Antonino Di Pino

Cardiovascular Risk Profile in Subjects With Prediabetes and New-Onset Type 2 Diabetes Identified by HbA 1c According to American Diabetes Association Criteria

OBJECTIVE We investigated the cardiovascular risk profile in subjects with prediabetes and new-onset type 2 diabetes identified by glycated hemoglobin A1c (HbA1c) according to the new American Diabetes Association criteria. RESEARCH DESIGN AND METHODS Arterial stiffness, intima-media thickness (IMT), soluble receptor for advanced glycation end products (sRAGEs), and oral glucose tolerance test (OGTT) were evaluated in 274 subjects without a previous history of diabetes. The subjects were stratified into three groups according to the HbA1c levels. RESULTS The subjects with prediabetes (n = 117, HbA1c 5.7–6.4% [39–46 mmol/mol]) showed a higher augmentation (Aug), augmentation index (AugI), and IMT compared with those with lower HbA1c; however, these values were similar to those of subjects with HbA1c >6.5% (48 mmol/mol). When we further analyzed the subjects with prediabetes but included only subjects with normal glucose tolerance (NT) in the analysis, AugI and IMT still remained significantly higher than their levels in control subjects with HbA1c <5.7% (39 mmol/mol). After multiple regression analyses including several cardiovascular risk factors, only HbA1c, age, and sRAGE were significantly correlated with the IMT, whereas age and 1-h postload glucose were the major determinants of AugI. CONCLUSIONS Our data show that subjects with prediabetes according to HbA1c, but with both NT according to the OGTT and normal fasting glycemia, have an altered IMT and AugI. These data suggest that a simple, reproducible, and less expensive marker such as HbA1c may be better able to identify prediabetic subjects at high cardiovascular risk compared with fasting glycemia or OGTT alone.

Beta and alpha cell function in metabolically healthy but obese subjects: Relationship with entero-insular axis†

Obesity is widely acknowledged as a critical risk factor for metabolic complications. Among obese subjects, there is a phenotype of metabolically healthy but obese (MHO) individuals that shows a favorable cardiometabolic risk profile. We aimed to evaluate the potential mechanisms underlying the metabolic profile of this subset, including alpha and beta cell function and entero‐insular axis.

Low Endogenous Secretory Receptor for Advanced Glycation End-Products Levels Are Associated With Inflammation and Carotid Atherosclerosis in Prediabetes.

CONTEXT Prediabetes is associated with atherosclerotic vascular damage. OBJECTIVE We investigated the correlation of endogenous secretory receptor for advanced glycation end-products (esRAGE), total soluble RAGE (sRAGE) and markers of inflammation, with early cardiovascular disease in subjects with prediabetes. We particularly focused on individuals with prediabetes identified only by glycated hemoglobin A1c (HbA1c) (5.7–6.4%) who had normal fasting glucose and were normotolerant after oral glucose tolerance test. DESIGN This was a cross-sectional study. SETTING The study was conducted in the Department of Clinical and Molecular Medicine, University of Catania, Italy. MAIN OUTCOME MEASURE sRAGE, esRAGE, carboxymethyl-lysine, S100A12, HbA1c, fasting glycemia, oral glucose tolerance test, pulse wave velocity, and intima-media thickness were evaluated in subjects with prediabetes. PATIENTS Three hundred eighty subjects without previous history of diabetes were stratified into three groups: controls (n = 99), prediabetes (n = 220), and new-onset type 2 diabetes (n = 61). RESULTS Subjects with prediabetes exhibited the following: lower esRAGE (0.29 ± 0.18 vs 0.45 ± 0.26 ng/mL; P < .05) and higher S100A12 levels than controls. RT-PCR analysis in mononuclear cells revealed that the mRNA expression level of the esRAGE splice variant progressively decreased in patients with prediabetes and type 2 diabetes with respect to controls. No difference was observed in sRAGE and carboxymethyl-lysine plasma levels between the groups. After multiple regression analyses, only age, HbA1c, and hs-CRP were independently associated with esRAGE levels. Age, HbA1c, and esRAGE were the major determinants of intima-media thickness, whereas S100A12 and systolic blood pressure were the major determinants of pulse wave velocity. When we analyzed the subjects with HbA1c prediabetes (normal fasting glucose/normotolerant and HbA1c 5.7–6.4%), esRAGE and inflammatory markers plasma levels still remained significantly different in respect to controls. CONCLUSIONS Subjects with HbA1c prediabetes exhibited significantly reduced esRAGE levels and increased levels of markers of inflammation. These alterations are associated with early markers of cardiovascular disease.

