High TG to HDL ratio plays a significant role on atherosclerosis extension in prediabetes and newly diagnosed type 2 diabetes subjects.

AIMS: We investigated the role of TG to HDL ratio (TG/HDL) on atherosclerosis extension, defined as presence of coronary artery calcium (CAC), carotid and femoral plaque, in prediabetes or newly diagnosed type 2 diabetes (T2D). METHODS: We performed a retrospective, cross-sectional, single centre study involving 440 prediabetes or newly diagnosed controlled T2D subjects. Participants underwent CAC analysis by computed tomography and carotid and femoral plaque evaluation by ultrasonography and were stratified in high TG/HDL (H-TG/HDL) or low TG/HDL (L-TG/HDL) group according to TG/HDL median value. We estimated atherosclerosis extension according to the number of involved vascular districts. RESULTS: CAC was higher in the H-TG/HDL group than L-TG/HDL group (29.15 [0.0-95.68] vs 0.0 [0.0-53.97] AU, P < .01) and CAC > 0 was more prevalent in the H-TG/HDL group than L-TG/HDL group (64.5% vs 45%, P < .001). Femoral atherosclerosis was higher in the H-TG/HDL group than L-TG/HDL group (57.3% vs 43.6%, P < .01). H-TG/HDL group exhibited a lower prevalence of subjects with 0-TWP compared to L-TG/HDL group (21.8% vs 38.6%, P < .01) and higher percentages of subjects with 2-TWP or 3-TWP than L-TG/HDL group (for 2-TWP 29.5% vs 21.5%, P < .05; for 3-TWP 32.7% vs 20.9%, P < .01). Multiple logistic regression analysis showed that a H-TG/HDL was inversely associated to 0-TWP (P < .05) and positively associated with 2-TWP (P < .05) and 3-TWP (P < .01). CONCLUSIONS: Our data suggest that TG/HDL is a marker of increased atherosclerotic extension in prediabetes and newly diagnosed T2D and may be useful to identify subjects with a higher cardiovascular risk profile.

Left ventricular geometry and periodontitis in patients with the metabolic syndrome.

OBJECTIVE: The 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 METHODS: A 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. RESULTS: Ten 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. CONCLUSION: This study suggests that periodontitis may be associated with concentric left ventricular remodeling, a predictive index of cardiovascular events. CLINICAL RELEVANCE: The 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 REGISTRATION: NCT03297749.

Pathophysiological, Molecular and Therapeutic Issues of Nonalcoholic Fatty Liver Disease: An Overview.

Nonalcoholic Fatty Liver Disease (NAFLD) represents the leading cause of liver disease in developed countries but its diffusion is currently also emerging in Asian countries, in South America and in other developing countries. It is progressively becoming one of the main diseases responsible for hepatic insufficiency, hepatocarcinoma and the need for orthotopic liver transplantation. NAFLD is linked with metabolic syndrome in a close and bidirectional relationship. To date, NAFLD is a diagnosis of exclusion, and liver biopsy is the gold standard for diagnosis. NAFLD pathogenesis is complex and multifactorial, mainly involving genetic, metabolic and environmental factors. New concepts are constantly arising in the literature promising new diagnostic and therapeutic tools. One of the challenges will be to better characterize not only NAFLD development but overall NAFLD progression, in order to better identify NAFLD patients at higher risk of metabolic, cardiovascular and neoplastic complications. This review analyses NAFLD epidemiology and the different prevalence of the disease in distinct groups, particularly according to sex, age, body mass index, type 2 diabetes and dyslipidemia. Furthermore, the work expands on the pathophysiology of NAFLD, examining multiple-hit pathogenesis and the role of different factors in hepatic steatosis development and progression: genetics, metabolic factors and insulin resistance, diet, adipose tissue, gut microbiota, iron deposits, bile acids and circadian clock. In conclusion, the current available therapies for NAFLD will be discussed.

