Smoking and diabetes: dangerous liaisons and confusing relationships.

The combined harmful effects of cigarette smoking and hyperglycemia can accelerate vascular damage in patients with diabetes who smoke, as is well known. Can smoking cause diabetes? What are the effects of smoking on macro and microvascular complications? Now growing evidence indicates that regular smokers are at risk of developing incident diabetes. Since the prevalence rates of smoking in patients with diabetes are relatively similar to those of the general population, it is essential to address the main modifiable risk factor of smoking to prevent the onset of diabetes and delay the development of its complications. Quitting smoking shows clear benefits in terms of reducing or slowing the risk of cardiovascular morbidity and mortality in people with diabetes. Does quitting smoking decrease the incidence of diabetes and its progression? What are the effects of quitting smoking on complications? The current evidence does not seem to unequivocally suggest a positive role for quitting in patients with diabetes. Quitting smoking has also been shown to have a negative impact on body weight, glycemic control and subsequent increased risk of new-onset diabetes. Moreover, its role on microvascular complications of the disease is unclear. What are the current smoking cessation treatments, and which ones are better for patients with diabetes? Stopping smoking may be of value for diabetes prevention and management of the disease and its macrovascular and microvascular complications. Unfortunately, achieving long-lasting abstinence is not easy and novel approaches for managing these patients are needed. This narrative review examines the evidence on the impact of smoking and smoking cessation in patients with diabetes and particularly in type 2 diabetes mellitus and its complications. In addition, management options and potential future directions will be discussed.

Inflammation and ventricular-vascular coupling in hypertensive patients with metabolic syndrome.

BACKGROUND AND AIMS: Metabolic syndrome (MetS) is currently considered to raise the risk for type 2 diabetes and cardiovascular events. It has been suggested that part of this risk excess may be due to a cluster of additional factors associated with MetS. We aimed to investigate the role of inflammation on the ventricular-vascular coupling in patients with MetS. METHODS AND RESULTS: We enrolled a total of 227 hypertensive patients (106 with MetS and 121 without MetS) matched for age and gender. Aortic pulse wave velocity (aPWV), intima-media thickness (IMT) and high sensitivity C-reactive protein (CRP) increased according to the number of MetS components. Patients with MetS showed increased aPWV (11.5 ± 3.7 vs. 10.3 ± 2.5 m/s, P = 0.03) compared with controls. In a model adjusted for age, sex, heart rate and mean blood pressure, aPWV resulted increased in patients with CKD (beta 1.29 m/s, 95%CI 0.61-1.96 m/s, P < 0.001) and MetS (beta 0.89 m/s, 95%CI 0.28-1.51 m/s, P = 0.005). After additional adjustment for CRP and IMT, the slope of aPWV was respectively reduced by 16% and 62%, suggesting that inflammation and intima-media thickening could contribute to aortic stiffening in patients with MetS. In these patients, aPWV was also associated with left-ventricular mass index (beta 0.79 g/m2.7, 95%CI 0.05-1.52 g/m2.7, P = 0.05). CONCLUSION: MetS is characterized by an inflammation-dependent acceleration in cardiovascular ageing. This pattern of pathophysiological abnormalities may contribute to amplify the burden of cardiovascular risk in patients with MetS.

Detecting familial hypercholesterolemia by serum lipid profile screening in a hospital setting: Clinical, genetic and atherosclerotic burden profile.

BACKGROUND AND AIMS: Familial hypercholesterolemia (FH) is underdiagnosed and public cholesterol screening may be useful to find new subjects. In this study, we aim to investigate the prevalence of FH patients in a hospital screening program and evaluate their atherosclerotic burden using intima-media thickness (IMT). METHODS AND RESULTS: We screened 1575 lipid profiles and included for genetic analysis adults with a low-density lipoprotein (LDL) cholesterol >190 mg/dL and triglycerides <200 mg/dL and first-degree child relatives with LDL cholesterol >160 mg/dL and triglycerides <200 mg/dL. The diagnosis of FH was presumed by Dutch Lipid Clinic Network (DLCN) criteria and confirmed by the presence of the genetic variant. Mean common carotid intima-media thickness (IMT) was assessed using consensus criteria. After confirming LDL cholesterol value and excluding secondary hypercholesterolemia, 56 subjects with a DLCN ≥4 performed genetic analysis. Of these, 26 had an FH genetic variant. The proportion of patients with a mutation having a DLCN score of 6-8 was 75%; in individuals with a DLCN score >8 it was 100%. Mean IMT was higher in FH patients compared to non FH (0.73 [0.61-0.83] vs 0.71 [0.60-0.75] mm, p < 0.01). Moreover, we detected two mutations not previously described. Finally, simple regression analysis showed a correlation of IMT with LDL cholesterol >190 mg/dL and corneal arcus (p < 0.01 and p < 0.001, respectively). CONCLUSIONS: A hospital screening was useful to detect FH subjects with increased atherosclerosis. Also, next-generation sequencing was able to detect new FH mutations.

