Prediction of mortality and major cardiovascular complications in type 2 diabetes: External validation of UK Prospective Diabetes Study outcomes model version 2 in two European observational cohorts.

AIM: To externally validate the UK Prospective Diabetes Study Outcomes Model version 2 (UKPDS-OM2) by comparing the predicted and observed outcomes in two European population-based cohorts of people with type 2 diabetes. MATERIALS AND METHODS: We used data from the Casale Monferrato Survey (CMS; n = 1931) and a subgroup of the Hoorn Diabetes Care System (DCS) cohort (n = 5188). The following outcomes were analysed: all-cause mortality, myocardial infarction (MI), ischaemic heart disease (IHD), stroke, and congestive heart failure (CHF). Model performance was assessed by comparing predictions with observed cumulative incidences in each cohort during follow-up. RESULTS: All-cause mortality was overestimated by the UKPDS-OM2 in both the cohorts, with a bias of 0.05 in the CMS and 0.12 in the DCS at 10 years of follow-up. For MI, predictions were consistently higher than observed incidence over the entire follow-up in both cohorts (10 years bias 0.07 for CMS and 0.10 for DCS). The model performed well for stroke and IHD outcomes in both cohorts. CHF incidence was predicted well for the DCS (5 years bias -0.001), but underestimated for the CMS cohort. CONCLUSIONS: The UKPDS-OM2 consistently overpredicted the risk of mortality and MI in both cohorts during follow-up. Period effects may partially explain the differences. Results indicate that transferability is not satisfactory for all outcomes, and new or adjusted risk equations may be needed before applying the model to the Italian or Dutch settings.

Peptides Derived From Insulin Granule Proteins Are Targeted by CD8+ T Cells Across MHC Class I Restrictions in Humans and NOD Mice.

The antigenic peptides processed by ß-cells and presented through surface HLA class I molecules are poorly characterized. Each HLA variant (e.g., the most common being HLA-A2 and HLA-A3) carries some peptide-binding specificity. Hence, features that, despite these specificities, remain shared across variants may reveal factors favoring ß-cell immunogenicity. Building on our previous description of the HLA-A2/A3 peptidome of ß-cells, we analyzed the HLA-A3-restricted peptides targeted by circulating CD8+ T cells. Several peptides were recognized by CD8+ T cells within a narrow frequency (1-50/106), which was similar in donors with and without type 1 diabetes and harbored variable effector/memory fractions. These epitopes could be classified as conventional peptides or neoepitopes, generated either via peptide cis-splicing or mRNA splicing (e.g., secretogranin-5 [SCG5]-009). As reported for HLA-A2-restricted peptides, several epitopes originated from ß-cell granule proteins (e.g., SCG3, SCG5, and urocortin-3). Similarly, H-2Kd-restricted CD8+ T cells recognizing the murine orthologs of SCG5, urocortin-3, and proconvertase-2 infiltrated the islets of NOD mice and transferred diabetes into NOD/scid recipients. The finding of granule proteins targeted in both humans and NOD mice supports their disease relevance and identifies the insulin granule as a rich source of epitopes, possibly reflecting its impaired processing in type 1 diabetes.

Dysfunctional eating in type 2 diabetes mellitus: A multicenter Italian study of socio-demographic and clinical associations.

BACKGROUND AND AIMS: Dysfunctional eating might impact on the management and metabolic control of type 2 diabetes (T2DM), modifying adherence to healthy diet and food choices. METHODS AND RESULTS: In a multicenter study, we assessed the prevalence of dysfunctional eating in 895 adult outpatients with T2DM (51% males, median age 67, median BMI 30.3 kg/m2). Socio-demographic and clinical characteristics were recorded; dysfunctional eating was tested by validated questionnaires (Eating Attitude Test-EAT-26, Binge Eating Scale-BES; Night Eating Questionnaire-NEQ); food intake and adherence to Mediterranean diet were also measured (in-house developed questionnaire and Mediterranean Diet Score-MDS). Obesity was present in 52% of cases (10% obesity class III), with higher rates in women; 22% had HbA1c ≥ 8%. The EAT-26 was positive in 19.6% of women vs. 10.2% of men; BES scores outside the normal range were recorded in 9.4% of women and 4.4% of men, with 3.0% and 1.5% suggestive of binge eating disorder, respectively. Night eating (NEQ) was only present in 3.2% of women and 0.4% of men. Critical EAT and BES values were associated with higher BMI, and all NEQ + ve cases, but one, were clustered among BES + ve individuals. Calorie intake increased with BES, NEQ, and BMI, and decreased with age and with higher adherence to Mediterranean diet. In multivariable logistic regression analysis, female sex, and younger age were associated with increase risk of dysfunctional eating. CONCLUSION: Dysfunctional eating is present across the whole spectrum of T2DM and significantly impacts on adherence to dietary restriction and food choices.