Chronic Exposure to Palmitate Impairs Insulin Signaling in an Intestinal L-cell Line: A Possible Shift from GLP-1 to Glucagon Production.

Obesity and type 2 diabetes mellitus (T2DM) are characterized by insulin resistance and impaired glucagon-like peptide-1 (GLP-1) secretion/function. Lipotoxicity, a chronic elevation of free fatty acids in the blood, could affect insulin-signaling in many peripheral tissues. To date, the effects of lipotoxicity on the insulin receptor and insulin resistance in the intestinal L-cells need to be elucidated. Moreover, recent observations indicate that L-cells may be able to process not only GLP-1 but also glucagon from proglucagon. The aim of this study was to investigate the effects of chronic palmitate exposure on insulin pathways, GLP-1 secretion and glucagon synthesis in the GLUTag L-cell line. Cells were cultured in the presence/absence of palmitate (0.5 mM) for 24 h to mimic lipotoxicity. Palmitate treatment affected insulin-stimulated GLP-1 secretion, insulin receptor phosphorylation and IRS-1-AKT pathway signaling. In our model lipotoxicity induced extracellular signal-regulated kinase (ERK 44/42) activation both in insulin stimulated and basal conditions and also up-regulated paired box 6 (PAX6) and proglucagon expression (Gcg). Interestingly, palmitate treatment caused an increased glucagon secretion through the up-regulation of prohormone convertase 2. These results indicate that a state of insulin resistance could be responsible for secretory alterations in L-cells through the impairment of insulin-signaling pathways. Our data support the hypothesis that lipotoxicity might contribute to L-cell deregulation.

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.

Assessment of adrenocortical reserve in stable patients with cirrhosis.

BACKGROUND & AIMS: Adrenal insufficiency (AI) is reported in critically ill patients with cirrhosis and is associated with increased mortality. It is unclear if AI is an underlying condition or triggered by critical events (e.g. sepsis). We investigated AI in cirrhosis without infection or hemodynamic instability. METHODS: A total of 101 consecutive patients with cirrhosis were studied. AI was defined by a total serum cortisol (TC) <18 µg/dl at 20 or 30 min after injection of 1 µg of tetracosactrin. Transcortin, calculated free cortisol (cFC), and free cortisol index (FCI) were assessed in a subgroup of 41 patients, with FCI>12 representing normal adrenal function. RESULTS: AI was present in 38 patients (38%). Child score (median, 10 vs 7, p<0.0001), MELD score (median, 17 vs 12, p<0.0001), ascites (68% vs 37%, p<0.01), basal TC (median,7.6 vs 14.9 µg/dl, p<0.001), albumin (28 ± 0.8 vs 33 ± 0.7 g/L, p<0.0001), INR (median, 1.6 vs 1.2, p<0.0001), total bilirubin (median, 51 vs 31 µmol/L, p<0.05), total cholesterol (median, 120 vs 142, p<0.05), and LDL (median, 76 vs 81, p<0.05) were significantly different between those with and without AI. ROC curves showed a basal TC ≤ 12.8 µg/dl to be a cut-off value closely associated with AI. The cFC was significantly related to TC for baseline values (R=0.94, p<0.0001), peak values (R=0.90, p<0.0001), and delta values (R=0.95, p<0.0001), in patients with and without AI. However, no patient had a FCI<12. CONCLUSIONS: AI defined by an abnormal response to 1 µg tetracosactrin is frequent in stable patients with cirrhosis, in the absence of infections or hemodynamic instability and is related to the severity of liver disease. However, evaluation of the true incidence of AI should comprise direct assays of free cortisol. Clinical consequences of AI need to be explored.

Effect of PCSK9 inhibitors on pulse wave velocity and monocyte-to-HDL-cholesterol ratio in familial hypercholesterolemia subjects: results from a single-lipid-unit real-life setting.