Altered expression of uncoupling protein 2 in GLP-1-producing cells after chronic high glucose exposure: implications for the pathogenesis of diabetes mellitus

Glucagon-like peptide-1 (GLP-1) is a gut L-cell hormone that enhances glucose-stimulated insulin secretion. Several approaches that prevent GLP-1 degradation or activate the GLP-1 receptor are being used to treat type 2 diabetes mellitus (T2DM) patients. In T2DM, GLP-1 secretion has been suggested to be impaired, and this defect appears to be a consequence rather than a cause of impaired glucose homeostasis. However, although defective GLP-1 secretion has been correlated with insulin resistance, little is known about the direct effects of chronic high glucose concentrations, which are typical in diabetes patients, on GLP-1-secreting cell function. In the present study, we demonstrate that glucotoxicity directly affects GLP-1 secretion in GLUTag cells chronically exposed to high glucose. Our results indicate that this abnormality is associated with a decrease in ATP production due to the elevated expression of mitochondrial uncoupling protein 2 (UCP2). Furthermore, UCP2 inhibition using small interfering RNA (siRNA) and the application of glibenclamide, an ATP-sensitive potassium (KATP(+)) channel blocker, reverse the GLP-1 secretion defect induced by chronic high-glucose treatment. These results show that glucotoxicity diminishes the secretory responsiveness of GLP-1-secreting cells to acute glucose stimulation. We conclude that the loss of the incretin effect, as observed in T2DM patients, could at least partially depend on hyperglycemia, which is typical in diabetes patients. Such an understanding may not only provide new insight into diabetes complications but also ultimately contribute to the identification of novel molecular targets within intestinal L-cells for controlling and improving endogenous GLP-1 secretion.

Update on pre-diabetes: Focus on diagnostic criteria and cardiovascular risk

Pre-diabetes, which is typically defined as blood glucose concentrations higher than normal but lower than the diabetes threshold, is a high-risk state for diabetes and cardiovascular disease development. As such, it represents three groups of individuals: Those with impaired fasting glucose (IFG), those with impaired glucose tolerance (IGT) and those with a glycated haemoglobin (HbA1c) between 39-46 mmol/mol. Several clinical trials have shown the important role of IFG, IGT and HbA1c-pre-diabetes as predictive tools for the risk of developing type 2 diabetes. Moreover, with regard to cardiovascular disease, pre-diabetes is associated with more advanced vascular damage compared with normoglycaemia, independently of confounding factors. In view of these observations, diagnosis of pre-diabetes is mandatory to prevent or delay the development of the disease and its complications; however, a number of previous studies reported that the concordance between pre-diabetes diagnoses made by IFG, IGT or HbA1c is scarce and there are conflicting data as to which of these methods best predicts cardiovascular disease. This review highlights recent studies and current controversies in the field. In consideration of the expected increased use of HbA1c as a screening tool to identify individuals with alteration of glycaemic homeostasis, we focused on the evidence regarding the ability of HbA1c as a diagnostic tool for pre-diabetes and as a useful marker in identifying patients who have an increased risk for cardiovascular disease. Finally, we reviewed the current evidence regarding non-traditional glycaemic biomarkers and their use as alternatives to or additions to traditional ones.

Atorvastatin but Not Pravastatin Impairs Mitochondrial Function in Human Pancreatic Islets and Rat β-Cells. Direct Effect of Oxidative Stress

