MG53 does not mark cardiovascular risk and all-cause mortality in subjects with type 2 diabetes: A prospective, observational study.

AIMS: Subjects with type 2 diabetes (T2D) are characterized by a high cardiovascular morbidity and mortality. MG53, a marker of peripheral insulin resistance, has been linked with impaired ß-cell function and decreased ß-cell survival, and its circulating levels are increased in T2D. Its relationship with the cardiovascular risk profile and mortality in T2D is currently unknown. METHODS: In this longitudinal study, MG53 was measured in serum samples collected at baseline for 296 Caucasian participants in the MIND.IT study, relating its circulating levels with the cardiovascular risk profile and all-cause mortality over a 17-years follow up. RESULTS: As compared to a reference cohort of 234 healthy subjects, MG53 levels were higher in T2D individuals (p < 0.001), and higher in T2D women than in men (p = 0.001). In the whole study cohort, MG53 levels were directly related to HbA1c (r2 0.029; p = 0.006) and systolic blood pressure (r2 0.032; p = 0.004). There was no difference in baseline MG53 levels between deceased and alive participants, neither predict all-cause mortality. CONCLUSIONS: MG53 does not mark the cardiovascular risk profile neither predict long-term mortality in Caucasian T2D individuals.

Impulse Oscillometry, Small Airways Disease, and Extra-Fine Formulations in Asthma and Chronic Obstructive Pulmonary Disease: Windows for New Opportunities.

In recent years, the perspective of management of respiratory disease has been gradually changing in light of the increasing evidence of small airways as the major site of airflow obstruction contributing to the development of both COPD and asthma already in early stages of disease. First and foremost, the evidence is redefining disease severity, identifying small airways disease phenotypes and early signs of disease, and revising prevalence and overall epidemiological data as well. Much effort has been put toward the instrumental assessment of small airways' involvement and early detection. Several clinical trials have evaluated the advantage of extra-fine formulations which can best target the small airways in uncontrolled asthma and severe COPD. Here, we briefly present a practical overview of the role of the small airways in disease, the most appropriate diagnostic methods for quantifying their impairment, and provide some insight into the costs of respiratory management in Italy, especially in sub-optimally controlled disease.

Clinical Implications of Switching Lipid Lowering Treatment from Rosuvastatin to Other Agents in Primary Care.

INTRODUCTION: Switching from any statin to another non-equipotent lipid lowering treatment (LLT) may cause a low-density lipoprotein cholesterol increase and has been associated with a higher probability of negative cardiovascular outcomes. The aim of the study was to assess the impact of switching from rosuvastatin to any other LLT on clinical outcomes in primary care. METHODS: This was a retrospective analysis based on data from IMS Health Longitudinal Patient Database, which is a general practice database including information of more than 1.0 million patients representative of the Italian population by age, and medical conditions. Patients that started on rosuvastatin (10-40 mg/day) between January 2011 and December 2013 were considered. The date of the first prescription was defined as the index date (ID). The observation period lasted from the ID to September 2015 or until LLT discontinuation, or the occurrence of an acute myocardial infarction (AMI), or death. RESULTS: The primary end point of the study was the occurrence of an AMI during the observation period. The final study population included 10,368 patients. During the observation period, 2452 (23.6%) patients were switched from rosuvastatin to another LLT. The majority of patients (55.6%) were switched to atorvastatin, followed by simvastatin (24.9%), simvastatin/ezetimibe combination (10.0%) and other statins (9.5%). Female gender (HR, hazard ratio, 1.10, 95% CI, confidence interval, 1.02-1.19, p = 0.04) and the presence of chronic kidney disease (HR 1.47, 95% CI 1.16-1.86, p = 0.05) were associated with a higher probability of switch. During the observation period, 113 patients experienced an AMI (incidence of 6.7 AMI/1000 patient-years). Multivariate analysis with Cox proportional hazards method, including switching as a time-dependent covariate, demonstrated that changing from rosuvastatin to another LLT was an independent predictor of AMI (HR 2.2, 95% CI 1.4-3.5, p = 0.001). CONCLUSION: We conclude that switching from rosuvastatin to another non-equipotent LLT may impart an increased risk of AMI and should be avoided. FUNDING: AstraZeneca SpA.

