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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., (© 2024. The Author(s).)

Elevated levels of the gut pro-hormone Proneurotensin (proNT) have been found to predict development of cardiovascular disease. However, it is still unknown whether higher proNT levels are associated with subclinical vascular damage. Herein, we investigated the relationship between higher proNT concentrations and augmented pulse pressure (PP) and carotid intima-media thickness (cIMT), indicators of increased arterial stiffness and subclinical atherosclerosis, respectively. Clinical characteristics, PP and cIMT were evaluated in 154 non-diabetic individuals stratified into tertiles according to fasting serum proNT concentrations. We found that, subjects with higher proNT levels exhibited a worse lipid profile and insulin sensitivity, increased C-reactive protein levels, along with higher values of PP and cIMT as compared to the lowest proNT tertile. Prevalence of elevated PP (≥ 60 mmHg) and subclinical carotid atherosclerosis (IMT > 0.9 mm) was increased in the highest tertile of proNT. In a logistic regression analysis adjusted for several confounders, subjects with higher proNT levels displayed a fivefold raised risk of having elevated PP values (OR 5.36; 95%CI 1.04-27.28; P = 0.05) and early carotid atherosclerosis (OR 4.81; 95%CI 1.39-16.57; P = 0.01) as compared to the lowest proNT tertile. In conclusion, higher circulating levels of proNT are a biomarker of subclinical vascular damage independent of other atherosclerotic risk factors., (© 2024. The Author(s).)

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 18 F-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., (© 2024. The Author(s).)

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).)

Background and Objectives : The NUCB2 gene and its polymorphisms were identified as novel players in the regulation of food intake, potentially leading to obesity (OBE) and altered eating behaviors. Naltrexone/bupropion SR (NB) showed good efficacy and tolerability for treating OBE and altered eating behaviors associated with binge eating disorder (BED). This prospective study investigates the influence of NUCB2 gene polymorphism on NB treatment response in OBE and BED. Materials and Methods : Body mass index (BMI), eating (EDE-Q, BES, NEQ, GQ, Y-FAS 2.0) and general psychopathology (BDI, STAI-S) were evaluated at baseline (t0) and after 16 weeks (t1) of NB treatment in patients with OBE and BED (Group 1; N = 22) vs. patients with OBE without BED (Group 2; N = 20). Differences were evaluated according to the rs757081 NUCB2 gene polymorphism. Results : NUCB2 polymorphism was equally distributed between groups. Although weight at t0 was higher in Group 1, weight loss was similar at t1 in both groups. BMI was not influenced by NUCB2 polymorphism. In Group 1, the CG-genotype reported significant improvement in eating psychopathology while the GG-genotype reported improvement only for FA. No differences were observed in Group 2. Conclusions : Patients diagnosed with BED and treated with NB exhibited a more favorable treatment response within the CG-genotype of the NUCB2 polymorphism.

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.)

Objective: Prior evidence indicates that individuals with obesity have an accelerated intestinal glucose absorption. This cross-sectional study evaluated whether those with overweight or obesity display higher duodenal protein levels of the glucose carriers sodium-glucose cotransporter 1 (SGLT-1), glucose transporter 2 (GLUT-2), and glucose transporter 5 (GLUT-5)., Methods: SGLT-1, GLUT-2, and GLUT-5 protein levels were assessed on duodenal mucosa biopsies of 52 individuals without diabetes categorized on the basis of their BMI as lean, with overweight, or with obesity., Results: Individuals with overweight and obesity exhibited progressively increased duodenal protein levels of SGLT-1 and GLUT-5 as compared with the lean group. Conversely, no differences in duodenal GLUT-2 abundance were found among the three groups. Univariate analysis showed that SGLT-1 and GLUT-5 protein levels were positively correlated with BMI, waist circumference, 1-hour post-load glucose, fasting and post-load insulin, and insulin secretion and resistance levels. Furthermore, a positive relationship was detected between intestinal GLUT-5 levels and serum uric acid concentrations, a product of fructose metabolism known to be involved in the pathogenesis of obesity and its complications., Conclusions: Individuals with overweight and obesity display enhanced duodenal SGLT-1 and GLUT-5 abundance, which correlates with increased postprandial glucose concentrations, insulin resistance, and hyperinsulinemia., (© 2023 The Obesity Society.)

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 18 F-Fluorodeoxyglucose ( 18 F-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 (MVO 2 ) (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 MVO 2 . 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 (β 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., (© 2023. The Author(s).)

The circadian rhythm regulates biological processes that occur within 24 h in living organisms. It plays a fundamental role in maintaining biological functions and responds to several inputs, including food intake, light/dark cycle, sleep/wake cycle, and physical activity. The circadian timing system comprises a central clock located in the suprachiasmatic nucleus (SCN) and tissue-specific clocks in peripheral tissues. Several studies show that the desynchronization of central and peripheral clocks is associated with an increased incidence of insulin resistance (IR) and related diseases. In this review, we discuss the current knowledge of molecular and cellular mechanisms underlying the impact of circadian clock dysregulation on insulin action. We focus our attention on two possible mediators of this interaction: the phosphatases belonging to the pleckstrin homology leucine-rich repeat protein phosphatase family (PHLPP) family and the deacetylase Sirtuin1. We believe that literature data, herein summarized, suggest that a thorough change of life habits, with the return to synchronized food intake, physical activity, and rest, would doubtless halt the vicious cycle linking IR to dysregulated circadian rhythms. However, since such a comprehensive change may be incompatible with the demand of modern society, clarifying the pathways involved may, nonetheless, contribute to the identification of therapeutic targets that may be exploited to cure or prevent IR-related diseases.

