Efficacy of a training programme for the management of diabetes mellitus in the hospital: A randomized study (stage 2 of GOVEPAZ healthcare).

AIMS: To assess the efficacy of a structured educational intervention for health professionals on the appropriateness of inpatient diabetes care and on some clinical outcomes in hospitalised subjects. METHODS: A multicentre (6 regional hospitals) cluster-randomized (2:1) two parallel-group pragmatic intervention trials, as a part of the GOVEPAZ study, was conducted in three clinical settings, that is, Internal Medicine, Surgery and Intensive Care. Intervention consisted of a 2-month structured education of clinical staff to inpatient diabetes care. Twelve wards - 2 for each hospital - and 6 wards - 1 for each hospital - were randomized to usual care and to the intervention arm, respectively. Consecutively hospitalised diabetic subjects (n = 524, age 74 ± 14 years, 57% males, median HbA1C 57 mmol/mol) were included. The clinical appropriateness of inpatient diabetes management was assessed by a previously validated multi-domain performance score (PS). Clinical outcomes included hypoglycemia, glucose control biomarkers, clinical conditions at discharge and inpatient mortality rate. RESULTS: A numerically, but not statistically significant, higher PS (+0.94; 95% C.I.: -0.53 - +2.4) was achieved in the intervention than in the usual care wards. Hypoglycemias (p = 0.32), glucose control (p = 0.89) and survival rates (p = 0.71) were similar in the two experimental arms. Plasma glucose on admission (OR = 1.52 per 1 SD; C.I. 1.07-2.17; p = 0.021) and the number of hypoglycemic events per patient (OR = 1.55 per 1 SD; C.I.:1.11-2.16; p = 0.011) were independently associated with the inpatient mortality rate. CONCLUSIONS: Structured education of the clinical staff failed to improve the inpatient appropriateness of diabetes care or clinical outcomes. In-hospital hypoglycemia was confirmed to be an independent indicator of death risk.

A performance score of the quality of inpatient diabetes care is a marker of clinical outcomes and suggests a cause-effect relationship between hypoglycaemia and the risk of in-hospital mortality.

AIMS: To build a tool to assess the management of inpatients with diabetes mellitus and to investigate its relationship, if any, with clinical outcomes. MATERIALS AND METHODS: A total of 678 patients from different settings, Internal Medicine (IMU, n = 255), General Surgery (GSU, n = 230) and Intensive Care (ICU, n = 193) Units, were enrolled. A work-flow of clinical care of diabetes was created according to guidelines. The workflow was divided into five different domains: (a) initial assessment; (b) glucose monitoring; (c) medical therapy; (d) consultancies; (e) discharge. Each domain was assessed by a performance score (PS), computed as the sum of the scores achieved in a set of indicators of clinical appropriateness, management and patient empowerment. Appropriate glucose goals were included as intermediate phenotypes. Clinical outcomes included: hypoglycaemia, survival rate and clinical conditions at discharge. RESULTS: The total PS and those of initial assessment and glucose monitoring were significantly lower in GSU with respect to IMU and ICU (P < .0001). The glucose monitoring PS was associated with lower risk of hypoglycaemia (OR = 0.55; P < .0001), whereas both the PSs of glucose monitoring and medical therapy resulted associated with higher in-hospital survival only in the IMU ward (OR = 6.67 P = .001 and OR = 2.38 P = .03, respectively). Instrumental variable analysis with the aid of PS of glucose monitoring showed that hypoglycaemia may play a causal role in in-hospital mortality (P = .04). CONCLUSIONS: The quality of in-hospital care of diabetes may affect patient outcomes, including glucose control and the risk of hypoglycaemia, and through the latter it may influence the risk of in-hospital mortality.

Glucose- and Lipid-Related Biomarkers Are Affected in Healthy Obese or Hyperglycemic Adults Consuming a Whole-Grain Pasta Enriched in Prebiotics and Probiotics: A 12-Week Randomized Controlled Trial.