Telomere length is independently associated with subclinical atherosclerosis in subjects with type 2 diabetes: a cross-sectional study.

AIMS: Individuals with type 2 diabetes show shorter leukocyte telomere length (LTL) compared to people without diabetes. Reduced LTL is associated with increased carotid intima-media thickness (IMT) in healthy subjects. The aim of the study is to assess whether LTL also correlates with IMT in patients with diabetes. METHODS: In a cohort of 104 subjects with type 2 diabetes and atherogenic dyslipidemia, we assessed anthropometric, hemodynamic and metabolic parameters. Common carotid IMT was expressed as the maximum IMT. LTL was assessed by a specific real-time PCR reaction. RESULTS: At univariate analysis, IMT values were positively correlated with age (p < 0.001), previous history of cardiovascular events (p < 0.005), fasting plasma glucose (p < 0.01), HbA1c (p < 0.05) and negatively correlated with LTL (p < 0.05). In a multivariate model, age (p < 0.001) and LTL (p < 0.05) were the only independent predictors of maximum IMT, with an adjusted R (2) of 0.22. CONCLUSIONS: LTL is an independent predictor of subclinical atherosclerosis pointing to a role of LTL as an early marker of vascular burden and cardiovascular disease also in type 2 diabetes.

Effectiveness of treat-to-target strategy for LDL-cholesterol control in type 2 diabetes: post-hoc analysis of data from the MIND.IT study.

BACKGROUND: The paper presents a post-hoc analysis of the intensity of dyslipidaemia care operated in the first 2 years of Multiple-Intervention-in-type-2-Diabetes.ITaly (MIND.IT) study. DESIGN AND METHODS: MIND.IT is a multicentric, randomized, two-parallel arm trial involving 1461 type 2 diabetic patients at high cardiovascular (CV) risk. The study compares the usual care (UC) of CV prevention with a multifactorial intensive care (IC) approach aiming at achieving target values for the main CV risk factors according to a step-wise treat-to-target approach. RESULTS: Proportion of patients on target for low-density lipoprotein cholesterol (LDL-C) was about 10% at baseline and increased significantly more with IC than UC (43 vs. 27%; p < 0.001). However, the majority (57%) of patients, in this intended intensively treated cohort, failed to achieve the proposed target. Average LDL-C decreased from 144 ± 35 to 108 ± 31 mg/dl with IC and from 142 ± 28 to 118 ± 32 with UC (p-for-interaction <0.0001). IC was associated with a significantly greater increase in statin prescription and lower withdrawal from treatment than UC (43 vs. 11% and 28 vs. 61%, respectively; both p < 0.001). However, the new treatments were characterized in both groups by the use of low starting doses (≤ 10 mg of atorvastatin, equivalent dose in more than 90% of patients) without increase in case of missed target. CONCLUSIONS: The application of a multifactorial treat-to-target intervention is associated with a significant improvement in LDL-C beyond usual practice. However, the change in LDL-C appears to be more related to an increased number of treated patients and a decreased treatment withdrawal than to a true treat-to-target approach.

Feasibility and effectiveness in clinical practice of a multifactorial intervention for the reduction of cardiovascular risk in patients with type 2 diabetes: the 2-year interim analysis of the MIND.IT study: a cluster randomized trial.