Metabolic syndrome is a condition characterized by a clustering of metabolic abnormalities associated with an increased risk of type 2 diabetes and cardiovascular disease. An impaired insulin-stimulated myocardial glucose metabolism has been shown to be a risk factor for the development of cardiovascular disease in patients with type 2 diabetes. Whether cardiac insulin resistance occurs in subjects with metabolic syndrome remains uncertain. To investigate this issue, we evaluated myocardial glucose metabolic rate using cardiac dynamic 18 F-FDG-PET combined with euglycemic-hyperinsulinemic clamp in three groups: a group of normal glucose tolerant individuals without metabolic syndrome ( n = 10), a group of individuals with type 2 diabetes and metabolic syndrome ( n = 19), and a group of subjects with type 2 diabetes without metabolic syndrome ( n = 6). After adjusting for age and gender, individuals with type 2 diabetes and metabolic syndrome exhibited a significant reduction in insulin-stimulated myocardial glucose metabolic rate (10.5 ± 9.04 μmol/min/100 g) as compared with both control subjects (32.9 ± 9.7 μmol/min/100 g; P < 0.0001) and subjects with type 2 diabetes without metabolic syndrome (25.15 ± 4.92 μmol/min/100 g; P = 0.01). Conversely, as compared with control subjects (13.01 ± 8.53 mg/min x Kg FFM), both diabetic individuals with metabolic syndrome (3.06 ± 1.7 mg/min × Kg FFM, P = 0.008) and those without metabolic syndrome (2.91 ± 1.54 mg/min × Kg FFM, P = 0.01) exhibited a significant reduction in whole-body insulin-stimulated glucose disposal, while no difference was observed between the 2 groups of subjects with type 2 diabetes with or without metabolic syndrome. Univariate correlations showed that myocardial glucose metabolism was positively correlated with insulin-stimulated glucose disposal ( r = 0.488, P = 0.003), and negatively correlated with the presence of metabolic syndrome ( r = -0.743, P < 0.0001) and with its individual components. In conclusion, our data suggest that an impaired myocardial glucose metabolism may represent an early cardio-metabolic defect in individuals with the coexistence of type 2 diabetes and metabolic syndrome, regardless of whole-body insulin resistance., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Succurro, Vizza, Papa, Cicone, Monea, Tradigo, Fiorentino, Perticone, Guzzi, Sciacqua, Andreozzi, Veltri, Cascini and Sesti.)

Background: The association of circulating asymmetric dimethylarginine (ADMA) levels with cardiovascular risk and arterial stiffness has been reportedly demonstrated, although the causal involvement of ADMA in the pathogenesis of these conditions is still debated. Dimethylaminohydrolase 2 (DDAH2) is the enzyme responsible for ADMA hydrolysis in the vasculature, and carriers of the polymorphism rs9267551 C in the 5'-UTR of DDAH2 have been reported to have higher DDAH2 expression and reduced levels of serum ADMA. Approach and Results: We genotyped rs9267551 in 633 adults of European ancestry and measured their carotid-femoral pulse wave velocity (cfPWV), the gold-standard method to estimate arterial stiffness. cfPWV resulted significantly lower in rs9267551 C allele carriers (Δ = -1.12 m/s, P < 0.01) after correction for age, sex and BMI, and a univariate regression showed that the presence of rs9267551 C variant was negatively associated with cfPWV (β = -0.110, P < 0.01). In a multivariable regression model, subjects carrying the rs9267551 C allele manifested significantly lower cfPWV than GG carriers (β = -0.098, P = 0.01) independently from several potential confounders. We measured circulating ADMA levels in a subset of 344 subjects. A mediation analysis revealed that the effect of DDAH2 rs9267551 genotype on cfPWV was mediated by the variation in ADMA levels. Conclusions: These evidences hint that the presence of rs9267551 C allele may explain, at least in part, a reduction in vessel rigidity as measured by cfPWV, and support the attribution of a causative role to ADMA in the pathogenesis of arterial stiffness., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Averta, Mancuso, Spiga, Miceli, Succurro, Fiorentino, Perticone, Mannino, Thamtarana, Sciacqua, Sesti and Andreozzi.)

Objective: To investigate the impact of albumin levels on the aspirin efficacy, since aspirin inhibits platelet aggregation (PA) by cyclooxygenase one irreversible acetylation that is less effective in patients with type 2 diabetes mellitus (T2DM). Patients and Methods: A total of 612 aspirin (100 mg/day)-treated T2DM patients were followed-up for 54.4 ± 7.3 months. The primary endpoint, a composite of cardiovascular events (CVEs) including CV death, myocardial infarction, ischemic stroke and coronary revascularization, was analysed according to baseline values of serum albumin (≥ or < 3.5 g/dL). Serum thromboxane (Tx)B 2 was also measured. Results: 250 (40.8%) patients had serum albumin < 3.5 g/dL; these patients were overweight and had higher values of fibrinogen ( p = 0.009), high sensitivity C-reactive protein ( p = 0.001) and fasting plasma glucose ( p < 0.0001) compared to those with albumin ≥ 3.5 g/dL. During follow-up, 86 CVEs were recorded, 49 and 37 in patients with serum albumin < or ≥3.5 g/dL, respectively ( p = 0.001). At multivariable Cox regression analysis, serum albumin < 3.5 g/dL (hazard ratio [HR] 1.887, 95% confidence interval [CI] 1.136-3.135, p = 0.014), age (HR 1.552 for every 10 years, 95%CI 1.157-2.081, p = 0.003), fasting plasma glucose (HR 1.063, 95%CI 1.022-1.105, p = 0.002) and beta-blocker use (HR 0.440, 95%CI 0.270-0.717, p = 0.001) were associated to CVEs. Serum TxB 2 levels ( n = 377) were 0.32 ± 0.12 and 0.24 ± 0.12 ng/ml in patients with albumin < or ≥ 3.5 g/dL, respectively ( p < 0.001). Conclusion: In T2DM patients, the efficacy of aspirin varies according to albumin levels. Hypoalbuminemia associated with impaired TxB 2 inhibition and an increased risk of long-term CVEs., Competing Interests: FV declares that he has received consulting fees from Bayer and Shionogi. DA declares that he has received consulting fees or honoraria from Abbott, Amgen, Aralez, AstraZeneca, Bayer, Biosensors, Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, Daiichi-Sankyo, Eli Lilly, Haemonetics, Janssen, Merck, PhaseBio, PLx Pharma, Pfizer, Sanofi, and The Medicines Company and has received payments for participation in review activities from CeloNova and St Jude Medical. DA also declares that his institution has received research grants from Amgen, AstraZeneca, Bayer, Biosensors, CeloNova, CSL Behring, Daiichi-Sankyo, Eisai, Eli Lilly, Gilead, Idorsia, Janssen, Matsutani Chemical Industry Co., Merck, Novartis, Osprey Medical, Renal Guard Solutions, and the Scott R. MacKenzie Foundation. GS declares that has received speaker/consulting honoraria from Novo Nordisk, Eli Lilly, AstraZeneca, Boehringer Ingelheim, Merck Sharp andamp; Dohme (MSD), Sanofi, Novartis, Sobi, Daiichi Sankyo, Theras, L-Nutra, Mundipharma, Omikron, and Servier. PP declares that has received speaker/consulting honoraria from Boehringer Ingelheim, Daiichi Sankyo, Pfizer, BMS, Bayer. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Sciacqua, Andreozzi, Succurro, Pastori, Cammisotto, Armentaro, Mannino, Fiorentino, Pignatelli, Angiolillo, Sesti and Violi.)