AIMS: Subjects with familial hypercholesterolemia (FH) are characterized by an increased amount of low-density lipoprotein cholesterol (LDL-C) that promotes a continuous inflammatory stimulus. Our aim was to evaluate the effect of PCSK9-i on inflammatory biomarkers, neutrophil-to-lymphocyte ratio, monocyte-to-high-density lipoprotein ratio (MHR), and on early atherosclerosis damage analyzed by pulse wave velocity (PWV) in a cohort of FH subjects. METHODS: In this prospective observational study, we evaluated 56 FH subjects on high-intensity statins plus ezetimibe and with an off-target LDL-C. All subjects were placed on PCSK9-i therapy and obtained biochemical analysis as well as PWV evaluation at baseline and after six months of PCSK9-i therapy. RESULTS: After six months of add-on PCSK9-i therapy, only 42.9% of FH subjects attained LDL-C targets. As expected, a significant reduction of LDL-C (- 49.61%, p < 0.001) was observed after PCSK9-i therapy. Neutrophil count (NC) and MHR were reduced by PCSK9-i (-13.82% and -10.47%, respectively, p value for both < 0.05) and PWV significantly decreased after PCSK9-i therapy (- 20.4%, p < 0.05). Finally, simple regression analyses showed that ∆ PWV was significantly associated with ∆ LDL-C (p < 0.01), ∆ NC and ∆ MHR (p value for both < 0.05). CONCLUSIONS: In conclusion, PCSK9-i therapy significantly improved lipid and inflammatory profiles and PWV values in FH subjects; our results support the positive effect of PCSK9-i in clinical practice.

Analysis of Arterial Stiffness and Sexual Function after Adding on PCSK9 Inhibitor Treatment in Male Patients with Familial Hypercholesterolemia: A Single Lipid Center Real-World Experience.

Familial hypercholesterolemia (FH) subjects have high low-density lipoprotein cholesterol (LDL-C) and may be at high risk of erectile dysfunction and atherosclerotic cardiovascular diseases. We evaluated the effect of PCSK9-i on sexual function evaluated by the Male Sexual Health Questionnaire (MSHQ) and the International Index of Erectile Function (IIEF-5) questionnaire and on pulse wave velocity (PWV) in FH male subjects. In this prospective observational study, we evaluated 30 FH male patients on high-intensity statins plus ezetimibe and with an LDL-C off-target. All patients added PCSK9-i treatment and obtained clinical assessment at baseline and after six months of PCSK9-i. As expected, LDL-C significantly decreased after adding-on PCSK9-i (-48.73%, p < 0.001). MSHQ and PWV significantly improved after adding-on PCSK9-i (for MSHQ 93.63 ± 6.28 vs. 105.41 ± 5.86, p < 0.05; for PWV 9.86 ± 1.51 vs. 7.7 ± 1.42, p < 0.05); no significant change of IIEF-5 was found. Finally, a simple regression showed that ∆ MSHQ was significantly associated with ∆ LDL-C and ∆ PWV (p value for both <0.05). In conclusion, PCSK9-i therapy significantly improves lipid profile, PWV, and sexual function in FH male patients; our results support the favorable function of PCSK9-i on these parameters.

Arterial stiffness improvement after adding on PCSK9 inhibitors or ezetimibe to high-intensity statins in patients with familial hypercholesterolemia: A Two-Lipid Center Real-World Experience.

