Maria Masulli

Fasting plasma free fatty acid concentrations and Pro12Ala polymorphism of the peroxisome proliferator‐activated receptor (PPAR) γ2 gene in healthy individuals

background The Pro12Ala polymorphism of the peroxisome proliferator‐activated receptor (PPAR) γ gene has been associated in some, but not all, studies with lower body mass index (BMI) and improved insulin sensitivity; how an altered transcriptional activity of PPARγ2 could influence insulin sensitivity is currently unclear. The free fatty acids (FFAs) released from adipose tissue triglycerides via lipolysis are key mediators of impaired insulin sensitivity; however, no study has described the relationship of the Pro12Ala mutation with circulating levels of FFAs under physiological conditions.

Addition of either pioglitazone or a sulfonylurea in type 2 diabetic patients inadequately controlled with metformin alone: Impact on cardiovascular events. A randomized controlled trial

BACKGROUND AND AIMS Metformin is the first-line therapy in type 2 diabetes. In patients inadequately controlled with metformin, the addition of a sulfonylurea or pioglitazone are equally plausible options to improve glycemic control. However, these drugs have profound differences in their mechanism of action, side effects, and impact on cardiovascular risk factors. A formal comparison of these two therapies in terms of cardiovascular morbidity and mortality is lacking. The TOSCA.IT study was designed to explore the effects of adding pioglitazone or a sulfonylurea on cardiovascular events in type 2 diabetic patients inadequately controlled with metformin. METHODS Multicentre, randomized, open label, parallel group trial of 48 month duration. Type 2 diabetic subjects, 50-75 years, BMI 20-45 Kg/m(2), on secondary failure to metformin monotherapy will be randomized to add-on a sulfonylurea or pioglitazone. The primary efficacy outcome is a composite endpoint of all-cause mortality, nonfatal myocardial infarction, nonfatal stroke, and unplanned coronary revascularization. Principal secondary outcome is a composite ischemic endpoint of sudden death, fatal and non-fatal myocardial infarction and stroke, endovascular or surgical intervention on the coronary, leg or carotid arteries, major amputations. Side effects, quality of life and economic costs will also be evaluated. Efficacy, safety, tolerability, and study conduct will be monitored by an independent Data Safety Monitoring Board. End points will be adjudicated by an independent external committee. CONCLUSIONS TOSCA.IT is the first on-going study investigating the head-to-head comparison of adding a sulfonylurea or pioglitazone to existing metformin treatment in terms of hard cardiovascular outcomes. REGISTRATION Clinicaltrials.gov ID NCT00700856.

Iron Deficiency and Cardiovascular Disease: An Updated Review of the Evidence

Body iron status has been suggested to be related to the development of cardiovascular disease (CVD). Biologically plausible mechanisms for this association have been described, however epidemiological studies on iron status and CVD risk have provided conflicting results. The lack of consistency is likely explained by differences in the study design, the measures used for the assessment of iron status, the definition of outcomes, and adjustment for confounders. To help clarify the available evidence, we report a systematic review of published cross-sectional, longitudinal, and intervention studies evaluating the relationship between different measures of iron status and CVD risk. The most likely scenario that emerges from the available studies is that, in the reference range, iron status has a neutral effect. Extreme conditions of iron deficiency, as well as of iron overload, are associated with modestly increased CVD risk, although with different proposed mechanisms.

Variants of uncoupling protein‐2 gene and obesity: interaction with peroxisome proliferator‐activated receptorγ2

objective  To analyse the association of the UCP2 gene, alone or in combination with the PPARγ2 gene, with obesity.

