuals.

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/m2 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.