BACKGROUND: Familial hypercholesterolemia (FH) is characterized by increased cardiovascular risk; despite-high intensity statins, only few patients with FH achieve the recommended low-density lipoprotein cholesterol (LDL-C) targets. OBJECTIVE: We aimed to evaluate the effectiveness of six-month add-on therapy with proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9-i) or ezetimibe on lipid profile and pulse wave velocity (PWV) in patients with FH. METHODS: In this observational study, we evaluated 98 genetically confirmed patients with FH with an LDL-C off-target despite high-intensity statins with or without ezetimibe; of these, 53 patients (statin plus ezetimibe) added PCSK9-i (PCSK9-i group) and 45 (statin only) added ezetimibe (EZE group) per applicable guidelines and reimbursement rules. All patients obtained biochemical analysis and PWV evaluation at baseline and after six months of optimized treatment. RESULTS: After 6 months of add-on therapy, most patients achieving LDL-C targets were in the PCSK9-i group (77.3% PCSK9-i group vs 37.8% EZE group, P < .001). The PCSK9-i group achieved both a greater LDL-C and PWV reduction than the EZE group [-51% vs -22.8%, P < .001 and -15% vs -8.5%, P < .01, respectively]. In a linear regression analysis, we showed a coefficient (r) of 0.334 for the relationship between ΔPWV and ΔLDL (P < .05); moreover, in an exploratory analysis, the relationship appeared to be stronger in patients with FH without cardiovascular events (r = 0.422, P < .01). CONCLUSIONS: Lipid and PWV profiles in patients with FH significantly improved after addition of PCSK9-i or ezetimibe to high-intensity statin therapy; moreover, ΔPWV was associated with ΔLDL. Our results are consistent with a beneficial role of these novel therapies in FH subjects.

Impaired glucagon suppression and reduced insulin sensitivity in subjects with prediabetes undergoing atorvastatin therapy.

OBJECTIVE: Statin therapy has been linked to an increased risk of type 2 diabetes in high-risk populations; however, the pathophysiology of this association remains to be clarified. We investigated glucagon suppression and its relationship with insulin resistance in prediabetic subjects undergoing atorvastatin therapy; in addition, we studied molecular insulin signaling in pancreatic α-cells exposed to atorvastatin in vitro. DESIGN AND METHODS: Fifty subjects with prediabetes were divided into two groups based on atorvastatin therapy. All subjects underwent an oral glucose tolerance test. Early (0-30 min), late (30-120 min) and overall (0-120 min) glucagon suppression were evaluated. Insulin sensitivity was estimated by the insulin sensitivity index (ISI0-120). Insulin signaling pathway and insulin-mediated glucagon suppression were investigated in pancreatic αTC1-6 cells chronically exposed (24 or 48 h) to atorvastatin (100 ng/mL). RESULTS: Individuals on statin therapy (n = 26) showed a significantly reduced early (0-30 min) (P = 0.003) and overall (0-120 min) (P = 0.01) glucagon suppression compared with controls (n = 24). In multivariate regression analysis, early glucagon suppression (0-30 min) exhibited a significant correlation with statin therapy. Regression analysis showed a significant association between ISI 0-120 and early0-30 (r = 0.33, P < 0.05) and overall0-120 (r = 0.38, P < 0.05) glucagon suppression. Moreover, in αTC1-6 cells atorvastatin treatment affected insulin-mediated glucagon suppression, insulin receptor phosphorylation and IRS-1-AKT pathway signaling. CONCLUSIONS: Prediabetic patients undergoing statin therapy exhibit impaired glucagon suppression associated with lower insulin sensitivity. Our data revealed a new molecular aspect behind the deregulation of insulin sensitivity secondary to statin exposure.

1 h Postload Glycemia Is Associated with Low Endogenous Secretory Receptor for Advanced Glycation End Product Levels and Early Markers of Cardiovascular Disease.

