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.

Compromised cardiac autonomic function in non-diabetic subjects with 1 h post-load hyperglycemia: a cross-sectional study.

BACKGROUND: A compromised cardiac autonomic function has been found in subjects with insulin resistance related disorders such as obesity, impaired glucose tolerance (IGT) and type 2 diabetes and confers an increased risk of adverse cardiovascular outcomes. Growing evidence indicate that 1 h plasma glucose levels (1hPG) during an oral glucose tolerance test (OGTT) ≥ 155 mg/dl identify amongst subjects with normal glucose tolerance (NGT) a new category of prediabetes (NGT 1 h-high), harboring an increased risk of cardiovascular organ damage. In this study we explored the relationship between 1 h post-load hyperglycemia and cardiac autonomic dysfunction. METHODS: Presence of cardiac autonomic neuropathy (CAN) defined by cardiovascular autonomic reflex tests (CARTs) and heart rate variability (HRV), assessed by 24-h electrocardiography were evaluated in 88 non-diabetic subjects subdivided on the basis of OGTT data in: NGT with 1 h PG < 155 mg/dl (NGT 1 h-low), NGT 1 h-high and IGT. RESULTS: As compared to subjects with NGT 1 h-low, those with NGT 1 h-high and IGT were more likely to have CARTs defined CAN and reduced values of the 24 h time domain HVR parameters including standard deviation of all normal heart cycles (SDNN), standard deviation of the average RR interval for each 5 min segment (SDANN), square root of the differences between adjacent RR intervals (RMSSD), percentage of beats with a consecutive RR interval difference > 50 ms (PNN50) and Triangular index. Univariate analyses showed that 1hPG, but not fasting and 2hPG, was inversely associated with all the explored HVR parameters and positively with CARTs determined presence of CAN. In multivariate regression analysis models including several confounders we found that 1hPG was an independent contributor of HRV and presence of CAN. CONCLUSION: Subjects with 1hPG ≥ 155 mg/dl have an impaired cardiac autonomic function.

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.

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.

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.

The relationship of food addiction with binge eating disorder and obesity: A network analysis study.

Food addiction (FA) has been associated with binge eating disorder (BED) and obesity at varying levels of severity and treatment outcomes. Despite much debate and scientific interest in FA, the mechanisms that underlie its co-occurrence with both conditions are not yet well understood. In order to understand this relationship, this study explores FA in a clinical sample of individuals with BED and obesity using network analysis (NA). A total of 303 patients (151 with BED and 152 with obesity) completed a battery of tests that investigated eating psychopathology, eating behaviours, emotional dysregulation, depression and FA. Two different NAs were conducted to investigate the interaction between these variables and FA. The BED and obesity groups were comparable in age (38 ± 14 vs. 42 ± 13 years), body mass index (38.8 ± 8.5 vs 42.4 ± 7.8), sex and demographics. According to the expected influence values, binge eating severity and depression were identified as the central nodes in both networks. In the BED group, binge eating severity was the central node and showed strong connections to both FA and grazing. In contrast, in the obesity group, depression was the central node, but its connections were weak, with only marginal associations to FA. These results suggest that FA represents an important and distinct construct of the two populations. In patients with BED, FA is intimately connected to other loss-of-control-related eating behaviours, such as binge eating and grazing. Conversely, in those with obesity, depression explains the relationship of FA with pathological eating behaviours. The presence of FA seems to be a distinguishing characteristic in the psychopathology of patients suffering from obesity with and without BED, and this could have implications for the prevention, treatment and management of these disorders.

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.

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.

Non-alcoholic fatty liver disease is associated with cardiovascular disease in subjects with different glucose tolerance.

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.

One-hour post-load hyperglycemia combined with HbA1c identifies individuals with higher risk of cardiovascular diseases: Cross-sectional data from the CATAMERI study.

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.

Chronic continuous exenatide infusion does not cause pancreatic inflammation and ductal hyperplasia in non-human primates.

In this study, we aimed to evaluate the effects of exenatide (EXE) treatment on exocrine pancreas of nonhuman primates. To this end, 52 baboons (Papio hamadryas) underwent partial pancreatectomy, followed by continuous infusion of EXE or saline (SAL) for 14 weeks. Histological analysis, immunohistochemistry, Computer Assisted Stereology Toolbox morphometry, and immunofluorescence staining were performed at baseline and after treatment. The EXE treatment did not induce pancreatitis, parenchymal or periductal inflammatory cell accumulation, ductal hyperplasia, or dysplastic lesions/pancreatic intraepithelial neoplasia. At study end, Ki-67-positive (proliferating) acinar cell number did not change, compared with baseline, in either group. Ki-67-positive ductal cells increased after EXE treatment (P = 0.04). However, the change in Ki-67-positive ductal cell number did not differ significantly between the EXE and SAL groups (P = 0.13). M-30-positive (apoptotic) acinar and ductal cell number did not change after SAL or EXE treatment. No changes in ductal density and volume were observed after EXE or SAL. Interestingly, by triple-immunofluorescence staining, we detected c-kit (a marker of cell transdifferentiation) positive ductal cells co-expressing insulin in ducts only in the EXE group at study end, suggesting that EXE may promote the differentiation of ductal cells toward a ß-cell phenotype. In conclusion, 14 weeks of EXE treatment did not exert any negative effect on exocrine pancreas, by inducing either pancreatic inflammation or hyperplasia/dysplasia in nonhuman primates.