High intake of dietary advanced glycation end-products is associated with increased arterial stiffness and inflammation in subjects with type 2 diabetes.

BACKGROUND AND AIMS: Modern diets are high in advanced glycation end-products (dAGEs), derived from processing methods, exerting a pivotal role in promoting atherosclerotic risk. In this cross-sectional study we investigate the relationship between dAGE intake, arterial stiffness, inflammatory profile and macronutrient composition, in subjects with type 2 diabetes without overt cardiovascular disease. METHODS AND RESULTS: Arterial stiffness, carboxy-methyl-lysine, endogenous secretory receptor for AGEs (esRAGE), high sensitivity C reactive protein (hs-CRP), S100A12 and macronutrient intake were evaluated in 85 subjects with type 2 diabetes. The subjects were stratified into two groups according to dAGE consumption: high and low dAGE intake (≥ or <15.000 kU/day, respectively). Subjects with high dAGE intake (n = 45) showed a higher augmentation, augmentation index and pulse wave velocity (PWV) compared with those subjects with low dAGE intake (18 ± 5.4 vs 12.2 ± 6.3 mmHg, P < 0.05; 38.3 ± 5.4 vs 29.3 ± 10%; 9.2 ± 1.4 m/sec vs 7.9 ± 1.7, P < 0.05, respectively). hs-CRP were higher in subjects with high dAGE intake [0.42 (0.18-0.54) vs 0.21 (0.14-0.52) mg/dL, P < 0.05] whereas esRAGE plasma levels were lower [0.16 (0.23-0.81) vs 0.2 (0.14-0.54) ng/dL, P < 0.05]. Simple regression analysis showed a correlation between dAGEs and fat intake. Multivariate analysis showed an independent association between augmentation, systolic blood pressure (BP) and dAGE consumption; BMI and esRAGE were the major determinants of PWV. CONCLUSIONS: Our data suggests that a chronic high dAGE diet could lead to a vascular dysfunction and inflammatory activation, contributing to the development of vascular complications in subjects with type 2 diabetes. Testing this hypothesis may represent a direction of future research.

Intracellular and extracellular miRNome deregulation in cellular models of NAFLD or NASH: Clinical implications.

BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD) represents the most common chronic liver disease in industrialized countries. NAFLD has the potential to progress through the inflammatory phase of nonalcoholic steatohepatitis (NASH) to fibrosis, cirrhosis, and hepatocellular carcinoma. Identifying patients at risk for this transition is a relevant clinical challenge. The complexity of these phenotypes in vivo made necessary the development of in vitro models in order to dissect the molecular signalling affected in NAFLD and NASH, but also to identify potential circulating biomarkers. METHODS AND RESULTS: We profiled the expression of 754 cellular and medium-secreted human miRNAs in HepG2 cells after lipotoxic (Palmitate, model of NASH) or not-lipotoxic stimuli (Oleate-Palmitate, model of NAFLD). Results were validated through Single TaqMan assays. We performed computational analysis of miRNA targets and pathways. Oleate-palmitate treatment induced a variation of 2.8% and 10% of total miRNAs in cells and medium, respectively; palmitate treatment caused 10% and 19% intracellular and extracellular miRNA deregulation, respectively. We validated miR-126, miR-150, miR-223, miR-483-3p, miR-1226*, and miR-1290 deregulation. Through computational analysis, we observed that targets of both intracellular and extracellular DE miRNAs were involved in processes associated with the onset and progression of NAFLD and NASH, such as fatty acid metabolism, apoptosis and inflammation. CONCLUSIONS: These data would be useful to elucidate the role of miRNAs in the pathogenesis and progression of the NAFLD spectrum, but they also allow the identification of novel potential biomarkers for differential diagnosis to be tested in vivo.

Lipid and liver abnormalities in haemoglobin A1c-defined prediabetes and type 2 diabetes.