We investigated the correlation of the soluble receptor for advanced glycation end products (sRAGE) and endogenous secretory RAGE (esRAGE) with markers of cardiovascular disease in subjects with normal glucose tolerance (NGT) and 1 h postload glucose ≥155 mg/dL after an oral glucose tolerance test. We stratified 282 subjects without a previous diagnosis of diabetes into three groups: 123 controls (NGT and 1 h postload glycemia <155 mg/dL), 84 NGT and 1 h postload glycemia ≥155 mg/dL (NGT 1 h high), and 75 subjects with impaired fasting glucose and/or impaired glucose tolerance (IFG/IGT). NGT 1 h high subjects exhibited lower esRAGE (0.36 ± 0.18 vs. 0.4 5 ± 0.2, p < 0.05) and higher S100A12 levels than controls (5684 (3193.2-8295.6) vs. 3960.1 (2101.8-7419), p < 0.05). Furthermore, they showed an increased pulse wave velocity (PWV) and intima-media thickness (IMT). No differences were found between the NGT 1 h high group and the IFG/IGT group regarding cardiometabolic profiles. After multiple regression analyses, esRAGE was associated with glycated hemoglobin (HbA1c) and high-sensitivity C-reactive protein (hs-CRP). Age, HbA1c, and esRAGE were the determinants of IMT, whereas S100A12 and systolic pressure were the determinants of PWV. The NGT 1 h high group exhibited low esRAGE levels and an altered cardiometabolic profile. HbA1c, S100A12, and hs-CRP were associated with these alterations. In conclusion, subjects with NGT are not a homogeneous population, and they present different cardiovascular and glycometabolic risks.

Analysis of HDL-microRNA panel in heterozygous familial hypercholesterolemia subjects with LDL receptor null or defective mutation.

In the last years increasing attention has been given to the connection between genotype/phenotype and cardiovascular events in subjects with familial hypercholesterolemia (FH). MicroRNAs (miRs) bound to high-density lipoprotein (HDL) may contribute to better discriminate the cardiovascular risk of FH subjects. Our aim was to evaluate the HDL-miR panel in heterozygous FH (HeFH) patients with an LDLR null or defective mutation and its association with pulse wave velocity (PWV). We evaluated lipid panel, HDL-miR panel and PWV in 32 LDLR null mutation (LDLR-null group) and 35 LDLR defective variant (LDLR-defective group) HeFH patients. HDL-miR-486 and HDL-miR-92a levels were more expressed in the LDLR-null group than the LDLR-defective group. When we further stratified the study population into three groups according to both the LDLR genotype and history of ASCVD (LDLR-null/not-ASCVD, LDLR-defective/not-ASCVD and LDLR/ASCVD groups), both the LDLR/ASCVD and the LDLR-null/not-ASCVD groups had a higher expression of HDL-miR-486 and HDL-miR-92a than the LDLR-defective/not-ASCVD group. Finally, HDL-miR-486 and HDL-miR-92a were independently associated with PWV. In conclusion, the LDLR-null group exhibited HDL-miR-486 and HDL-miR-92a levels more expressed than the LDLR-defective group. Further studies are needed to evaluate these HDL-miRs as predictive biomarkers of cardiovascular events in FH.

Analysis of S100A12 plasma levels in hyperlipidemic subjects with or without familial hypercholesterolemia.

AIMS: Inflammation is a key regulatory process that links hypercholesterolemia and immune mechanisms promoting atherosclerosis. Inflammatory biomarkers may be helpful to better define the atherosclerotic burden in patients with high cholesterol levels such as familial hypercholesterolemia (FH). Our aim was to evaluate the concentration of S100A12 protein in FH patients and its association with pulse wave velocity (PWV). METHODS: We measured glucose and lipid profile, S100A12, sRAGE, esRAGE and PWV in 39 patients with a genetically confirmed diagnosis of FH and 39 hypercholesterolemic subjects without a clinical diagnosis of FH (Dutch score ≤ 3). All subjects were on statin treatment at the time of the enrollment. RESULTS: No difference of glucose and lipid profile was found in the two groups. FH patients had higher S100A12 plasma levels than non-FH subjects (12.87 ± 4.82 vs. 8.57 ± 4.87 ng/mL, p < 0.01). No difference of hs-CRP, sRAGE and esRAGE was found between the two groups. Also, PWV was higher in FH patients than non-FH subjects (8.63 ± 0.92 vs. 6.68 ± 0.73 m/s, p < 0.05). Finally, S100A12 was independently correlated with age (p < 0.01), genetic mutation (p < 0.01) and PWV (p < 0.001). CONCLUSIONS: FH patients exhibited higher S100A12 levels than non-FH subjects. A novel vascular inflammation pathway, other than hs-CRP, might be useful to better characterize cardiovascular risk profile.

