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.

Profiles of sulfonylurea use in Diabetes Mellitus type 2: an analysis of clinical practice over the last 10 years.

AIMS: Describing the evolution over time in the use of sulfonylureas (SUs) and the characteristics of patients at first prescription and at interruption of treatment with SUs. METHODS: Retrospective evaluation of data from the Italian Association of Diabetologists (AMD) Annals registry (2010-2020), about T2D patients who started treatment with SUs. The longitudinal probability of remaining on SUs was estimated by Kaplan Meier survival curves. RESULTS: SU prescription decreased from 30.7 % (2010) to 12.9 % (2020). Patients started on SU were 68.2 ± 11.2 years old, mostly males (55.5 %), with diabetes duration = 10.1 ± 8.3 years, BMI = 29.7 ± 5.5 kg/m2, and HbA1c = 8.3 ± 1.7 % [67 mmol/mol]. After one year, the probability of staying on SU was 85.4 %, 75.9 % after two years, 68.2 % after 3 years, 56.6 % after 5 years. Patients who discontinued SUs had higher BMI and HbA1c, were younger, more often males and treated with insulin. Over time, the percentage of subjects switched to metformin, DPP4i, SGLT2i, and GLP1RA increased, whereas use of glinides, glitazones, acarbose and insulin declined. CONCLUSIONS: These data suggest a consensus, slowly, but increasingly aligning with the current National indications of dismissing SUs for the treatment of T2D. The new drugs for diabetes should represent a preferable choice in all patients who do not have specific contraindications.

Association between augmented levels of the gut pro-hormone Proneurotensin and subclinical vascular damage.

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.

Gut Permeability and Immune-Mediated Inflammation in Heart Failure.

Heart failure (HF) is characterized by low-grade immune-mediated inflammation due to increased Toll-like receptor (TLR) expression as response to endotoxin increase and dysregulated gut barrier permeability. We investigated TLR expression and possible gut dysbiosis in HF patients compared to a control group. We enrolled 80 Caucasian HF patients and 20 controls. Low-grade immune-mediated inflammation was evaluated by TLR expression, while gut dysbiosis by the detection of zonulin and bacterial endotoxin activity in a semi-quantitative (endotoxin activity assay [EAA]) and quantitative (limulus amebocyte lysate [LAL] test) way. Compared to controls, patients with HF showed significantly higher age and blood pressure values, worse metabolic profile and kidney function, higher inflammatory biomarkers levels, and lower levels of zonulin and endotoxin activity. When dividing failing patients in those with reduced ejection fraction (HF-rEF) and those with preserved ejection fraction (HF-pEF), HF-rEF patients showed significantly higher values of inflammatory biomarkers and TLR expression than HF-pEF patients. Gut permeability biomarkers inversely correlated with the severity of HF and positively with renal function. eGFR was retained as an independent predictor of zonulin variation in all the three groups of failing patients. Present data work to extend current knowledge about the role of gut microbiota in immune-mediated inflammation in HF.

Prognostic role of serum albumin levels in patients with chronic heart failure.

BACKGROUND: Hypoalbuminemia is common in heart failure (HF) patients; however, there are no data regarding the possible long-term prognostic role of serum albumin (SA) in the younger population with chronic HF without malnutrition. The aim of this study was to examine the long-term prognostic role of SA levels in predicting major adverse cardiac events (MACE) in middle-aged outpatients with chronic HF. METHODS: In the present retrospective analysis, 378 subjects with HF were enrolled. MACE (non-fatal ischemic stroke, non-fatal myocardial infarction, cardiac revascularization or coronary bypass surgery, and cardiovascular death), total mortality, and HF hospitalizations (hHF) occurrence were evaluated during a median follow-up of 6.1 years. RESULTS: In all population, 152 patients had a SA value < 3.5 g/dL and 226 had a SA value ≥ 3.5 g/dL. In patients with SA ≥ 3.5 g/dL, the observed MACE were 2.1 events/100 patient-year; while in the group with a worse SA levels, there were 7.0 events/100 patient-year (p < 0.001). The multivariate analysis model confirmed that low levels of SA increase the risk of MACE by a factor of 3.1. In addition, the presence of ischemic heart disease, serum uric acid levels > 6.0 mg/dL, chronic kidney disease, and a 10-year age rise, increased the risk of MACE in study participants. Finally, patients with SA < 3.5 g/dl had a higher incidence of hHF (p < 0.001) and total mortality (p < 0.001) than patients with SA ≥ 3.5 g/dl. CONCLUSIONS: Patients with chronic HF that exhibits low SA levels show a higher risk of MACE, hHF and total mortality.

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.

Glucagon kinetics assessed by mathematical modelling during oral glucose administration in people spanning from normal glucose tolerance to type 2 diabetes.

Background/Objectives: Glucagon is important in the maintenance of glucose homeostasis, with also effects on lipids. In this study, we aimed to apply a recently developed model of glucagon kinetics to determine the sensitivity of glucagon variations (especially, glucagon inhibition) to insulin levels ("alpha-cell insulin sensitivity"), during oral glucose administration. Subjects/Methods: We studied 50 participants (spanning from normal glucose tolerance to type 2 diabetes) undergoing frequently sampled 5-hr oral glucose tolerance test (OGTT). The alpha-cell insulin sensitivity and the glucagon kinetics were assessed by a mathematical model that we developed previously. Results: The alpha-cell insulin sensitivity parameter (named SGLUCA; "GLUCA": "glucagon") was remarkably variable among participants (CV=221%). SGLUCA was found inversely correlated with the mean glycemic values, as well as with 2-hr glycemia of the OGTT. When stratifying participants into two groups (normal glucose tolerance, NGT, N=28, and impaired glucose regulation/type 2 diabetes, IGR_T2D, N=22), we found that SGLUCA was lower in the latter (1.50 ± 0.50·10-2 vs. 0.26 ± 0.14·10-2 ng·L-1 GLUCA/pmol·L-1 INS, in NGT and IGR_T2D, respectively, p=0.009; "INS": "insulin"). Conclusions: The alpha-cell insulin sensitivity is highly variable among subjects, and it is different in groups at different glucose tolerance. This may be relevant for defining personalized treatment schemes, in terms of dietary prescriptions but also for treatments with glucagon-related agents.

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.

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

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

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.

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.