BACKGROUND: Synbiotic foods, which combine the action of prebiotics and probiotics along the gastrointestinal tract, can affect inflammatory and glucose-related markers. OBJECTIVE: The aim of this study was to investigate the effects on inflammatory and glycemia-related markers of a whole-grain pasta containing barley ß-glucans and Bacillus coagulans BC30, 6086 in healthy overweight or obese volunteers. METHODS: A single-blind, parallel, randomized, placebo-controlled dietary intervention study was carried out. Forty-one healthy sedentary overweight (body mass index [BMI] 25-29.9 kg/m2) and obese (BMI ≥30) volunteers, aged 30-65 y and low consumers of fruit and vegetables, ate 1 serving/d of whole-grain control (CTR) or innovative (INN) pasta for 12 wk and maintained their habitual diets. Biological samples were collected at baseline and every 4 wk for primary (plasma high-sensitivity C-reactive protein [hs-CRP] and fasting plasma lipid profile) and secondary outcomes (glycemia-related markers, blood pressure, fecal microbiota composition, and body weight). Between (CTR compared with INN) and within (among weeks) group differences were tested for the whole population and for subgroups stratified by baseline values of BMI (≥30) and glycemia (≥100 mg/dL). RESULTS: INN or CTR pasta consumption had no effect on primary and secondary outcomes over time, except for a significant increase in plasma γ-glutamyltransferase (GGT) after 12 wk of CTR pasta consumption. Comparisons between intervention groups revealed differences only at 12 wk: plasma GGT was higher in the CTR group; plasma hs-CRP, plasma LDL/HDL cholesterol ratio, and Bifidobacterium spp. were lower in the INN subgroup of obese volunteers; plasma resistin was lower and Faecalibacterium prausnitzii abundance was higher in the INN subgroup of hyperglycemic volunteers. CONCLUSIONS: A daily serving of a synbiotic whole-grain pasta had limited effects on primary and secondary outcomes in the entire group of volunteers but affected glycemia- and lipid-related markers and resistin in a subgroup of healthy obese or hyperglycemic volunteers. This trial was registered at clinicaltrials.gov as NCT02236533.

Claimed effects, outcome variables and methods of measurement for health claims on foods proposed under European Community Regulation 1924/2006 in the area of appetite ratings and weight management.

All the requests for authorisation to bear health claims under Articles 13(5) and 14 in the context of appetite ratings and weight management have received a negative opinion by the European Food Safety Authority (EFSA), mainly because of the insufficient substantiation of the claimed effects (CEs). This manuscript results from an investigation aimed to collect, collate and critically analyse the information related to outcome variables (OVs) and methods of measurement (MMs) in the context of appetite ratings and weight management compliant with Regulation 1924/2006. Based on the literature review, the appropriateness of OVs and MMs was evaluated for specific CEs. This work might help EFSA in the development of updated guidance addressed to stakeholders interested in bearing health claims in the area of weight management. Moreover, it could drive the applicants during the design of randomised controlled trials aimed to substantiate such claims.

Claimed effects, outcome variables and methods of measurement for health claims on foods related to the gastrointestinal tract proposed under regulation (EC) 1924/2006.

Most of the requests of authorisation to the use of health claims pursuant to Regulation EC 1924/2006 related to the gastrointestinal (GI) tract have received a negative opinion by the European Food Safety Authority (EFSA), mainly because of an insufficient substantiation of the claimed effect (CE). The present manuscript refers to the collection, collation and critical analysis of outcome variables (OVs) and methods of measurement (MMs) related to the GI tract compliant with Regulation 1924/2006. The critical evaluation of OVs and MMs was based on the literature review, with the final aim of defining their appropriateness in the context of a specific CE. The results obtained are relevant for the choice of the best OVs and MMs to be used in randomised controlled trials aimed to substantiate the claims on the GI tract. Moreover, the results can be used by EFSA for updating the guidance for the scientific requirements of such health claims.

Vildagliptin, but not glibenclamide, increases circulating endothelial progenitor cell number: a 12-month randomized controlled trial in patients with type 2 diabetes.