OBJECTIVE: To evaluate the feasibility and effectiveness of an intensive, multifactorial cardiovascular risk reduction intervention in a clinic-based setting. RESEARCH DESIGN AND METHODS: The study was a pragmatic, cluster randomized trial, with the diabetes clinic as the unit of randomization. Clinics were randomly assigned to either continue their usual care (n = 5) or to apply an intensive intervention aimed at the optimal control of cardiovascular disease (CVD) risk factors and hyperglycemia (n = 4). To account for clustering, mixed model regression techniques were used to compare differences in CVD risk factors and HbA1c. Analyses were performed both by intent to treat and as treated per protocol. RESULTS: Nine clinics completed the study; 1,461 patients with type 2 diabetes and no previous cardiovascular events were enrolled. After 2 years, participants in the interventional group had significantly lower BMI, HbA1c, LDL cholesterol, and triglyceride levels and significantly higher HDL cholesterol level than did the usual care group. The proportion of patients reaching the treatment goals was systematically higher in the interventional clinics (35% vs. 24% for LDL cholesterol, P = 0.1299; 93% vs. 82% for HDL cholesterol, P = 0.0005; 80% vs. 64% for triglycerides, P = 0.0002; 39% vs. 22% for HbA1c, P = 0.0259; 13% vs. 5% for blood pressure, P = 0.1638). The analysis as treated per protocol confirmed these findings, showing larger and always significant differences between the study arms for all targets. CONCLUSIONS: A multifactorial intensive intervention in type 2 diabetes is feasible and effective in clinical practice and it is associated with significant and durable improvement in HbA1c and CVD risk profile.

Ability of a high-total antioxidant capacity diet to increase stool weight and bowel antioxidant status in human subjects.

There is limited knowledge about the possible effect of unabsorbed dietary antioxidants that reach the large intestine on bowel habits. The aim of the present study was to investigate whether a dietary recommendation directed to increase diet total antioxidant capacity (TAC) is able to affect gut function in human subjects. In this cross-over intervention, nineteen subjects followed a high-TAC (HT) and a low-TAC (LT) diet for 2 weeks, which were comparable for energy, macronutrient, total dietary fibre and alcohol contents. At the end of each intervention period, the 48 h stool output was recorded. In the faecal samples obtained from a subset of nine subjects, moisture, pH, ammonia content, Lactobacillus and Bifidobacterium counts, faecal water antioxidants and genotoxicity were measured. A 3 d weighed food record was used to assess the diet composition during HT and LT diet intake. Significant increases in the intake of TAC, vitamins E and C and phenolic compounds were observed during the HT diet intake. The higher intake of antioxidants led to increased 48 h stool output (324 (SD 38) g in HT v. 218 (SD 22) g in LT), and to higher TAC and total phenolic concentrations in faecal water. No significant variation in the other measured parameters was observed between the diets. In conclusion, a diet selected to raise the intake of dietary antioxidants is able to increase stool bulk and antioxidant content of faeces.

The increase in plasma PAI-1 associated with insulin resistance may be mediated by the presence of hepatic steatosis.

OBJECTIVE: Recent evidence suggests that plasminogen-activator inhibitor-1 (PAI-1) is abundantly produced by the fatty liver, but it is unclear whether hepatic steatosis (HS) can mediate the increase in plasma PAI-1 induced by insulin resistance/compensatory hyperinsulinemia (IR/CH). METHODS AND RESULTS: To address this issue, we cross-sectionally evaluated IR/CH as area under the curve of plasma insulin (AUC-PI) concentrations during OGTT, metabolic profile, and ultrasound degree of HS in 235 healthy volunteers (132M, age: 60+/-7 years) with normal transaminase concentrations. Circulating PAI-1 was increased in subjects with classical features of IR/CH (overweight, high fasting and post-OGTT insulin and glucose, high triglycerides (TG), and low HDL-cholesterol), and significantly correlated to prevalence and degree of HS, but not to alcohol intake. In a multivariate model, AUC-PI, TG and degree of HS were independent predictors of plasma PAI-1 (R(2)=0.32). However, AUC-PI was significantly correlated to PAI-1 only in subjects with HS, suggesting an interaction between AUC-PI and HS. In addition, in the presence of HS and IR/CH, PAI-1 concentrations were increased to a similar extent both in heavy and moderate drinkers, suggesting that metabolic and alcoholic steatosis have a similar effect on the relationship between IR/CH and PAI-1. CONCLUSION: These results support the hypothesis that HS has a major impact on the relationship between IR/CH and plasma PAI-1 concentrations, and this effect seems to be unaffected by the etiology of the HS.

Dietary antioxidants and glucose metabolism.