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.

Gestational diabetes mellitus (GDM) is associated with a high risk of developing type 2 diabetes (T2DM) and cardiovascular disease (CVD). Identifying among GDM women those who are at high risk may help prevent T2DM and, possibly CVD. Several studies have shown that in women with GDM, hyperglycemia at 1 h during an oral glucose tolerance test (OGTT) (1-h PG) is not only associated with an increase in adverse maternal and perinatal outcomes but is also an independent predictor of T2DM. Interestingly, also in pregnant women who did not meet the criteria for a GDM diagnosis, 1-h PG was an independent predictor of postpartum impaired insulin sensitivity and beta-cell dysfunction. Moreover, maternal 1- and 2-h PG levels have been found to be independently associated with insulin resistance and impaired insulin secretion also during childhood. There is evidence that hyperglycemia at 1h PG during pregnancy may identify women at high risk of future CVD, due to its association with an unfavorable CV risk profile, inflammation, arterial stiffness and endothelial dysfunction. Overall, hyperglycemia at 1h during an OGTT in pregnancy may be a valuable prediction tool for identifying women at a high risk of future T2DM, who may then benefit from therapeutic strategies aimed at preventing cardiovascular outcomes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Succurro, Fraticelli, Franzago, Fiorentino, Andreozzi, Vitacolonna and Sesti.)

Objective: One-hour plasma glucose (1-h PG) during the oral glucose tolerance test (OGTT) is an accurate predictor of type 2 diabetes. We performed a meta-analysis to determine the optimum cutoff of 1-h PG for detection of type 2 diabetes using 2-h PG as the gold standard., Research Design and Methods: We included 15 studies with 35,551 participants from multiple ethnic groups (53.8% Caucasian) and 2,705 newly detected cases of diabetes based on 2-h PG during OGTT. We excluded cases identified only by elevated fasting plasma glucose and/or HbA 1c . We determined the optimal 1-h PG threshold and its accuracy at this cutoff for detection of diabetes (2-h PG ≥11.1 mmol/L) using a mixed linear effects regression model with different weights to sensitivity/specificity (2/3, 1/2, and 1/3)., Results: Three cutoffs of 1-h PG, at 10.6 mmol/L, 11.6 mmol/L, and 12.5 mmol/L, had sensitivities of 0.95, 0.92, and 0.87 and specificities of 0.86, 0.91, and 0.94 at weights 2/3, 1/2, and 1/3, respectively. The cutoff of 11.6 mmol/L (95% CI 10.6, 12.6) had a sensitivity of 0.92 (0.87, 0.95), specificity of 0.91 (0.88, 0.93), area under the curve 0.939 (95% confidence region for sensitivity at a given specificity: 0.904, 0.946), and a positive predictive value of 45%., Conclusions: The 1-h PG of ≥11.6 mmol/L during OGTT has a good sensitivity and specificity for detecting type 2 diabetes. Prescreening with a diabetes-specific risk calculator to identify high-risk individuals is suggested to decrease the proportion of false-positive cases. Studies including other ethnic groups and assessing complication risk are warranted., (© 2021 by the American Diabetes Association.)

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.

Background: Glucose alterations are associated with impaired cognition. The 1-h-post-load plasma glucose ≥155 mg/dl in non-diabetic subjects confers an increased risk of cardiovascular events and diabetes. This pilot study aimed to investigate whether the 1-h-post-load plasma glucose ≥155 mg/dl negatively affects the subcortical regions of the brain and the cognitive functions. Methods: We enrolled 32 non-diabetic subjects. Patients were divided into two groups based on 1-h- post-load plasma glucose value > or < 155 mg/dl: normal glucose tolerance (NGT) 1-h-high and NGT 1-h-low subjects. All subjects underwent 3 Tesla MRI and standard neuropsychological tests. Results: NGT 1-h-high subjects showed significantly lower values of both right (4.9 ± 0.9 vs. 5.1 ± 0.9 ml) and left (4.8 ± 1.1 vs. 5.1 ± 1.1 ml) hippocampal hemisphere volume, while right hemisphere hippocampal diffusivity was lower in the NGT 1-h-high group (10.0 ± 0.6 vs. 10.6 ± 0.5 10 -4 mm 2 s -1 ). NGT 1-h-high subjects also showed a poorer memory performance. In particular, for both Rey Auditory Verbal Learning Task (RAVLT)-immediate-recall and Free and Cued Selective Reminding Test (FCSRT)-delayed total recall, we found lower cognitive test scores in the NGT-1 h-high group (26.5 ± 6.3 and 10.4 ± 0.3, respectively). Conclusions: One-hour-post-load hyperglycemia is associated with morpho-functional subcortical brain alterations and poor memory performance tests., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Perticone, Di Lorenzo, Arabia, Arturi, Caroleo, Tassone, Pujia, Fiorentino, Chiriaco, Sesti, Quattrone and Perticone.)

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.)

Several studies in patients with chronic kidney disease or normal renal function have shown that high levels of tissue non-specific alkaline phosphatase (ALP) are associated with an increased risk of all cause and cardiovascular (CV) mortality. Considering the independent prognostic role of renal function, we investigated the possible association between ALP levels and estimated glomerular filtration rate (e-GFR) in a large cohort of hypertensive subjects. We enrolled 2157 never-treated uncomplicated hypertensive patients with ALP levels within normal range. In the whole population, e-GFR was strongly related to ALP (r = -0.43, P < 0.0001) with similar magnitude in females and in males, resulting ALP the second independent predictor of renal function. In a multiple linear regression model, both on crude (P < 0.001) and adjusted (P = 0.01) analyses age significantly modified the effect of a fixed increase in ALP (20 UI/L) on renal function so that the reduction in e-GFR associated to a 20 UI/L increase in ALP was of lower magnitude in younger patients and progressively of higher extent from 20 years of age onwards. In conclusion, present data indicate a significant relationship between ALP levels and e-GFR in uncomplicated hypertensive patients that is modulated by age and that persisted after adjusting for several confounders.

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.