Conventional and Neo-antigenic Peptides Presented by ß Cells Are Targeted by Circulating Naïve CD8+ T Cells in Type 1 Diabetic and Healthy Donors.

Although CD8+ T-cell-mediated autoimmune ß cell destruction occurs in type 1 diabetes (T1D), the target epitopes processed and presented by ß cells are unknown. To identify them, we combined peptidomics and transcriptomics strategies. Inflammatory cytokines increased peptide presentation in vitro, paralleling upregulation of human leukocyte antigen (HLA) class I expression. Peptide sources featured several insulin granule proteins and all known ß cell antigens, barring islet-specific glucose-6-phosphatase catalytic subunit-related protein. Preproinsulin yielded HLA-A2-restricted epitopes previously described. Secretogranin V and its mRNA splice isoform SCG5-009, proconvertase-2, urocortin-3, the insulin gene enhancer protein ISL-1, and an islet amyloid polypeptide transpeptidation product emerged as antigens processed into HLA-A2-restricted epitopes, which, as those already described, were recognized by circulating naive CD8+ T cells in T1D and healthy donors and by pancreas-infiltrating cells in T1D donors. This peptidome opens new avenues to understand antigen processing by ß cells and for the development of T cell biomarkers and tolerogenic vaccination strategies.

The role of cannabinoid signaling in acute and chronic kidney diseases.

The endogenous cannabinoids anandamide and 2-arachidonoylglycerol bind to the cannabinoid receptors of type 1 and 2. These receptors are also the binding sites for exogenous, both natural and synthetic, cannabinoids that are used for recreation purposes. Until recently, cannabinoids and cannabinoid receptors have attracted little interest among nephrologists; however, a full endocannabinoid system (ECS) is present in the kidney and it has recently emerged as an important player in the pathogenesis of diabetic nephropathy, drug nephrotoxicity, and progressive chronic kidney disease. This newly established role of the ECS in the kidney might have therapeutic relevance, as pharmacological modulation of the ECS has renoprotective effects in experimental animals, raising hope for future potential applications in humans. In addition, over the last years, there has been a number of reported cases of acute kidney injury (AKI) associated with the use of synthetic cannabinoids that appear to have higher potency and rate of toxicity than natural Cannabis. This poorly recognized cause of renal injury should be considered in the differential diagnosis of AKI, particularly in young people. In this review we provide an overview of preclinical evidence indicating a role of the ECS in renal disease and discuss potential future therapeutic applications. Moreover, we give a critical update of synthetic cannabinoid-induced AKI.

Heat Shock Proteins in Vascular Diabetic Complications: Review and Future Perspective.

Heat shock proteins (HSPs) are a large family of proteins highly conserved throughout evolution because of their unique cytoprotective properties. Besides assisting protein refolding and regulating proteostasis under stressful conditions, HSPs also play an important role in protecting cells from oxidative stress, inflammation, and apoptosis. Therefore, HSPs are crucial in counteracting the deleterious effects of hyperglycemia in target organs of diabetes vascular complications. Changes in HSP expression have been demonstrated in diabetic complications and functionally related to hyperglycemia-induced cell injury. Moreover, associations between diabetic complications and altered circulating levels of both HSPs and anti-HSPs have been shown in clinical studies. HSPs thus represent an exciting therapeutic opportunity and might also be valuable as clinical biomarkers. However, this field of research is still in its infancy and further studies in both experimental diabetes and humans are required to gain a full understanding of HSP relevance. In this review, we summarize current knowledge and discuss future perspective.

NTproBNP in insulin-resistance mediated conditions: overweight/obesity, metabolic syndrome and diabetes. The population-based Casale Monferrato Study.