Direct apoptotic effects of free fatty acids on human endothelial cells.

BACKGROUND AND AIM: Endothelial cell injury is a key event in the pathogenesis of diabetes-associated atherosclerosis and vascular complications. Increased apoptosis may contribute to the loss of endothelial integrity and leads to cardiovascular disease. This study was designed to elucidate whether high levels of free fatty acids (FFA) cause apoptosis and if so what is the possible role of insulin signaling alteration(s) in determining this effect. METHODS AND RESULTS: In human umbilical vein endothelial cells (HUVECs) cultured for 72h with high levels of FFA, apoptotic cells, detected by Annexin V-FITC and PI, were increased. Then we observed a decrease of Bcl-2/Bax ratio (pro-apoptotic condition), measured by RT-PCR and Western blot. As the Akt pathway is involved in insulin signaling and apoptosis, we investigated whether Akt mediated FFA apoptotic effects. HUVECs exposed to FFA showed an equal amount of total Akt protein content compared to controls. In HUVECs, FFA induced a significant decrease in phosphorylated active Akt. Furthermore, phosphorylated eNOS (active form) was decreased and cleaved caspase-9 (active form) was increased. These alterations were prevented when insulin at 10(-8)M was added in culture medium containing FFA. The insulin anti-apoptotic effect was prevented by Ly29400, a PI3K/Akt inhibitor. CONCLUSION: High levels of FFA cause HUVECs apoptosis through Akt inhibition; insulin can prevent these effects. Inappropriate FFA elevation may affect vascular endothelium by impairing cell survival via activation of apoptosis, thus contributing to the development of cardiovascular disease in type 2 diabetic patients.

New treatment options for lipid-lowering therapy in subjects with type 2 diabetes.

Dyslipidemias represent a variety of quantitative and/or qualitative lipoprotein abnormalities. According to etiology, we distinguish primary dyslipidemias with strictly genetic background and secondary ones with their origin in other disease or pathological states. Diabetic dyslipidemia is a type of secondary dyslipidemia and plays an important role in determining the cardiovascular risk of subjects with type 2 diabetes. In these patients, insulin resistance is responsible for overproduction and secretion of atherogenic very low density lipoprotein. In addition, insulin resistance promotes the production of small dense low-density lipoprotein (LDL) and reduces high-density lipoprotein (HDL) production. Cardiovascular disease remains a leading cause of morbidity and mortality in diabetic patients. Previous results support the role for small, dense LDL particles in the etiology of atherosclerosis and their association with coronary artery disease. Moreover, lowering LDL cholesterol reduces the risk of cardiovascular death. Therefore, the European guidelines for the management of dyslipidemias recommend an LDL cholesterol goal < 100 mg/dL in diabetic subjects without cardiovascular events. Moreover, if triglycerides (TG) are elevated (> 400 mg/dL), they recommend a non-HDL cholesterol goal < 130 mg/dL in diabetic individuals without cardiovascular events. Statins are the first line of LDL-lowering therapy in diabetic patients and combined therapy with ezetimibe and statins could be useful in very high cardiovascular risk diabetic subjects. Furthermore, the effect of a fibrate as an add-on treatment to a statin could improve the lipid profile in diabetic individuals with high TG and low HDL cholesterol. Regarding new therapies, recent data from phase III trials show that proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors considerably decrease LDL cholesterol. Thus, they may be useful in diabetic patients with concomitant diseases such as familial dyslipidemia, recurrent cardiovascular events, and elevated LDL cholesterol after second drug administration in addition to maximal statin dose or statin intolerance.