Objective: Impaired insulin-stimulated myocardial glucose uptake has occurred in patients with type 2 diabetes with or without coronary artery disease. Whether cardiac insulin resistance is present remains uncertain in subjects at risk for type 2 diabetes, such as individuals with impaired glucose tolerance (IGT) or those with normal glucose tolerance (NGT) and 1-h postload glucose ≥155 mg/dL during an oral glucose tolerance test (NGT 1-h high). This issue was examined in this study., Research Design and Methods: The myocardial metabolic rate of glucose (MRGlu) was measured by using dynamic 18 F-fluorodeoxyglucose positron emission tomography combined with a euglycemic-hyperinsulinemic clamp in 30 volunteers without coronary artery disease. Three groups were studied: 1 ) those with 1-h postload glucose <155 mg/dL (NGT 1-h low) ( n = 10), 2 ) those with NGT 1-h high ( n = 10), 3 ) and those with IGT ( n = 10)., Results: After adjusting for age, sex, and BMI, both subjects with NGT 1-h high (23.7 ± 6.4 mmol/min/100 mg; P = 0.024) and those with IGT (16.4 ± 6.0 mmol/min/100 mg; P < 0.0001) exhibited a significant reduction in global myocardial MRGlu; this value was 32.8 ± 9.7 mmol/min/100 mg in subjects with NGT 1-h low. Univariate correlations showed that MRGlu was positively correlated with insulin-stimulated whole-body glucose disposal ( r = 0.441; P = 0.019) and negatively correlated with 1-h ( r = -0.422; P = 0.025) and 2-h ( r = -0.374; P = 0.05) postload glucose levels, but not with fasting glucose., Conclusions: This study shows that myocardial insulin resistance is an early defect that is already detectable in individuals with dysglycemic conditions associated with an increased risk of type 2 diabetes, such as IGT and NGT 1-h high., (© 2020 by the American Diabetes Association.)

Obese subjects showed different cardiovascular risk depending by different insulin sensitivity status. We investigated the difference in left ventricular mass and geometry between metabolically healthy (MHO) and unhealthy (MUHO) obese subjects. From a cohort of 876 obese subjects (48.3 ± 14.1 years) without cardio-metabolic disease and stratified according to increasing values of Matsuda index after 75 g oral glucose tolerance test, we defined MHO ( n = 292) those in the upper tertile and MUHO ( n = 292) those in the lower tertile. All participants underwent echocardiographic measurements. Left ventricular mass was calculated by Devereux equation and normalized by height 2,7 and left ventricular hypertrophy (LVH) was defined by values >44 g/m 2.7 for females and >48 g/m 2.7 for males. Left ventricular geometric pattern was defined as concentric or eccentric if relative wall thickness was higher or lower than 0.42, respectively. MHO developed more commonly a concentric remodeling (19.9 vs. 9.9%; p = 0.001) and had a reduced risk for LVH (OR 0.46; p < 0.0001) than MUHO, in which the eccentric type was more prevalent (40.4 vs. 5.1%; p < 0.0001). We demonstrated that obese subjects-matched for age, gender and BMI-have different left ventricular mass and geometry due to different insulin sensitivity status, suggesting that diverse metabolic phenotypes lead to alternative myocardial adaptation.

: Type 2 diabetes mellitus (T2DM) is a risk factor for cognitive impairment. Ranolazine, an anti-ischemic drug used in the treatment of angina pectoris, has been shown to possess hypoglycemic properties in pre-clinical and clinical studies. The aim of this study was to evaluate the effects of ranolazine on glucose metabolism and cognitive function in a T2DM model of Wistar rats. Diabetes was induced by a high fat diet (HFD) and streptozotocin (STZ). The control group received a normal caloric diet (NCD) and sodium citrate buffer. Metformin, an effective hypoglycemic drug, was employed as a positive control. Animals were divided into the following groups: HFD/STZ + Ranolazine, HFD/STZ + Metformin, HFD/STZ + Vehicle, NCD + Vehicle, NCD + Ranolazine, and NCD + Metformin. Rats received ranolazine (20 mg/kg), metformin (300 mg/kg), or water, for 8 weeks. At the end of the treatments, all animals underwent to an intraperitoneal glucose tolerance test (IPGTT) and behavioral tests, including passive avoidance, novel object recognition, forced swimming, and elevate plus maze tests. Interleukin-6 plasma levels in the six treatment groups were assessed by Elisa assay. Body mass composition was estimated by nuclear magnetic resonance (NMR). Glucose responsiveness significantly improved in the HFD/STZ + Ranolazine ( p < 0.0001) and HFD/STZ + Metformin ( p = 0.003) groups. There was a moderate effect on blood glucose levels in the NCD + Ranolazine and NCD + Metformin groups. Lean body mass was significantly increased in the HFD/STZ + Ranolazine and HFD/STZ + Metformin animals, compared to HFD/STZ + Vehicle animals. Ranolazine improved learning and long-term memory in HFD/STZ + Ranolazine compared to HFD/STZ + Vehicle ( p < 0.001) and ameliorated the pro-inflammatory profile of diabetic mice. These results support the hypothesis of a protective effect of ranolazine against cognitive decline caused by T2DM., Competing Interests: The Authors declare no conflict of interests.