BACKGROUND AND AIMS: NTproBNP and BNP levels are reduced in obese subjects, but population-based data comparing the pattern of this relationship in the full spectrum of insulin-resistance mediated conditions, overweight/obesity, metabolic syndrome and diabetes, are limited. METHODS: The study-base were 3244 individuals aged 45-74 years, none of whom had heart failure, 1880 without diabetes and 1364 with diabetes, identified as part of two surveys of the population-based Casale Monferrato Study. All measurements were centralized. We examined with multiple linear regression and cubic regression splines the relationship between NTproBNP and BMI, independently of known risk factors and confounders. A logistic regression analysis was also performed to assess the effect of overweight/obesity (BMI ≥ 25 kg/m2), diabetes and metabolic syndrome on NTproBNP values. RESULTS: Out of the overall cohort of 3244 people, overweight/obesity was observed in 1118 (59.4%) non-diabetic and 917 (67.2%) diabetic subjects, respectively. In logistic regression, compared to normal weight individuals, those with a BMI ≥ 25 kg/m2 had a OR of 0.70 (95% CI 0.56-0.87) of having high NTproBNP values, independently of diabetes. As interaction between diabetes and NTproBNP was evident (p < 0.001), stratified analyses were performed. Diabetes either alone or combined with overweight/obesity or metabolic syndrome enhanced fourfold and over the OR of having high NTproBNP levels, while the presence of metabolic syndrome alone had a more modest effect (OR 1.54, 1.18-2.01) even after having excluded individuals with CVD. In the non-diabetic cohort, obesity/overweight and HOMA-IR ≥ 2.0 decreased to a similar extent the ORs of high NTproBNP [0.76 (0.60-0.95) and 0.74 (0.59-0.93)], but the association between overweight/obesity and NTproBNP was no longer significant after the inclusion into the model of HOMA-IR, whereas CRP > 3 mg/dl conferred a fully adjusted OR of 0.65 (0.49-0.86). CONCLUSIONS: NT-proBNP levels are lower in overweight/obesity, even in those with diabetes. Both insulin-resistance and chronic low-grade inflammation are involved in this relationship. Further intervention studies are required to clarify the potential role of drugs affecting the natriuretic peptides system on body weight and risk of diabetes.

Short term variation in NTproBNP after lifestyle intervention in severe obesity.

AIM: Natriuretic peptides are not only involved in cardiovascular adaption to various conditions, but also in metabolic diseases. We performed this study to assess the effect of a very short time of lifestyle inpatient intervention on NTproBNP values in normotensive subjects with severe obesity and normal cardiac function. METHODS: We recruited 14 consecutive obese normotensive subjects with normal cardiac function who were aged 30 years and more and were referred to inpatient rehabilitation in an academic clinic over a two months period. They were examined at baseline and after a 3-weeks program including dietary intervention with hypocaloric diet and assisted personalized physical aerobic and anaerobic activities and compared to age, sex and BMI-matched control subjects under usual care. RESULTS: BMI significantly decreased (40.8 ±1.6 vs 42.3 ± 1.6 kg/m2, p <0.0001). Median reduction in body weight was 4.9 kg (interquartile range 2.4-5.2 kg). After diet and exercise-induced weight loss, plasma NTproBNP levels showed an almost two-fold increase, which was statistically significant (28.2 ± 12.3 vs 17.2 ± 13.2 ng/L, p = 0.01), and particularly relevant in the subgroup with NT-proBNP values below median values compared to those with higher values (p = 0.02). No significant variations were found in control subjects (18.0 ± 13.0 vs 16.5 ± 11.2 ng/L, p = 0.18). The lipid profile was significantly ameliorated, and both HbA1c and insulin levels showed a marginally non-significant decrease after treatment. CONCLUSIONS: An almost two-fold increase in NTproBNP levels was evident after a very short time period of lifestyle intervention in normotensive severe obese patients without cardiac disease. This finding might have clinical relevance, considering the role of NT-proBNP as risk factor of impaired glucose tolerance.

Incidence of prolonged QTc and severe hypoglycemia in type 1 diabetes: the EURODIAB Prospective Complications Study.