Statins are a class of drugs widely prescribed as frontline therapy for lowering plasma LDL-cholesterol in cardiovascular risk prevention. Several clinical reports have recently suggested an increased risk of type 2 diabetes associated with chronic use of these drugs. The pathophysiology of this effect remains to be fully elucidated but impaired β-cell function constitutes a potential mechanism. The aim of this study was to explore the effect of a chronic treatment with lipophilic and hydrophilic statins on β-cell function, using human pancreatic islets and rat insulin-secreting INS-1 cells; we particularly focused on the role of mitochondria and oxidative stress. The present study demonstrates, for the first time, that atorvastatin (lipophilic) but not pravastatin (hydrophilic) affected insulin release and mitochondrial metabolism due to the suppression of antioxidant defense system and induction of ROS production in pancreatic β-cell models. Mevalonate addition and treatment with a specific antioxidant (N-AcetylCysteine) effectively reversed the observed defects. These data demonstrate that mitochondrial oxidative stress is a key element in the pathogenesis of statin-related diabetes and may have clinical relevance to design strategies for prevention or reduction of statin induced β-cell dysfunction and diabetes in patients treated with lipophilic statins.

HbA1c Identifies Subjects With Prediabetes and Subclinical Left Ventricular Diastolic Dysfunction

Context Prediabetes is associated with subclinical cardiac changes associated with heart failure development. Objective We investigated diastolic function and its association with markers of glycation and inflammation related to cardiovascular disease in patients with prediabetes. We focused on individuals with prediabetes identified only by glycated hemoglobin A1c [HbA1c; 5.7% to 6.4% and normal fasting glucose (NFG) and normal glucose tolerance (NGT) after an oral glucose tolerance test (OGTT)]. Design Cross-sectional study. Setting Departments of Clinical and Experimental Medicine and Cardiology, University of Catania, Catania, Italy. Main Outcome Measures HbA1c, OGTT, Doppler echocardiography, soluble receptor for advanced glycation end products (sRAGEs), and endogenous secretory RAGE (esRAGE) were evaluated. Patients We recruited 167 subjects with NFG/NGT who were stratified according to HbA1c level: controls (HbA1c <5.7%) and HbA1c prediabetes (HbA1c 5.7% to 6.4%). Results Patients with HbA1c prediabetes (n = 106) showed a lower peak mitral inflow in early diastole (E wave) to late diastolic atrial filling velocity (A wave) ratio (E/A ratio) than controls (n = 61) (1.10 ± 0.24 vs 1.18 ± 0.23; P < 0.05). They showed a higher left atrium volume (LAV) (28.4 ± 5 vs 22.1 ± 3; P < 0.05) and sphericity index (SI) (0.6 ± 0.06 vs 0.5 ± 0.05; P < 0.05). After multiple regression analyses, HbA1c, sRAGE, and esRAGE were the major determinants of E/A ratio, LAV, and SI. Conclusions Subjects with HbA1c prediabetes exhibited subclinical cardiac alterations associated with sRAGE, esRAGE, and HbA1c. These subjects would not have been classified as having prediabetes on the basis of fasting glycemia or post-OGTT values.

Left ventricular geometry and periodontitis in patients with the metabolic syndrome

ObjectiveThe presence of periodontal disease (PD) in subjects affected by the metabolic syndrome (MetS) may affect their risk of developing cardiovascular disease. The aim of this cross-sectional study was to investigate the systemic impact of PD in MetS, by assessing measures of sub-clinical atherosclerosis and left ventricular mass and geometry.Materials and methodsA total of 103 patients undergoing treatment for MetS were examined for confirmation of diagnosis, blood sampling, and measures of pulse wave velocity (PWV), carotid intima-media thickness (c-IMT), left ventricular mass index (LVM), and relative wall thickness (RWT). All subjects underwent a detailed dental assessment, including measurements of DMFT (decayed-missing-filled teeth) and periodontal parameters.ResultsTen patients (10%) were diagnosed with healthy-mild periodontitis, 38 patients (37%) were diagnosed in the moderate periodontitis group, and 55 (53%) had severe periodontitis. A total of 37% of subjects were affected by dental caries. Linear regression analysis revealed that patients with severe PD had increased average ventricular RWT (adjusted p = 0.032). Average full mouth probing pocket depth (PPD) was also associated with RWT (adjusted p = 0.006). No associations between PD and c-IMT, PWV, and LVM were detected after adjusted analyses.ConclusionThis study suggests that periodontitis may be associated with concentric left ventricular remodeling, a predictive index of cardiovascular events.Clinical relevanceThe presence of periodontitis in patients with MetS might have an effect on left ventricular geometry. These findings stress the importance of prevention, diagnosis, and management of periodontitis in patients with MetS.Trail registrationNCT03297749