Introduction: Insulin resistance plays a crucial role in the pathogenesis of type 2 diabetes and cardiovascular disease. The triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio, visceral adiposity index (VAI), lipid accumulation product (LAP) and triglycerides × fasting glucose (TyG) index are surrogate measures of insulin sensitivity based on anthropometric and/or biochemical parameters routinely collected in clinical practice. Herein, we compared the relationships of these four surrogate indexes with insulin sensitivity assessed by the gold standard euglycemic hyperinsulinemic clamp technique, and subclinical vascular damage., Research Design and Methods: 631 subjects with different degrees of glucose tolerance underwent euglycemic hyperinsulinemic clamp. The surrogate TG/HDL-C ratio, VAI, LAP and TyG indexes were computed. Pulse pressure and carotid intima-media thickness (IMT) were measured as indicators of subclinical vascular damage., Results: All the four surrogate indexes showed a significant correlation with insulin-stimulated glucose disposal in the whole study population. However, only LAP index had a significant association with insulin sensitivity across the different glucose tolerance groups. LAP index showed the highest area under the receiver operating characteristic curve (0.728) to detect individuals with insulin resistance defined as the bottom quartile of insulin-stimulated glucose disposal, followed by TG/HDL-C ratio (0.693), TyG index (0.688) and VAI (0.688). A significant association was found between the four indexes of insulin sensitivity and pulse pressure and IMT. All the four indexes have a similar ability to detect individuals with vascular atherosclerosis defined by IMT>0.9 mm. Conversely, LAP index had the greatest ability to recognize individuals with increased vascular stiffness defined by pulse pressure ≥60 mm Hg., Conclusion: Among the surrogate TG/HDL-C ratio, VAI, LAP and TyG indexes of insulin sensitivity, LAP index showed a significant association with insulin-stimulated glucose disposal across the different glucose tolerance categories and the highest ability to detect insulin resistance and subclinical vascular damage., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The glucagon-like peptide-1 receptor agonist exenatide improves glycemic control by several and not completely understood mechanisms. Herein, we examined the effects of chronic intravenous exenatide infusion on insulin sensitivity, β cell and α cell function and relative volumes, and islet cell apoptosis and replication in nondiabetic nonhuman primates (baboons). At baseline, baboons received a 2-step hyperglycemic clamp followed by an l-arginine bolus (HC/A). After HC/A, baboons underwent a partial pancreatectomy (tail removal) and received a continuous exenatide (n = 12) or saline (n = 12) infusion for 13 weeks. At the end of treatment, HC/A was repeated, and the remnant pancreas (head-body) was harvested. Insulin sensitivity increased dramatically after exenatide treatment and was accompanied by a decrease in insulin and C-peptide secretion, while the insulin secretion/insulin resistance (disposition) index increased by about 2-fold. β, α, and δ cell relative volumes in exenatide-treated baboons were significantly increased compared with saline-treated controls, primarily as the result of increased islet cell replication. Features of cellular stress and secretory dysfunction were present in islets of saline-treated baboons and absent in islets of exenatide-treated baboons. In conclusion, chronic administration of exenatide exerts proliferative and cytoprotective effects on β, α, and δ cells and produces a robust increase in insulin sensitivity in nonhuman primates.

Context: Impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) are highly pathophysiologic heterogeneous prediabetes conditions that can occur in all age groups, from youth to elderly people., Objective: We evaluated whether distinct age-related phenotypes exist among individuals with IFG or IGT., Research Design: 479 young (aged 18 to 35 years), 699 adult (45 to 55 years) and 240 older (≥65 years) subjects underwent an oral glucose tolerance test (OGTT). From the OGTT results, the participants were grouped as follows: young age and normal glucose tolerance (NGT), adult age and NGT, older age and NGT, IFG young subjects, IFG adult subjects, IFG older subjects, IGT young (Y-IGT) subjects, IGT adult (A-IGT) subjects, and IGT older (O-IGT) subjects., Main Outcome Measures: Insulin sensitivity and secretion, insulin clearance, and β-cell function., Results: Peripheral insulin sensitivity assessed using the Matsuda index, basal and glucose-stimulated insulin secretion, and β-cell function estimated using the disposition index were decreased in IFG adult subjects and IFG older subjects compared with IFG young subjects. A-IGT and Y-IGT subjects exhibited a progressively greater degree of hepatic insulin resistance assessed using the liver insulin resistance index, and reduced insulin clearance compared with O-IGT subjects. In contrast, the Matsuda index did not differ among Y-IGT, A-IGT, and O-IGT subjects. Basal and glucose-stimulated insulin secretion and β-cell function were lower in A-IGT and O-IGT subjects compared with Y-IGT individuals., Conclusions: Subjects with IFG or IGT exhibited different age-related pathophysiologic characteristics. A more precise phenotyping of subjects with IGT or IFG could help to better design individualized preventive approaches to counteract diabetes progression., (Copyright © 2019 Endocrine Society.)

Preclinical studies suggested that IgG2c isotype may specifically impair skeletal muscle insulin sensitivity in mice. In this study we investigated the association between serum levels of the four IgG subclasses and insulin sensitivity in non-diabetic individuals. Total IgG, IgG1, IgG2, IgG3 and IgG4 levels were measured in 262 subjects. Whole-body insulin sensitivity was assessed by euglycemic hyperinsulinemic clamp. IgG2 levels were positively correlated with BMI, waist circumference, 2-h post-load glucose levels and complement C3. Serum IgG2, but not IgG1, IgG3 and IgG4 levels were negatively correlated with whole-body insulin sensitivity (r = -0.17; P = 0.003) and muscle insulin sensitivity index (r = -0.16; P = 0.03) after adjustment for age and gender. No significant correlation was found between IgG2 levels and hepatic insulin resistance assessed by HOMA-IR and liver IR index. In a multivariable regression analysis including variables known to affect insulin sensitivity such as age, gender, BMI, smoking, lipids, inflammatory markers, fasting and 2-h post-load glucose levels, IgG2 levels were independently associated with insulin-stimulated glucose disposal (β = -0.115, 95% CI: -0.541 to -0.024; P = 0.03). These data demonstrate the independent association between higher levels of IgG2 and decreased whole-body insulin sensitivity, thus confirming in humans the animal-based evidence indicating the pathogenic role of IgG2 in insulin resistance.

Context: Recently, a value of 1-hour postload glucose concentration (1-h-PG) ≥155 mg/dL (8.6 mmol/L) in individuals with normal glucose tolerance (NGT) has been found to be associated with an increased risk for future type 2 diabetes mellitus (T2DM). In this review, we analyze the implication of 1-h-PG determination in prediction of T2DM and cardiovascular disease., Design: A literature search was performed using MEDLINE. We included all English studies published up to February 2018 in peer-reviewed journals that examined the relationship between 1-h-PG and diabetes, cardiometabolic alterations, organ damage, and cardiovascular disease., Results: Several longitudinal studies have consistently shown that 1-h-PG ≥155 mg/dL can recognize individuals at increased risk for future T2DM among subjects with NGT. Additionally, we describe the pathophysiological abnormalities associated with 1-h-PG ≥155 mg/dL including impaired insulin sensitivity, β-cell dysfunction, and increased glucose intestinal absorption, which are known to be involved in T2DM pathogenesis. Importantly, numerous studies have demonstrated that a value of 1-h-PG ≥155 mg/dL in individuals with NGT is not only linked to an increased risk for future T2DM, but also able to identify those having a worse cardiovascular phenotype and an increased risk of adverse cardiovascular outcomes., Conclusions: Although 1-h-PG determination is not currently recommended by the American Diabetes Association for identifying high-risk individuals, the available evidence indicates that a value of 1-h-PG ≥155 mg/dL may be a useful tool to recognize, among subjects with NGT, those at increased risk of T2DM and cardiovascular disease.