An increased waist-to-hip ratio is a key determinant of atherosclerotic burden in overweight subjects.

AIMS: The association of overweight status and cardiovascular disease is not clear. In this study we aimed to investigate coronary atherosclerotic disease, evaluated as coronary artery calcium score (CACs), in overweight patients with or without abdominal obesity as defined by waist-to-hip ratio (WHR). METHODS: We enrolled 276 patients aged between 40 and 70 years, with a body mass index of 25-29.9 kg/m2 and at least one cardiovascular risk factor. Exclusion criteria were history of diabetes, cardiovascular or renal disease. Patients were stratified in high WHR (H-WHR) or low WHR (L-WHR) group according to WHR (≥ 0.85 for women and ≥ 0.90 for men) and underwent multi-detector computed tomography for CACs. Mean carotid intima-media thickness (IMT) and plaque presence were equally assessed. RESULTS: CACs was higher in the H-WHR group compared to L-WHR (9.05 [0.0-83.48] vs 0.0 [0.0-64.7] AU, p < 0.01); the prevalence of CACs > 0 in the H-WHR group was significantly higher than subjects with L-WHR (59.6% vs 38.5%, p < 0.001). Moreover, H-WHR group had higher mean IMT (0.64 [0.56-0.72] vs 0.59 [0.55-0.67] mm, p < 0.05) and higher carotid plaque prevalence (63.7% vs 50.8%, p < 0.05) compared to subjects with L-WHR. Logistic regression showed that H-WHR was associated with presence of CACs and carotid plaque (p < 0.01). In a multiple linear regression, WHR was positively associated with CACs and IMT (p < 0.01). CONCLUSIONS: H-WHR is a marker of coronary and peripheral atherosclerotic burden in overweight patients.

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.

Atorvastatin but Not Pravastatin Impairs Mitochondrial Function in Human Pancreatic Islets and Rat ß-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 ß-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 ß-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 ß-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 ß-cell dysfunction and diabetes in patients treated with lipophilic statins.

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.

Hepatic insulin resistance in NAFLD: relationship with markers of atherosclerosis and metabolic syndrome components.

AIMS: Fat accumulation in the liver and in the muscle results in hepatic and muscle insulin resistance and has been associated with increased cardiovascular risk. It is unclear whether the individual role of hepatic and muscle insulin resistance in the onset of dyslipidaemia is observed in nonalcoholic fatty liver disease (NAFLD) patients and whether this association is mediated through traditional risk factors. The aim of this study was to assess hepatic and muscle insulin resistance in NAFLD and its relationship with carotid artery intima-media thickness (IMT) and the apoB/apoAI ratio as markers of atherosclerosis. METHODS: We studied 132 patients with a non-invasive diagnosis of NAFLD stratified into two groups according to the severity of steatosis at ultrasound scan. In all subjects, we measured hepatic insulin resistance (H-IR) and muscle insulin sensitivity index (MISI) by oral glucose tolerance test as proposed by DeFronzo, IMT, apoB/apoAI and the components of the metabolic syndrome (MS) as defined by ATP III. RESULTS: H-IR was significantly higher in moderate/severe steatosis than in the mild steatosis group (p < 0.0001). By contrast, MISI did not differ between the two groups. There was a significant correlation between H-IR, MISI and all of the components of MS. H-IR was significantly correlated with carotid IMT (r = 0.35; p < 0.0001) and the apoB/apoAI ratio (r = 0.43; p < 0.0001). Otherwise, a significant correlation was observed only between MISI and apoB/apoAI ratio. Multivariate analysis revealed that H-IR is related to early markers of atherosclerosis independent of MS components. CONCLUSIONS: In our study population, NAFLD was positively associated with carotid IMT, and this association is independent of MS components, but strictly related to H-IR that might contribute to the development of atherosclerosis through an impairment of the lipid profile in terms of the apoB/apoAI ratio. By contrast, no significant relation was observed between MISI and carotid IMT.