The TOSCA.IT Trial: A Study Designed to Evaluate the Effect of Pioglitazone Versus Sulfonylureas on Cardiovascular Disease in Type 2 Diabetes

The recently published American Diabetes Association (ADA)/European Association for the Study of Diabetes (EASD) position statement on the management of hyperglycemia in type 2 diabetes (T2D) (1) underlines the complexity of the therapeutic approach in T2D. This is due to both the increasing number of available drugs and to the paucity of solid data on the superiority of one compound over the others. By and large, antidiabetic drugs reduce blood glucose to a similar extent but have different impacts on cardiovascular (CV) risk factors, durability of efficacy, safety, and possible added values (2–4). A major challenge for clinicians is to select treatments that are capable of achieving and maintaining glucose control for as long as possible while minimizing the risk of chronic complications, including cardiovascular disease (CVD). This goal should be pursued with minimal side effects (mainly hypoglycemia). Although there is agreement on …

Measurement of the intrarenal arterial resistance index for the identification and prediction of diabetic nephropathy

BACKGROUND AND AIMS High intrarenal resistance index (RI) predicts renal function in several conditions; its use in the prediction of diabetic nephropathy (DN) is little explored. We aimed (1) to compare RI in diabetic and non diabetic hypertensive patients, and (2) to evaluate whether high RI is associated with clinical signs of DN and its progression over time. METHODS AND RESULTS DESIGN observational, prospective. PARTICIPANTS 92 type 2 diabetic patients and 37 non-diabetic controls aged 40-70, with hypertension and normal renal function. We measured ultrasound RI and, among others, creatinine, estimated glomerular filtration rate and urinary albumin excretion rate (AER) at baseline and after 4.5 years follow-up. Progression of albuminuric state (i.e., transition from baseline normo-microalbuminuria to follow-up micro-macroalbuminuria) was evaluated. RI was significantly higher in diabetic than non-diabetic participants (0.69+/-0.05 vs 0.59+/-0.05, p<0.001). Diabetic patients with RI>or=0.73, i.e., above the 80th percentile of the RI distribution, had significantly higher baseline AER and a more frequent progression of the albuminuric state compared to patients with RI<0.73 (27.7microg/mg [12.1-235.4] vs 15.1microg/mg [8.6-33.4]; 52.9% vs 9.5%, respectively). AER increased significantly from baseline to follow-up in patients with RI>or=0.73 (from 27.7microg/mg [12.1-235.4] to 265.0microg/mg [23.8-1018.1], p<0.01), but not in those with RI<0.73 (from 15.1microg/mg [8.6-33.4] to 16.1microg/mg [10.7-67.2], ns). OR for progression of albuminuric state, adjusted for established predictors of DN, including baseline AER, was 5.01 (1.4-17.7, 95% CI) for patients with RI>or=0.73 vs <0.73. Findings were confirmed in patients with normoalbuminuria at baseline. CONCLUSIONS In diabetic patients, high RI (>or=0.73) is associated with features of DN and its progression over time, independent of albuminuria.

Relation Among Lipoprotein Subfractions and Carotid Atherosclerosis in Alaskan Eskimos (from the GOCADAN Study)

Studies have been inconsistent regarding whether lipoprotein particle subfraction measures are useful indicators of cardiovascular risk. The present study evaluated the relation between lipoprotein particle concentrations and size, analyzed using nuclear magnetic resonance spectroscopy and measures of carotid atherosclerosis in a population with high cardiovascular risk but little hyperlipidemia. In this cross-sectional, population-based sample of Alaska Eskimos >or=35 years old (n = 656), a greater carotid intimal medial thickness was associated with greater low-density lipoprotein (LDL) cholesterol (p = 0.03) and total LDL particle concentration (p = 0.04), independently of other traditional risk factors. The effects of LDL cholesterol and LDL particle concentration on intimal medial thickness were additive (p = 0.015). Carotid plaque was associated with greater levels of LDL cholesterol (p = 0.01), greater concentrations of large LDL particles (p = 0.003), and a reduction in the size of the very-low-density lipoprotein particles (p = 0.03). The effects of LDL cholesterol and large LDL particles on the plaque score were additive. In conclusion, the carotid intimal medial thickness was associated with greater LDL particle concentrations. The association was strongest in those with greater LDL cholesterol levels. Plaque was associated with greater concentrations of LDL cholesterol, large LDL particles, and smaller very-low-density lipoprotein particles. It might be beneficial to determine the lipoprotein subfractions in populations with little hyperlipidemia.