Context: Type 2 diabetes (T2DM) is associated with a higher intestinal expression of the glucose transporters sodium/glucose cotransporter 1 (SGLT-1) and glucose transporter 2 (GLUT-2). It is currently unsettled whether prediabetes conditions characterized by postprandial hyperglycemia, such as impaired glucose tolerance (IGT) and normal glucose tolerance (NGT) with 1-hour postload glucose ≥155 mg/dL (8.6 mmol/L) (NGT-1h-high) are associated with increased expression of these glucose carriers in the intestine., Objective: We evaluated whether duodenal abundance of SGLT-1 and GLUT-2 is augmented in subjects with IGT and NGT-1h-high, in comparison with subjects with NGT and 1-hour postload glucose ˂155 mg/dL (NGT-1h-low)., Design: Cross-sectional., Patients: A total of 54 individuals underwent an upper gastrointestinal endoscopy., Main Outcome Measures: Duodenal SGLT-1 and GLUT-2 protein and messenger RNA levels were assessed by Western blot and reverse transcription polymerase chain reaction, respectively., Results: Of the 54 subjects examined, 18 had NGT-1h-low, 12 had NGT-1h-high, 12 had IGT, and 12 had T2DM. Duodenal SGLT-1 protein and messenger RNA levels were significantly higher in individuals with NGT-1h-high, IGT, or T2DM in comparison with NGT-1h-low subjects. GLUT-2 abundance was higher in individuals with T2DM in comparison with NGT-1h-low subjects; no substantial increase in GLUT-2 expression was observed in NGT-1h-high or IGT individuals. Univariate correlations showed that duodenal SGLT-1 abundance was positively correlated with 1-hour postload plasma glucose levels (r = 0.44; P = 0.003) but not with fasting or 2-hour postload glucose levels., Conclusions: Duodenal SGLT-1 expression is increased in individuals with 1-hour postload hyperglycemia or IGT, as well as in subjects with T2DM, and it positively correlates with early postload glucose excursion., (Copyright © 2017 Endocrine Society)

Hemoglobin glycation index (HGI), calculated as the difference between the observed value of HbA1 and the predicted HbA1c based on plasma glucose concentration, is a measure of the individual tendency toward non-enzymatic hemoglobin glycation which has been found to be positively associated with nephropathy in subjects with diabetes. In this cross-sectional study we aimed to evaluate whether higher HGI levels are associated with impaired kidney function also among nondiabetic individuals. The study group comprised 1505 White nondiabetic individuals stratified in quartiles according to HGI levels. Estimated glomerular filtration rate (eGFR) was calculated by using the MDRD equation. Individuals in the intermediate and high HGI groups exhibited a worse metabolic phenotype with increased levels of visceral obesity, total cholesterol, triglycerides, inflammatory biomarkers such as hsCRP and white blood cells count and lower values of HDL and insulin sensitivity assessed by Matsuda index in comparison to the lowest quartile of HGI. Subjects in the intermediate and high HGI groups displayed a graded decrease of eGFR levels in comparison with the lowest quartile of HGI. In a logistic regression analysis individuals in the highest quartile of HGI exhibited a significantly 3.6-fold increased risk of having chronic kidney disease (95% CI: 1.13-11.24, P = 0.03) and a significantly 1.6-fold increased risk of having a mildly reduced kidney function (95% CI: 1.19-2.28, P = 0.003) in comparison to individuals in the lowest HGI group. In conclusion HGI may be a useful tool to identify nondiabetic individuals with an increased risk of having kidney dysfunction., Competing Interests: CONFLICTS OF INTEREST All Authors have nothing to declare.

In vitro and in vivo studies suggest that IGF-1 has a role in erythropoiesis. There is evidence that the rs35767 C/T polymorphism near IGF1 is associated with plasma IGF-1 levels. We investigated the effect of this polymorphism on hemoglobin (Hb) concentration and anemia. The study group comprised 3286 adult Whites. The rs35767 polymorphism was screened using a TaqMan allelic discrimination assay. The rs35767 polymorphism was not associated with age, gender, BMI, waist circumference, smoking, blood pressure, plasma glucose, HbA1c, type 2 diabetes, HOMA-IR, hsCRP, eGFR, and lipid profile. Erythrocyte sedimentation rate (ESR), fibrinogen, and fasting insulin levels were significantly lower in TT genotype carriers compared with C allele carriers. Hb concentration was significantly higher in carriers of the TT genotype compared with C allele carriers, and a lower proportion of TT carriers had anemia. As compared with TT genotype carriers, those bearing the CC genotype had a 2.4-fold higher risk of anemia (OR 2.40, 95%CI 1.19-4.82), and those with the CT genotype had a 2.0-fold higher risk of anemia (OR 2.06, 95%CI 1.04-4.11). The association remained significant when fasting insulin, eGFR, smoking, diabetes, ACE inhibitors, sartans or diuretics treatments, use of metformin and pioglitazone were added to the model, but its independence was not retained after inclusion of fibrinogen and ESR values into the model. In conclusion, rs35767 TT allele carriers exhibited significantly higher concentrations of Hb, and lower risk of anemia compared with C allele carriers supporting the idea that IGF-1 plays a role in erythropoiesis homeostasis.

Hemoglobin glycation index (HGI), defined as the difference between the observed HbA1c value and the value of HbA1c predicted from plasma glucose levels, represents a measure of the degree of non-enzymatic glycation of hemoglobin and it has been found to be positively associated with micro- and macro-vascular complications in subjects with type 2 diabetes. To investigate the pathophysiological abnormalities responsible for the increased cardiovascular risk of patients with higher HGI, we evaluated the association of HGI with cardio-metabolic characteristics in nondiabetic offspring of type 2 diabetic individuals. Insulin sensitivity, measured by a hyperinsulinemic-euglycemic clamp, cardio-metabolic risk factors including lipid profile, uric acid and inflammatory factors, and ultrasound measurement of carotid intima-media thickness (IMT) were assessed in 387 nondiabetic individuals. Participants were stratified in tertiles according to HGI (high, moderate and low). As compared with subjects with low HGI, those with high HGI displayed an unfavorable cardio-metabolic risk profile having significantly higher values of BMI, waist circumference, triglycerides, uric acid, fasting insulin, inflammatory markers, such as high sensitivity C reactive protein, erythrocytes sedimentation rate, complement C3, fibrinogen, and white blood cell count, and carotid IMT, and lower HDL and insulin-stimulated glucose disposal. In a linear regression analysis model including several atherosclerotic risk factors such as gender, age, BMI, inflammatory factors, lipid profile, insulin-stimulated glucose disposal, fasting insulin, uric acid, and blood pressure, HGI was the major predictor of IMT (β = 0.35; P = 0.001). In a logistic regression analysis adjusted for confounders, individuals with high HGI showed a 2.7-fold increased risk of vascular atherosclerosis (OR 2.72, 95%CI 1.01-7.37) as compared with subjects with low HGI. The present findings support the notion that HGI may be a useful tool to identify a subset of nondiabetic individuals conceivably harboring a higher risk of cardiovascular disease.