PURPOSE OF REVIEW: Oxidative stress seems to play a pathogenic role in the vicious circle linking obesity, insulin resistance and type 2 diabetes. Hypothetically, dietary antioxidants should decrease oxidative stress and therefore improve glucose metabolism. However, many interventional trials evaluating the effect of antioxidant supplementation on insulin resistance, plasma glucose levels and risk of type 2 diabetes gave inconsistent results. RECENT FINDINGS: Many studies have recently demonstrated a positive effect of vitamin supplementation and of food enriched in antioxidant (seafood, whole nut, etc.) on markers of oxidative stress, insulin resistance, fasting plasma glucose and incidence of diabetes. The present paper critically reviews the consolidated notions on dietary antioxidant in view of the recent evidences. SUMMARY: Although a definitive estimation of the impact of dietary antioxidants on glucose metabolism is still lacking, food with high antioxidant concentrations seems to have a protective effect, improving oxidative stress-mediated detrimental effects on the vicious circle among obesity, insulin resistance and redox imbalance.

Food selection based on total antioxidant capacity can modify antioxidant intake, systemic inflammation, and liver function without altering markers of oxidative stress.

BACKGROUND: It is unknown whether diets with a high dietary total antioxidant capacity (TAC) can modify oxidative stress, low-grade inflammation, or liver dysfunction, all of which are risk factors for type 2 diabetes and cardiovascular disease. OBJECTIVE: We studied the effect of high- and low-TAC (HT and LT, respectively) diets on markers of antioxidant status, systemic inflammation, and liver dysfunction. DESIGN: In a crossover intervention, 33 healthy adults (19 men, 14 women) received the HT and LT diets for 2 wk each. Dietary habits were checked with a 3-d food record during both diet periods and the washout period. RESULTS: Fruit and vegetable, macronutrient, dietary fiber, and alcohol intakes did not differ significantly between the 2 diets, whereas dietary TAC, alpha-tocopherol, and ascorbic acid were significantly (P < 0.001) higher during the HT diet. Plasma alpha-tocopherol rose during the HT and decreased during the LT diet (P < 0.02 for difference) without changes in markers of oxidative stress except plasma malondialdehyde, which decreased unexpectedly during the LT diet (P < 0.05). Plasma high-sensitivity C-reactive protein, alanine aminotransferase, gamma-glutamyltranspeptidase, and alkaline phosphatase concentrations decreased during the HT compared with the LT diet (mean +/- SEM for pre-post changes: -0.72 +/- 0.37 compared with 1.05 +/- 0.60 mg/L, P < 0.01; -1.73 +/- 1.02 compared with 2.33 +/- 2.58 U/L, P < 0.01; -2.12 +/- 1.45 compared with 5.15 +/- 2.98 U/L, P < 0.05; and 1.36 +/- 1.34 compared with 5.06 +/- 2.00 U/L, P < 0.01, respectively). CONCLUSION: Selecting foods according to their TAC markedly affects antioxidant intake and modulates hepatic contribution to systemic inflammation without affecting traditional markers of antioxidant status.

Relation of plasma insulin levels to forearm flow-mediated dilatation in healthy volunteers.

Although several observations suggest that insulin resistance/compensatory hyperinsulinemia (IR/CH) has a direct effect on endothelial function, independently of the metabolic abnormalities associated with the defect in insulin action, this relation has not been evaluated in apparently healthy individuals. To address this issue, we measured endothelial-dependent vasodilation in response to forearm ischemia (flow-mediated dilation [FMD]) in 47 nonsmoking, healthy volunteers without known risk factors for atherosclerosis. Measurements were also made of multiple anthropometric, metabolic, and hemodynamic variables related to IR/CH. Decreases in FMD were significantly correlated (analysis of variance for linear trend) with (1) male gender (p = 0.003), (2) waist circumference (p = 0.038), (3) higher fasting plasma insulin (p = 0.015) and triglyceride concentrations (p = 0.023), and (4) lower concentrations of high-density lipoprotein cholesterol (p = 0.001). Multivariate linear regression analysis indicated that only plasma insulin (beta -0.424) was independently associated (p <0.001) with changes in FMD, and individual differences in insulin concentrations, along with gender and brachial artery diameter at baseline, accounted for approximately 39% of the variability in FMD. In conclusion, IR/CH is an independent predictor of decreases in endothelial-dependent vasodilation in apparently healthy individuals, in the absence of traditional risk factors for atherosclerosis.