BACKGROUND AND AIMS: We aimed to investigate lipid abnormalities and liver steatosis in patients with HbA1c-defined prediabetes and type 2 diabetes compared to individuals with HbA1c-defined normoglycaemia. METHODS AND RESULTS: Ninety-one subjects with prediabetes according to HbA1c, i.e. from 5.7 to 6.4% (39-46 mmol/mol), 50 newly diagnosed patients with HbA1c-defined type 2 diabetes (HbA1c ≥6.5% [≥48 mmol/mol]), and 67 controls with HbA1c lower than 5.7% (<39 mmol/mol), were studied. Fasting blood samples for lipid profiles, fatty liver index (FLI), bioimpedance analysis, ultrasound scan of the liver, and BARD (body mass index, aspartate aminotransferase/alanine aminotransferase ratio, diabetes) score for evaluation of liver fibrosis, were performed in all subjects. In comparison to controls, subjects with prediabetes were characterised by: lower apolipoprotein AI and HDL cholesterol levels, higher blood pressure, triglycerides levels and apolipoprotein B/apolipoprotein AI ratio, higher FLI, increased prevalence of and more severe hepatic steatosis, similar BARD score, and higher total body fat mass. In comparison to subjects with diabetes, subjects with prediabetes exhibited: similar blood pressure and apolipoprotein B/apolipoprotein AI ratio, similar FLI, reduced prevalence of and less severe hepatic steatosis, lower BARD score, increased percent fat and lower total body muscle mass. In comparison to controls, subjects with diabetes showed: lower apolipoprotein AI and HDL cholesterol levels, higher blood pressure and triglycerides levels, higher FLI, increased prevalence of and more severe hepatic steatosis, higher BARD score, and higher total body muscle mass. Moreover, HbA1c was correlated with BMI, HOMA-IR, triglycerides, HDL cholesterol, AST, and ALT. CONCLUSIONS: Subjects with HbA1c-defined prediabetes and type 2 diabetes, respectively, are characterised by abnormalities in lipid profile and liver steatosis, thus exhibiting a severe risk profile for cardiovascular and liver diseases.

Separate impact of metabolic syndrome and altered glucose tolerance on early markers of vascular injuries.

OBJECTIVE: We investigated the separate impact of metabolic syndrome (MS) and altered glucose tolerance on early markers of vascular injuries. METHODS: Intima-media thickness (IMT) and pulse wave analysis (PWA), were evaluated in 132 overweight or obese subjects, with (MS(+)) or without (MS(-)) MS; subjects were further classified as normotolerant (NT) or with altered glucose tolerance (AGT) according to a 2 h oral glucose tolerance test (OGTT). RESULTS: In MS(+) patients, IMT was higher than in the MS(-) group, and PWA revealed higher augmentation pressure (Aug, the contribution that wave reflection makes to systolic arterial pressure) and lower subendocardial viability ratio (SEVR, an estimate of myocardial perfusion). When analyzed according to glucose tolerance, IMT was higher in MS(+)NT subjects and AGT patients with and without MS, vs. MS(-)NT subjects. Logistic regression modeling showed that both AGT and MS were independently associated with increased IMT. However, only MS remained associated with IMT after adjustment for age. SEVR was reduced only in MS(+) patients, independently of glucose tolerance. In both groups, Aug and AugI were higher in the AGT group, but the correlation with 2 h-plasma glucose disappeared when corrected for age. CONCLUSION: Both MS and AGT altered IMT, but the effect of AGT disappears when age is added to the multiple regression model. In contrast, arterial stiffness was affected differently in the two categories: in subjects with MS, the subendocardial viability ratio (an estimate of myocardial perfusion) was impaired, while in subjects with AGT, both Aug and AugI were increased. These data suggest that applying the definition of MS might help to better characterize cardiovascular risk in subjects with altered glucose tolerance or obesity.

[Lymphocytes Fox P3 and chronic C hepatitis: preliminary results]. / Ruolo dei linfociti FoxP3 nella infezione cronica da virus C. Risultati preliminari di un protocollo di studio clinico.

OBJECTIVES: Characterization of Treg lymphocytes (CD4+CD25+) in immune response in patients with chronic viral hepatitis C. MATERIALS AND METHODS: Two groups of patients were included: Group A (10 patients with chronic hepatitis C); Group B (10 healthy controls). In both groups, liver markers, liver function tests, lymphocyte typing, serum HCV-RNA were assessed. Liver biopsy was executed in Group A only. Peripheral venous samples were analyzed by citofluorimetric analysis, liver biopsy's samples were studied by immunohistochemistry. RESULTS: Group A patients showed a larger expression of Treg (CD4+CD25+) in peripheral blood than Group B with an ipo-expression of a subpopulation of Treg FoxP3+ (CD4+CD25hi). Group B patients showed a higher ratio (CD4+CD25hi/CD4+CD25+) than Group A. Liver biopsy samples showed a clear positivity for FoxP3+ Treg cells in the inflammatory infiltrated. CONCLUSION: Our study's preliminary results seem to indicate that Treg lymphocytes are really involved in flogistic process in course of chronic hepatitis C. Peripheral blood of infected patients (Group A) shows a low expression of Foxp3+ cells because they are sequestrated in the liver. These cells could be involved in the pathogenesis of the chronic disease and they would be employed how potential agents for a immunomodulatory therapy.