Context: Individuals with glycated hemoglobin (HbA1c)-defined prediabetes (HbA1c value of 5.7-6.4%) and 1-hour plasma glucose ≥155 mg/dL during an oral glucose tolerance test have an increased risk of developing type 2 diabetes., Objective: To evaluate the degree to which HbA1c-defined prediabetes and 1-hour postload glucose ≥155 mg/dL individually and jointly associate with hepatic steatosis and related biomarkers., Design and Patients: A cross-sectional analysis was performed on 1108 White individuals., Setting: Ambulatory care., Main Outcome Measures: Anthropometric and metabolic characteristics including hepatic steatosis assessed by ultrasonography., Results: Compared with the normal group (HbA1c <5.7%), HbA1c-defined prediabetic and diabetic individuals exhibit higher values of fasting, 1-hour, and 2-hour postload glucose; fasting and 2-hour postload insulin; triglycerides; uric acid; homeostasis model of assessment for insulin resistance; liver insulin resistance index; liver enzymes; and inflammatory biomarkers; and lower levels of high-density lipoprotein cholesterol and IGF-1. Prediabetic and diabetic subjects have increased risk of hepatic steatosis (1.5- and 2.46-fold, respectively). Stratifying participants according to HbA1c and 1-hour postload glucose, we found that individuals with HbA1c-defined prediabetes and 1-hour postload glucose ≥155 mg/dL have significantly higher risk of hepatic steatosis as compared with individuals with HbA1c-defined prediabetes but 1-hour postload glucose <155 mg/dL. Individuals with HbA1c-defined prediabetes and 1-hour postload glucose ≥155 mg/dL exhibit higher values of liver enzymes; fasting, 1-hour, and 2-hour postload glucose; insulin; triglycerides; uric acid; and inflammatory biomarkers; and lower levels of high-density lipoprotein and IGF-1., Conclusions: These data suggest that a value of 1-hour postload glucose ≥155 mg/dL may be helpful to identify a subset of individuals within HbA1c-defined glycemic categories at higher risk of hepatic steatosis.

Context: Subjects with normal glucose tolerance (NGT) but 1-h postload glucose ≥ 155 mg/dL (NGT-1h-high) exhibit an intermediate cardiometabolic risk profile between individuals with NGT and impaired glucose tolerance (IGT)., Objective: This study aimed to evaluate whether NGT-1h-high subjects have different cardiometabolic characteristics and an increased risk of type 2 diabetes compared with individuals with isolated impaired fasting glucose (IFG)., Setting, Design, and Patients: A cross-sectional analysis was performed on 595 nondiabetic subjects who underwent an oral glucose tolerance test and an euglycemic hyperinsulinemic clamp in an ambulatory care setting. In addition, a longitudinal analysis was performed on 392 individuals, who were reexamined after a followup of 5.2 ± 0.9 y., Main Outcome Measures: Insulin sensitivity, beta-cell function, and risk of developing diabetes were measured., Results: Subjects with NGT-1h-high have a significant reduction of peripheral insulin sensitivity and beta-cell function, assessed by the disposition index, compared with either 1-h postload glucose < 155 mg/dL (NGT-1h-low) or IFG individuals, but not compared with IGT. Among the 392 subjects studied in the longitudinal analysis the incidence rate of type 2 diabetes over the follow-up period was 2.9, 16.7, 12.5, and 31.4% for subjects with NGT-1h-low, NGT-1h-high, IFG, and IGT, respectively. In a Cox proportional hazard regression analysis the risk of developing diabetes for NGT-1h-high subjects was 4.02 (95% confidence interval [CI] 1.06-15.26); an even higher risk (6.67; 95% CI, 2.09-21.24) was observed in subjects with IGT, but not in the isolated IFG group (1.91; 95% CI, 0.44-8.29)., Conclusions: NGT-1h-high subjects exhibit a higher risk of developing diabetes than those with IFG or NGT-1h-low, likely due to decreased insulin sensitivity and beta-cell function.

Aims: We hypothesized that a disproportionate activation of the glucosamine (GlcN) pathway, caused by a prolonged exposure to hyperglycaemia, could impair endothelial integrity promoting endoplasmic reticulum (ER) stress. We also tested the possibility that SRT1720 may be able to counteract GlcN-induced ER stress., Methods and Results: Human umbilical vein endothelial cells (HUVECs), human cardiac microvascular endothelial cells, and human retinal endothelial cells were treated with GlcN in the presence or absence of the chemical chaperone phenyl butyric acid (PBA) or SRT1720. Expression of ER stress markers, activation of apoptosis, and pro-inflammatory/pro-thrombotic pathways were evaluated by western blot, real-time RT-PCR, and ELISA assays. GlcN treatment resulted in a significantly increased expression of the major ER stress mediators. ER stress activation was paralleled by increased levels of apoptotic markers and by pro-inflammatory/pro-coagulant pathway activation. In HUVECs, ER stress inhibition by PBA alleviated a GlcN-induced pro-apoptotic and pro-inflammatory/pro-thrombotic state, suggesting a crucial role of ER stress in endothelial dysfunction caused by GlcN. Furthermore, SRT1720 treatment abolished GlcN-induced ER stress and reversed its effects on apoptosis and pro-inflammatory/pro-coagulant pathways. This SRT1720 action was mediated by its ability to modulate Raptor acetylation, thus inhibiting mammalian target of Rapamycin complex 1 (mTORC1)-dependent protein synthesis and alleviating ER overload., Conclusions: Our data show that GlcN promotes a pro-apoptotic and pro-inflammatory/pro-thrombotic phenotype in endothelial cells by activating ER stress. The observation that SRT1720, inhibiting ER stress, was able to counteract GlcN effects lays the basis for future studies aimed to exploit this drug and cognate compounds in the treatment of endothelial dysfunction and atherosclerosis., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)

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 β-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., (Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

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.