Hyperinsulinemia predicts hepatic fat content in healthy individuals with normal transaminase concentrations.

Although the prevalence of insulin resistance (IR) and compensatory hyperinsulinemia (CH) is increased in patients with nonalcoholic fatty liver disease, the role of IR/CH in regulation of hepatic fat content in healthy volunteers with normal concentrations of alanine transaminase (ALT) has not been defined. To address this issue, hepatic fat content was quantified by ultrasound in 69 (30 men, 39 women) healthy individuals, without known risk factors for liver disease and with plasma ALT concentrations of less than 30 U/L. Experimental variables quantified included body mass index, waist circumference, systolic and diastolic blood pressures, and fasting plasma glucose, fasting plasma insulin (FPI), and lipid concentrations. Subjects were classified as having no (55%), mild (27%), or moderate to severe (18%) hepatic steatosis on the basis of the ultrasound results. Statistically significant (P < .05-.001) correlations (Spearman rho values) existed between liver fat content and ALT (0.26), body mass index (0.52), waist circumference (0.50), systolic blood pressure (0.28), diastolic blood pressure (0.27), fasting plasma glucose (0.47), FPI (0.56), triglycerides (0.30), and high-density lipoprotein cholesterol (-0.35). Multivariate general discriminant analysis and multiple linear regression analysis indicated that FPI was the only independent predictor (P < .001) of both liver fat content and ALT concentrations. Fasting plasma insulin (a surrogate estimate of IR/CH) predicts hepatic fat content and ALT in healthy volunteers with normal transaminase concentrations, independently of the other anthropometric and metabolic variables measured.

Relationship between leptin, insulin, body composition and liver steatosis in non-diabetic moderate drinkers with normal transaminase levels.

OBJECTIVE: Obesity and insulin resistance play a major role in the development of liver steatosis (LS), but also relative leptin resistance has been reported to correlate with LS in humans. Our objective was to investigate the relationship between serum leptin, insulin, obesity and LS in non-diabetic males (n = 74) and postmenopausal females (n = 50) with normal transaminase levels and low-to-moderate alcohol intake. METHODS: A medical history to retrieve information about health status, current medications, alcohol consumption and history of viral or toxic hepatitis; a physical examination including height, weight, waist circumference and blood pressure; a fasting blood draw for the determination of glucose, insulin, leptin, lipid profile, transaminases and uric acid; an oral glucose tolerance test to exclude type 2 diabetes; a dual-energy X-ray absorptiometry scan to assess fat mass (FM) and lean body mass (LBM), and an echography of the liver to assess LS. RESULTS: Fasting leptin and insulin were highly correlated with FM in men (R = 0.767 and R = 0.495 respectively, P < 0.001) and women (R = 0.713 and R = 0.526 respectively, P < 0.001). After correction for FM, leptin showed a significant negative correlation with LBM in men (R = -0.240, P = 0.039), but not in women (R = -0.214, P = 0.132). The positive relationship observed between leptin, insulin and LS persisted after adjustment of leptin and insulin for body composition only in men (R = 0.415, P < 0.001 and R = 0.339, P = 0.003 respectively for leptin and insulin vs LS). Adjusted means (95% confidence intervals) of leptin increased significantly across categories of LS in men even when insulin was considered in the model (absent = 7.1 ng/ml (5.6-8.5), mild = 8.2 ng/ml (7.2-9.2), moderate/severe = 12.1 ng/ml (10.3-14.0); P < 0.001), whereas no significant relationship was observed between insulin and LS after leptin was accounted for. CONCLUSION: Serum concentrations of leptin and insulin are positively correlated in men independently of body composition, but not in postmenopausal women. In men, the steatogenic effect of hyperinsulinemia/insulin resistance in the context of low-to-moderate alcohol consumption appears to be mediated by high concentrations of serum leptin, whereas body fat alone could identify postmenopausal women at high risk for LS.