Lower incidence of macrovascular complications in patients on insulin glargine versus those on basal human insulins: A population-based cohort study in Italy

BACKGROUND AND AIM The aim of this study was to compare the use of insulin glargine and intermediate/long-acting human insulin (HI) in relation to the incidence of complications in diabetic patients. METHODS AND RESULTS A population-based cohort study was conducted using administrative data from four local health authorities in the Abruzzo Region (900,000 inhabitants). Diabetic patients without macrovascular diseases and treated with either intermediate/long-acting HI or glargine were followed for 3-years; the incidence of diabetic (macrovascular, microvascular and metabolic) complications was ascertained by hospital discharge claims and estimated using Cox proportional hazard models. Propensity score (PS) matching was also used to adjust for significant differences in the baseline characteristics between the two groups. RESULTS Overall, 1921 diabetic patients were included: 744 intermediate/long-acting HI and 1177 glargine users. During the 3-year follow-up, 209 (28.1%) incident events of any diabetic complication occurred in the intermediate/long-acting HI and 159 (13.5%) in the glargine group. After adjustment for covariates, glargine users had an HR (95% CI) of 0.57 (0.44-0.74) for any diabetic complication and HRs of 0.61 (0.44-0.84), 0.58 (0.33-1.04) and 0.35 (0.18-0.70) for macrovascular, microvascular and metabolic complications, respectively, compared to intermediate/long-acting HI users. PS analyses supported these findings. CONCLUSIONS The use of glargine is associated with a lower risk of macrovascular complications compared with traditional basal insulins. However, limitations inherent to the study design including the short length of observation and the lack of data on metabolic control or diabetes duration, do not allow us to consider this association as a proof of causality.

Renal Duplex Sonographic Evaluation of Type 2 Diabetic Patients

The purpose of this study was to evaluate the renal volume and intrarenal hemodynamics with duplex sonography in a group of diabetic patients with normal renal function in comparison to nondiabetic controls.

Lower Rate of Cardiovascular Complications in Patients on Bolus Insulin Analogues: A Retrospective Population-Based Cohort Study

Background Few studies are available evaluating the impact of rapid-acting insulin analogues on long-term diabetes outcomes. Our aim was to compare the use of rapid-acting insulin analogues versus human regular insulin in relation to the occurrence of diabetic complications in a cohort of diabetic patients through the analysis of administrative databases. Methods A population-based cohort study was conducted using administrative data from four local health authorities in the Abruzzo Region (900,000 inhabitants). Diabetic patients free of macrovascular disease at baseline and treated either with human regular insulin or rapid-acting insulin analogues were followed for a maximum of 3 years. The incidence of diabetic complications was ascertained by hospital discharge claims. Hazard ratios (HRs) and 95% CIs of any diabetic complication and macrovascular, microvascular and metabolic complications were estimated separately using Cox proportional hazard models adjusted for patients’ characteristics and anti-diabetic drug use. Propensity score matching was also used to adjust for significant difference in the baseline characteristics between the two treatment groups. Results A total of 2,286 patients were included: 914 receiving human regular insulin and 1,372 rapid-acting insulin analogues. During the follow-up, 286 (31.3%) incident events occurred in the human regular insulin group and 235 (17.1%) in the rapid-acting insulin analogue group. After propensity score-based matched-pair analyses, rapid-acting insulin analogues users had a HR of 0.73 (0.58–0.92) for any diabetes-related complication and HRs of 0.73 (0.55–0.93) and 0.55 (0.32–0.96) for macrovascular and metabolic complications respectively, as compared with human regular insulin users. No difference between the two groups was found for microvascular complications. Conclusions Our findings suggest that the use of rapid-acting insulin analogues is associated with a lower risk of cardiovascular and metabolic complications compared with human regular insulin use.