Impaired insulin sensitivity measured by estimated glucose disposal rate is associated with decreased myocardial mechano-energetic efficiency in non-diabetic individuals.

BACKGROUND AND AIMS: Impaired myocardial mechano-energetic efficiency (MEE) has been associated with cardiac insulin resistance measured by dynamic positron emission tomography (PET) with 18F-fluorodeoxyglucose (18F-FDG) combined with euglycemic-hyperinsulinemic clamp. Estimate glucose disposal rate (eGDR) index has a good correlation with whole-body insulin sensitivity. It remains unsettled whether eGDR index is a suitable proxy of cardiac insulin sensitivity as well as its association with myocardial MEE. The aims of this study were: 1) to compare eGDR index with HOMA-IR, QUICKI and FIRI indexes for association with myocardial glucose metabolic rate (MrGlu); and 2) to determine the association of eGDR index with myocardial MEE. METHODS: We evaluated MrGlu using PET with 18F-FDG combined with euglycemic-hyperinsulinemic clamp in 50 individuals without history of coronary heart disease. Myocardial MEE per gram of left ventricular mass (MEEi) was measured in 1181 subjects by echocardiography. eGDR (mg kg-1/min) was calculated as: 21.158 - (0.09 × waist circumference in cm) - (3.407 × hypertension, 1 = yes 0 = no) - (0.551 × HbA1c%). RESULTS: eGDR index was more strongly associated with myocardial MrGlu than HOMA-IR, QUICKI, and FIRI indexes (r = -0.662, r = -0.492, r = 0.570, and r = -0.492, respectively). Individuals in the lower tertiles of eGDR exhibited a significant reduction of MEEi as compared to those in the highest tertile (P < 0.001). In a stepwise multivariate linear regression analysis eGDR index was the major determinant of MEEi independently of well-established cardio-metabolic risk factors. CONCLUSIONS: These data suggest that the eGDR index may be a useful marker to identifying individuals at high cardiovascular risk.

Pathophysiological characteristics of subjects with intermediate hyperglycemia and type 2 diabetes identified by 1-hour plasma glucose during an oral glucose tolerance test.

AIMS: The International Diabetes Federation (IDF) has recently recommended determination of 1-hour plasma glucose (1-hPG) during an oral glucose tolerance test (OGTT) to diagnose intermediate hyperglycemia (IH) and type 2 diabetes (T2DM). Herein, we investigated the cardiometabolic characteristics of individuals with IH and T2DM according to IDF criteria. METHODS: We studied 3086 individuals stratified on the basis of fasting, 1-hPG and 2-hPG in four groups: 1) normal glucose tolerance (NGT), 2) isolated impaired fasting glucose (iIFG,), 3) IH (fasting glucose < 126 mg/dL, 1-hPG 155-208 mg/dL, and/or 2-hPG 140-199 mg/dL, and 4) newly diagnosed T2DM (fasting glucose, 1-hPG and/or 2-hPG≥126 mg/dL, 209 mg/dL and 200 mg/dL, respectively). RESULTS: Individuals with IH and T2DM exhibited higher adiposity, blood pressure, uric acid, a worse lipid and inflammatory profile and a progressive reduction in Matsuda index of insulin sensitivity, insulinogenic index, and disposition index as compared to the NGT group. Moreover, individuals with IH and T2DM exhibited lower Matsuda, insulinogenic, and disposition indexes as compared to the iIFG group. CONCLUSIONS: 1-h PG-based criteria for diagnosis of IH and diabetes identify individuals having an unfavorable cardiometabolic risk profile with a progressive reduction in insulin sensitivity associated with impaired ß cell function.

Myocardial mechano-energetic efficiency is not impaired in patients with metabolically healthy overweight and obesity.

OBJECTIVE: Reduced myocardial mechano-energetic efficiency (MEE) was associated with BMI. Subgroups of individuals with increased BMI but favorable cardiovascular risk profile were identified as individuals with "metabolically healthy overweight" (MHOW) and "metabolically healthy obesity" (MHO), respectively. We aim to investigate whether those with MHOW/MHO, defined as those having none of the components of metabolic syndrome, exhibit impaired MEE compared with their unhealthy counterparts. METHODS: Myocardial MEE per gram of left ventricular mass (MEEi) was assessed by echocardiography in 2190 nondiabetic individuals participating in the CATAnzaro MEtabolic RIsk factors (CATAMERI) study who were divided, according to BMI and metabolic status, into groups of individuals with metabolically healthy normal weight (MHNW), metabolically unhealthy normal weight (MUNW), MHOW, metabolically unhealthy overweight (MUOW), MHO, and metabolically unhealthy obesity (MUO). RESULTS: After adjusting for age and sex, no differences in myocardial MEEi were observed among individuals with MHNW, MHOW, and MHO (p = 0.56). Myocardial MEEi was comparable among individuals with MUNW, MUOW, and MUO (p = 0.21). Individuals with MHNW, MHOW, and MHO displayed significantly higher myocardial MEEi compared with their unhealthy counterparts. CONCLUSIONS: Increased BMI is not an obligate determinant for reduced myocardial MEEi. Other known components of metabolic syndrome rather than increased BMI contributed to reduced myocardial MEEi.