Objective: To determine the ability of the proposed diagnostic value of a 1-h OGTT glucose ≥155mg/dL to identify individuals with non-alcoholic fatty liver disease (NAFLD) diagnosed by ultrasonography in a cohort of adult white individuals., Design: The study group comprised 710 white individuals participating to the CATAnzaro MEtabolic RIsk factors (CATAMERI) Study, a cross-sectional study assessing cardio-metabolic risk factors in individuals carrying at least one risk factor including dysglycemia, overweight/obesity, hypertension, dyslipidemia. a 75 g oral Oral Glucose Tolerance Test (OGTT) was performed with 0, 30, 60, 90 and 120 min sampling for plasma glucose and insulin measurements. Cardio-metabolic risk factors including alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyltransferase (GGT) were assessed in the whole cohort., Results: Of the 710 participants examined, 295 had normal glucose tolerance (NGT) with 1-hour post-load plasma glucose <155 mg/dL (NGT 1h-low), 109 individuals had NGT 1h-high, 104 had isolated impaired fasting glucose (IFG), and 202 had impaired glucose tolerance (IGT). As compared with NGT 1h-low, NGT 1h-high and IGT subjects exhibited significantly higher body mass index (BMI), triglycerides, high sensitivity C reactive protein, ALT, GGT, and hepatic insulin resistance (IR), assessed by the liver IR index, as well as lower high density lipoprotein, and insulin-like growth factor-1 (IGF-1) levels. In a logistic regression analysis adjusted for age, gender, and BMI, NGT 1h-high participants had a 1.5-fold increased risk of having NAFLD and an even increased risk was observed in subjects with IGT (1.8-fold), but not in the isolated IFG group (1.01-fold)., Conclusions: These data suggest that the value of a 1-hour OGTT glucose ≥155 mg/dL may be helpful to identify a subset of NGT individuals at risk for NAFLD.

Evidence suggests that nonalcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are associated with an increased risk of chronic kidney disease (CKD). In this study we aimed to evaluate whether the severity of liver fibrosis estimated by NAFLD fibrosis score is associated with higher prevalence of CKD in individuals with NAFLD. To this end NAFLD fibrosis score and estimated glomerular filtration rate (eGFR) were assessed in 570 White individuals with ultrasonography-diagnosed NAFLD. As compared with subjects at low probability of liver fibrosis, individuals at high and intermediate probability showed an unfavorable cardio-metabolic risk profile having significantly higher values of waist circumference, insulin resistance, high sensitivity C-reactive protein, fibrinogen, uric acid and lower insulin-like growth factor-1 levels. Individuals at high and intermediate probability of liver fibrosis have lower eGFR after adjustment for gender, smoking, glucose tolerance status, homeostasis model assessment index of insulin resistance (HOMA-IR index), diagnosis of metabolic syndrome, statin therapy, anti-diabetes and anti-hypertensive treatments (P = 0.001). Individuals at high probability of liver fibrosis had a 5.1-fold increased risk of having CKD (OR 5.13, 95%CI 1.13-23.28; P = 0.03) as compared with individuals at low probability after adjustment for age, gender, and BMI. After adjustment for glucose tolerance status, statin therapy, and anti-hypertensive treatment in addition to gender, individuals at high probability of liver fibrosis had a 3.9-fold increased risk of CKD (OR 3.94, 95%CI 1.11-14.05; P = 0.03) as compared with individuals at low probability. In conclusion, advanced liver fibrosis, determined by noninvasive fibrosis markers, is associated with CKD independently from other known factors.

Chronic hyperglycemia impairs insulin action, resulting in glucotoxicity, which can be ameliorated in animal models by inducing glucosuria with renal glucose transport inhibitors. Here, we examined whether reduction of plasma glucose with a sodium-glucose cotransporter 2 (SGLT2) inhibitor could improve insulin-mediated tissue glucose disposal in patients with type 2 diabetes. Eighteen diabetic men were randomized to receive either dapagliflozin (n = 12) or placebo (n = 6) for 2 weeks. We measured insulin-mediated whole body glucose uptake and endogenous glucose production (EGP) at baseline and 2 weeks after treatment using the euglycemic hyperinsulinemic clamp technique. Dapagliflozin treatment induced glucosuria and markedly lowered fasting plasma glucose. Insulin-mediated tissue glucose disposal increased by approximately 18% after 2 weeks of dapagliflozin treatment, while placebo-treated subjects had no change in insulin sensitivity. Surprisingly, following dapagliflozin treatment, EGP increased substantially and was accompanied by an increase in fasting plasma glucagon concentration. Together, our data indicate that reduction of plasma glucose with an agent that works specifically on the kidney to induce glucosuria improves muscle insulin sensitivity. However, glucosuria induction following SGLT2 inhibition is associated with a paradoxical increase in EGP. These results provide support for the glucotoxicity hypothesis, which suggests that chronic hyperglycemia impairs insulin action in individuals with type 2 diabetes.

Reduced insulin clearance has been shown to predict the development of type 2 diabetes. Recently, it has been suggested that plasma glucose concentrations ≥ 8.6 mmol/l (155 mg/dl) at 1 h during an oral glucose tolerance test (OGTT) can identify individuals at high risk for type 2 diabetes among those who have normal glucose tolerance (NGT 1 h-high). The aim of this study was to examine whether NGT 1 h-high have a decrease in insulin clearance, as compared with NGT individuals with 1-h post-load glucose <8.6 mmol/l (l (155 mg/dl, NGT 1 h-low). To this end, 438 non-diabetic White individuals were subjected to OGTT and euglycemic-hyperinsulinemic clamp to evaluate insulin clearance and insulin sensitivity. As compared with NGT 1 h-low individuals, NGT 1 h-high had significantly higher 1-h and 2-h post-load plasma glucose and 2-h insulin levels as well as higher fasting glucose and insulin levels. NGT 1 h-high exhibited also a significant decrease in both insulin sensitivity (P<0.0001) and insulin clearance (P = 0.006) after adjusting for age, gender, adiposity measures, and insulin sensitivity. The differences in insulin clearance remained significant after adjustment for fasting glucose (P = 0.02) in addition to gender, age, and BMI. In univariate analyses adjusted for gender and age, insulin clearance was inversely correlated with body weight, body mass index, waist, fat mass, 1-h and 2-h post-load glucose levels, fasting, 1-h and 2-h post-load insulin levels, and insulin-stimulated glucose disposal. In conclusion, our data show that NGT 1 h-high have a reduction in insulin clearance as compared with NGT 1 h-low individuals; this suggests that impaired insulin clearance may contribute to sustained fasting and post-meal hyperinsulinemia.