BACKGROUND: Fewer circulating endothelial progenitor cells (EPCs) and increased plasma (C-term) stromal cell-derived factor 1α (SDF-1α), a substrate of DPP-4, are biomarkers, and perhaps mediators, of cardiovascular risk and mortality. Short-term/acute treatment with DPP-4 inhibitors improve EPC bioavailability; however, long-term effects of DPP-4i on EPCs bioavailability/plasma (C-term) SDF-1α are unknown. METHODS: Randomized (2:1) open-label trial to compare the effects of vildagliptin (V) (100 mg/day) vs glibenclamide (G) (2.5 mg bid to a maximal dose of 5 mg bid) on circulating EPC levels at 4 and 12 months of treatment in 64 patients with type 2 diabetes in metformin failure. At baseline, and after 4 and 12 months, main clinical/biohumoral parameters, inflammatory biomarkers, concomitant therapies, EPC number (CD34+/CD133+/KDR+/106 cytometric events) and plasma (C-term) SDF-1α (R&D system) were assessed. RESULTS: Baseline characteristics were comparable in the two groups. V and G similarly and significantly (p < 0.0001) improved glucose control. At 12 months, V significantly increased EPC number (p < 0.05) and significantly reduced (C-term) SDF-1α plasma levels (p < 0.01) compared to G, with no differences in inflammatory biomarkers. CONCLUSIONS: V exerts a long-term favorable effect on EPC and (C-term) SDF-1α levels at glucose equipoise, thereby implying a putative beneficial effect on vascular integrity. Trial registration Clinical Trials number: NCT01822548; name: Effect of Vildagliptin vs. Glibenclamide on Circulating Endothelial Progenitor Cell Number Type 2 Diabetes. Registered 28 March, 2013.

Effects of a New Nutraceutical Formulation (Berberine, Red Yeast Rice and Chitosan) on Non-HDL Cholesterol Levels in Individuals with Dyslipidemia: Results from a Randomized, Double Blind, Placebo-Controlled Study.

Increased non high-density lipoprotein (HDL)/low-density lipoprotein (LDL) cholesterol levels are independent risk factors for cardiovascular (CV) mortality with no documented threshold. A new combination of nutraceuticals (berberine 200 mg, monacolin K 3 mg, chitosan 10 mg and coenzyme Q 10 mg) with additive lipid-lowering properties has become available. The aim of the study is to test the efficacy of the nutraceutical formulation (one daily) in lowering non-HDL cholesterol vs. placebo at 12 weeks in individuals with non-HDL-cholesterol levels ≥160 mg/dL. 39 subjects (age 52 ± 11 years; 54% females; body mass index 27 ± 4 kg/m²) were randomized (3:1) in a double blind phase II placebo-controlled study. At baseline, 4 and 12 weeks main clinical/biohumoral parameters, pro-inflammatory cytokines, (gut)-hormones, proprotein convertase subtilisin/kexin type 9 (PCSK9) levels and endothelial progenitor cell (EPC) number were assessed. Baseline characteristics were comparable in the two groups. The intervention significantly decreased non-HDL cholesterol (-30 ± 20 mg/dL; p = 0.012), LDL cholesterol (-31 ± 18 mg/dL, p = 0.011) and apolipoprotein (Apo) B (-14 ± 12 mg/dL, p = 0.030) levels compared to the placebo. Pro-inflammatory, hormonal, PCSK9 and EPC levels remained stable throughout the study in both groups. The intervention was well tolerated. Three adverse events occurred: Epstein Barr virus infection, duodenitis and asymptomatic but significant increase in creatine phosphokinase (following intense physical exercise) which required hospitalization. The tested nutraceutical formulation may represent a possible therapeutic strategy in dyslipidemic individuals in primary prevention.

Effects of naringenin and its phase II metabolites on in vitro human macrophage gene expression.