[Ultrasound in diagnosis of superior mesenteric artery syndrome]. / Imaging con ultrasuoni nella diagnosi della sindrome dell'arteria mesenterica superiore.

OBJECTIVE: To reveal a possible reduction of the aorto-mesenteric angle and to diagnose suspected cases of superior mesenteric artery (SMA) syndrome. It was controlled, prospective study in which, in order to reveal a possible reduction of aorto-mesenteric angle, the following techniques. MATERIALS AND METHODS: In a cohort of patients referred to our department by their general practitioners for unexplained dyspepsia and/or abdominal pain an abdominal ultrasonography with power colour Doppler was performed; patients with reduced SMA angle were screened by gastroduodenoscopy, hypotonic duodenography, contrast-enhanced spiral computerized tomography. RESULTS: In a cohort of 1468 patients, 460 subjects were taken into consideration, specifi cally the patients where US and power colour Doppler had been adequately performed. US detected a signifi cant reduction of the SMA angle in 20 of those patients; in these 20 subjects, gastroscopy showed duodenal compressive pulsation in 5 of the 20 patients under examination, and X-ray revealed a compression of the third segment of the duodenum in 18 of them. The following CT examination confi rmed the presence of a reduced angle and various degrees of duodenal compression in all patients. US and CT examinations gave overlapping results (p>0.05) in diagnosing pathological aorta-mesenteric angle. CONCLUSIONS: The analysis of data led the authors to believe that the incidence of reduced aorto-mesenteric angle and SMA syndrome might be underrated. US power colour Doppler imaging that is a rapid, repeatable, and non invasive, low cost and easy to perform diagnostic procedure, is useful in epidemiological screening of reduced aorto-mesenteric angle to diagnose suspected cases of SMA syndrome in patients with inexplicable abdominal pain.

Effects of antioxidants on postprandial oxidative stress and endothelial dysfunction in subjects with impaired glucose tolerance and type 2 diabetes.

AIM: To compare changes in the oxidation-reduction balance and endothelial function before and after meal in patients with type 2 diabetes or impaired glucose tolerance and determine the effects of standard antioxidant supplementation. METHODS: Forty diabetics and 40 subjects with impaired glucose tolerance were compared with a control group. We assessed before and after a test meal (homogenized milkshake containing 80 g of saturated fat, amounting to 1,480 kcal), some reactive oxygen species, inflammation markers and flow-mediated vascular dilatation. These parameters were then reassessed after standard antioxidant treatment. RESULTS: After the meal, diabetics, subjects with impaired glucose tolerance and controls had higher levels of oxidant compounds compared to fasting levels. In subjects with diabetes and impaired glucose tolerance (IGT), Vascular Adhesion Molecule-1 and CRP were higher after the meal--diabetic subjects exhibited lower fasting flow-mediated dilatation, which deteriorated significantly after the meal. Antioxidant administration significantly improved the parameters investigated in all subjects. CONCLUSIONS: In diabetic subjects, altered glycaemia and lipaemia are closely correlated with markers of systemic oxidative stress. Our results show that the abnormal changes in oxidative-reductive balance parameters are paralleled by similar changes in markers of endothelial dysfunction and inflammation at 4 h after ingestion of a fatty meal. Supplementation with a pool of antioxidants can reduce oxidative stress and inflammation in healthy subjects and, more importantly, in IGT patients. This previous aspect suggests that the timing of antioxidant supplementation has an important role in endothelium protection in healthy and pre-diabetic subjects, and along with prompt antioxidant treatment before irreversible endothelial damage has occurred, may have an important protective role in subjects with IGT-patients who require administration of adequate dietary antioxidants.

Analysis of survival functions by a logistic derivation model: the "generalized de moivre" function.

PIP: "The Generalized De Moivre (GDM) is an analytical survival function deriving from the idea originally put forth by De Moivre.... We compare the GDM and the [Heligman-Pollard model].... We discuss the interpretation of the parameters of the GDM, and we show how they vary according to the mortality context examined, and how they can be profitably used for practical purposes.... [We] argue for a wider use of the GDM in computer-aided demographic analysis of survival." The models are tested using data from Italian life tables for the period 1901-1992. (EXCERPT)^ieng