Naringenin, together with its glycosidic forms, is a flavanone abundant in grapefruit and orange. It has been detected in human plasma, following citrus juice intake, at sub-µmolar concentrations, and its main phase II conjugated metabolites (naringenin-7-O-glucuronide and narigenin-4'-O-glucuronide) have been identified in urine. Recent evidence suggests a potential active anti-inflammatory role of flavonoids on macrophages, cells actively involved in atherogenesis. The aim of this study was to evaluate the effects of naringenin and its phase II metabolites on the expression of specific genes in differently activated macrophages at concentrations coherent with dietary exposure. Results suggest that phase II metabolites, as well as the aglyconic form of naringenin, were able to perturb macrophage gene expression in directions that are not always consistent with anti-inflammatory effects. Moreover, the effects of metabolites were not always consistent with each other and with those of their aglycone, underlining the paramount importance of testing physiological forms of phytochemicals within in vitro experimental models. In vivo studies are needed to further explore these observations and investigate their practical consequences.

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.

Clinically driven semi-supervised class discovery in gene expression data.

MOTIVATION: Unsupervised class discovery in gene expression data relies on the statistical signals in the data to exclusively drive the results. It is often the case, however, that one is interested in constraining the search space to respect certain biological prior knowledge while still allowing a flexible search within these boundaries. RESULTS: We develop an approach to semi-supervised class discovery. One component of our approach uses clinical sample information to constrain the search space and guide the class discovery process to yield biologically relevant partitions. A second component consists of using known biological annotation of genes to drive the search, seeking partitions that manifest strong differential expression in specific sets of genes. We develop efficient algorithmics for these tasks, implementing both approaches and combinations thereof. We show that our method is robust enough to detect known clinical parameters in accordance with expected clinical values. We also use our method to elucidate cardiovascular disease (CVD) putative risk factors. AVAILABILITY: MonoClaD (Monotone Class Discovery). See http:// bioinfo.cs.technion.ac.il/people/zohar/MonoClad/. SUPPLEMENTARY INFORMATION: Supplementary data is available at http://bioinfo.cs.technion.ac.il/people/zohar/MonoClad/software. html

Correction: Identification of an early transcriptomic signature of insulin resistance and related diseases in lymphomonocytes of healthy subjects.

[This corrects the article DOI: 10.1371/journal.pone.0182559.].

Claimed effects, outcome variables and methods of measurement for health claims proposed under European Community Regulation 1924/2006 in the area of blood glucose and insulin concentrations.

Most requests for authorization to bear health claims under Articles 13(5) and 14 related to blood glucose and insulin concentration/regulation presented to the European Food Safety Authority (EFSA) receive a negative opinion. Reasons for such decisions are mainly ascribable to poor substantiation of the claimed effects. In this scenario, a project was carried out aiming at critically analysing the outcome variables (OVs) and methods of measurement (MMs) to be used to substantiate health claims, with the final purpose to improve the quality of applications provided by stakeholders to EFSA. This manuscript provides a position statement of the experts involved in the project, reporting the results of an investigation aimed to collect, collate and critically analyse the information relevant to claimed effects (CEs), OVs and MMs related to blood glucose and insulin levels and homoeostasis compliant with Regulation 1924/2006. The critical analysis of OVs and MMs was performed with the aid of the pertinent scientific literature and was aimed at defining their appropriateness (alone or in combination with others) to support a specific CE. The results can be used to properly select OVs and MMs in a randomized controlled trial, for an effective substantiation of the claims, using the reference method(s) whenever available. Moreover, results can help EFSA in updating the guidance for the scientific requirements of health claims.

Claimed Effects, Outcome Variables and Methods of Measurement for Health Claims on Foods Related to Vision Proposed Under Regulation (EC) 1924/2006.

Adequate visual function has a strong impact on the quality of life of people. Several foods and food components have been hypothesized to play a role in the maintenance of normal visual function and in the prevention of eye diseases. Some of these foods/food components have been the object of a request of authorization for use of health claims under Articles 13(5) or 14 of the Regulation (EC) 1924/2006. Most of these requests have received a negative opinion from the European Food Safety Authority (EFSA) due to the choice of inappropriate outcome variables (OVs) and/or methods of measurement (MMs) applied in the studies used to substantiate the claims. This manuscript refers to the collection, collation and critical analysis of OVs and MMs related to vision. Guidance document and requests for authorization of health claims were used to collect OVs and MMs related to vision. A literature review was performed to critically analyse OVs and MMs, with the aim of defining their appropriateness in the context of a specific claimed effect related to vision. The results highlight the importance of adequate choices of OVs and MMs for an effective substantiation of claims related to visual function.

Identification of an early transcriptomic signature of insulin resistance and related diseases in lymphomonocytes of healthy subjects.

Insulin resistance is considered to be a pathogenetic mechanism in several and diverse diseases (e.g. type 2 diabetes, atherosclerosis) often antedating them in apparently healthy subjects. The aim of this study is to investigate with a microarray based approach whether IR per se is characterized by a specific pattern of gene expression. For this purpose we analyzed the transcriptomic profile of peripheral blood mononuclear cells in two groups (10 subjects each) of healthy individuals, with extreme insulin resistance or sensitivity, matched for BMI, age and gender, selected within the MultiKnowledge Study cohort (n = 148). Data were analyzed with an ad-hoc rank-based classification method. 321 genes composed the gene set distinguishing the insulin resistant and sensitive groups, within which the "Adrenergic signaling in cardiomyocytes" KEGG pathway was significantly represented, suggesting a pattern of increased intracellular cAMP and Ca2+, and apoptosis in the IR group. The same pathway allowed to discriminate between insulin resistance and insulin sensitive subjects with BMI >25, supporting his role as a biomarker of IR. Moreover, ASCM pathway harbored biomarkers able to distinguish healthy and diseased subjects (from publicly available data sets) in IR-related diseases involving excitable cells: type 2 diabetes, chronic heart failure, and Alzheimer's disease. The altered gene expression profile of the ASCM pathway is an early molecular signature of IR and could provide a common molecular pathogenetic platform for IR-related disorders, possibly representing an important aid in the efforts aiming at preventing, early detecting and optimally treating IR-related diseases.

Stearic acid at physiologic concentrations induces in vitro lipotoxicity in circulating angiogenic cells.

BACKGROUND AND AIMS: Saturated free fatty acids (SFAs) can induce lipotoxicity in different cells. No studies have investigated the effects of SFA in circulating angiogenic cells (CACs), which play a key role in endothelial repair processes. The aim of the study was to assess the effects of SFAs, specifically stearic acid (SA), on viability and function of CACs and to investigate potential underlying molecular mechanisms. METHODS: CACs were isolated from healthy subjects by established methods. CACs were incubated with BSA-complexed stearate (100 µM) to assess the time course (from 8 to 24 h exposure) of the effects on viability and apoptosis (activation of caspases 3/7), angiogenic function (tube formation assay), pro-inflammatory cytokine (IL-1ß, IL-6, IL-8, MCP-1 and TNFα) gene expression (qPCR) and secretion (ELISA), activation of MAPK (JNK, p38 and Erk1/2) by Western blot and endoplasmic reticulum (ER) stress marker (CHOP, BIP, ATF4, XBP-1 and sXBP-1) gene expression by qPCR. RESULTS: Stearic acid activates effector caspases in CACs in a dose- and time-dependent manner. SA also impairs CAC function and increases pro-inflammatory molecule (IL-1ß, IL-6, IL-8, MCP-1 and TNFα) gene expression and secretion in CACs starting from 3 h of incubation. The activation of JNK by SA mediates pro-inflammatory response, but it may be not necessary for apoptosis. Moreover, SA induces the expression of ER stress markers across the three branches of the ER stress response. CONCLUSIONS: In humans, both function and viability of CACs are exquisitely vulnerable to physiologic concentrations of stearate; lipotoxic impairment of endothelial repair processes may be implicated in vascular damage caused by SFAs.

Claimed Effects, Outcome Variables and Methods of Measurement for Health Claims Proposed Under European Community Regulation 1924/2006 in the Framework of Maintenance of Skin Function.

Evidence suggests a protective role for several nutrients and foods in the maintenance of skin function. Nevertheless, all the requests for authorization to use health claims under Article 13(5) in the framework of maintenance of skin function presented to the European Food Safety Authority (EFSA) have received a negative opinion. Reasons for such failures are mainly due to an insufficient substantiation of the claimed effects, including the choice of inappropriate outcome variables (OVs) and methods of measurement (MMs). The present paper reports the results of an investigation aimed at collecting, collating and critically analyzing the information with relation to claimed effects (CEs), OVs and MMs related to skin health compliance with Regulation 1924/2006. CEs, OVs and MMs were collected from both the EFSA Guidance document and from the authorization requests of health claims under Article 13(5). The critical analysis of OVs and MMs was based on a literature review, and was aimed at defining their appropriateness (alone or in combination with others) in the context of a specific CE. The results highlight the importance of an adequate choice of OVs and MMs for an effective substantiation of the claims.

Dietary glycemic index and liver steatosis.

BACKGROUND: Insulin resistance (IR) and liver steatosis (LS) are interlinked metabolic derangements whose prevalence is rapidly increasing, but the effect of dietary carbohydrate quality on LS is unknown. OBJECTIVE: The objective was to describe the relation of IR and LS to total carbohydrate, total dietary fiber, and the glycemic index (GI) and glycemic load of the diet. DESIGN: The study was a cross-sectional evaluation of 247 apparently healthy subjects who had no evidence of viral, toxic, or autoimmune hepatitis and who were unselected for alcohol intake. The homeostasis model assessment index was used as a surrogate measure of IR, and a liver echography was used as a proxy for LS grading. Dietary data were collected by using 3-d food records. Total carbohydrate intake, total dietary fiber, GI, and glycemic load were calculated by using a semiquantitative food-frequency questionnaire concerning the dietary sources of carbohydrates. RESULTS: The prevalence of high-grade LS (HG-LS) increased significantly across quartiles of dietary GI (P for trend < 0.034): HG-LS in the 4th quartile (high GI) was twice that in the first 3 quartiles (low to medium GIs), whereas no relation was observed with total carbohydrates, total dietary fiber, or glycemic load. In insulin-sensitive subjects (first 3 quartiles of homeostasis model assessment index of IR), the prevalence of HG-LS did not differ significantly between GI groups, but, in insulin-resistant subjects (4th quartile of homeostasis model assessment index of IR), it was twice as high in those with high GI as in those with low to medium GIs (P = 0.005). CONCLUSIONS: High-GI dietary habits are associated with HG-LS, particularly in insulin-resistant subjects. Dietary advice on the quality of carbohydrate sources therefore may be a complementary tool for preventing or treating LS of metabolic origin.

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.

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.

Association of insulin resistance, hyperleptinemia, and impaired nitric oxide release with in-stent restenosis in patients undergoing coronary stenting.

BACKGROUND: Previously undiagnosed diabetes, impaired glucose tolerance, and insulin resistance are common in patients with acute myocardial infarction and coronary heart disease (CHD) and might be involved in early restenosis after stent implantation. To evaluate whether markers of insulin resistance syndrome, including leptin, and endothelial dysfunction are related to increased rate of early restenosis, we studied nondiabetic patients with CHD after successful coronary stenting. METHODS AND RESULTS: Both patients with CHD undergoing coronary stenting (120 patients) and control subjects (58 patients) were submitted to an oral glucose tolerance test (OGTT). Fasting leptin levels and fasting and postglucose load insulin sensitivity were assessed. Endothelial function was measured by nitrite and nitrate release (NOx) during OGTT. More than 50% of patients treated with stent implantation presented impaired glucose tolerance or type 2 diabetes, which was previously undiagnosed. These patients also had higher glucose, insulin, and leptin levels than control subjects. Among the stented patients, insulin and leptin levels were higher in patients with restenosis than in patients without restenosis. A significant increase in NOx levels was found during OGTT both in patients without restenosis and in control subjects. On the contrary, NOx profiles were blunted in patients with restenosis. At multiple regression analysis, only DeltaAUC-NOx areas and insulin sensitivity index showed an independent correlation with the minimal lumen diameter at follow-up. CONCLUSIONS: We demonstrated that insulin resistance and endothelial dysfunction are independent predictors of early restenosis after coronary stenting.