AIMS: To assess the independent role of severe hypoglycemia on 7-year cumulative incidence of prolonged QTc in a large cohort of patients with type 1 diabetes. METHODS: People with type 1 diabetes recruited by the EURODIAB Prospective Complications Study who had normal QTc were examined at baseline and after 7 years with standardized methods (n = 1415; mean age ± SD 32.1 ± 9.6 years; diabetes duration 14.2 ± 8.8 years). Hypoglycemic episodes were assessed by a questionnaire. QTc was calculated according to Bazett's formula. In logistic regression analysis, we examined the role of severe hypoglycemia (none, 1-2, or 3 and more episodes/year) on the cumulative incidence of prolonged QTc, independently of age, sex, HbA1c, blood pressure, BMI, physical activity, distal symmetrical and autonomic neuropathy. RESULTS: In total, 264/1415 (17%) patients had incident prolonged QTc. Compared to those with persistently normal QTc, a greater proportion of incident cases had 3 and more hypoglycemic episodes at baseline (16.3 vs 11.2%, p = 0.03) and after 7 years (15.2 vs 9.6%, p = 0.01). In logistic regression analysis, 3 or more episodes of severe hypoglycemia at baseline did not increase cumulative incidence of prolonged QTc (OR 1.34, 95% CI 0.88-2.03). By contrast, severe hypoglycemia at the follow-up examination was associated with higher incidence of QTc prolongation (OR 1.68, 1.09-2.58), which reverted to not significant after adjustment for diabetic neuropathy. CONCLUSIONS: Severe hypoglycemia was not associated with incidence QTc prolongation in type 1 diabetic patients from the EURODIAB PCS.

Dual therapy targeting the endocannabinoid system prevents experimental diabetic nephropathy.

BACKGROUND: The endocannabinoid system has been implicated in the pathogenesis of diabetic nephropathy (DN). We investigated the effect of combined therapy with AM6545, a 'peripherally' restricted cannabinoid receptor type 1 (CB1R) neutral antagonist, and AM1241, a cannabinoid receptor type 2 (CB2R) agonist, in experimental DN. METHODS: Renal function and structure, podocyte proteins and markers of both fibrosis and inflammation were studied in streptozotocin-induced diabetic mice treated for 14 weeks with vehicle, AM6545, AM1241 and AM6545-AM1241. RESULTS: Single treatment with either AM6545 or AM1241 alone reduced diabetes-induced albuminuria and prevented nephrin loss both in vivo and in vitro in podocytes exposed to glycated albumin. Dual therapy performed better than monotherapies, as it abolished albuminuria, inflammation, tubular injury and markedly reduced renal fibrosis. Converging anti-inflammatory mechanisms provide an explanation for this greater efficacy as dual therapy abolished diabetes-induced renal monocyte infiltration and M1/M2 macrophage imbalance in vivo and abrogated the profibrotic effect of M1 macrophage-conditioned media on cultured mesangial cells. CONCLUSION: 'Peripheral' CB1R blockade is beneficial in experimental DN and this effect is synergically magnified by CB2R activation.

MicroRNA-126 and micro-/macrovascular complications of type 1 diabetes in the EURODIAB Prospective Complications Study.

AIMS: Increasing evidence suggests a potential role of circulating miRNAs as clinical biomarkers, and loss of miRNA-126 has been proposed as a predictor of type 2 diabetes onset. However, a systematic analysis of circulating miRNAs in type 1 diabetic patients with micro-/macrovascular complications has not yet been performed. METHODS: A cross-sectional nested case-control study from the EURODIAB Prospective Complications Study of 455 type 1 diabetic patients was performed. Case subjects (n = 312) were defined as those with one or more complications of diabetes; control subjects (n = 143) were those with no evidence of any complication. A differential miRNA expression profiling was performed in pooled serum samples from cases and controls. Furthermore, miR-126 levels were quantified by qPCR in all individual samples and associations with diabetic complications investigated. RESULTS: Twenty-five miRNAs differed in pooled samples from cases and controls. miR-126 levels were significantly lower in case than in control subjects, even after adjustment for age and sex. In logistic regression analyses, miR-126 was negatively associated with all complications (OR = 0.85, 95 % CI 0.75-0.96) as well as with each micro-/macrovascular complication examined separately. This was likely dependent of diabetes as associations were no longer significant after adjustment for both hyperglycemia and diabetes duration. However, a significant 25 % risk reduction, independent of age, sex, A1C, and diabetes duration, was still observed for proliferative retinopathy (OR = 0.75, 95 % CI 0.59-0.95). CONCLUSIONS: In this large cohort of type 1 diabetic subjects, we found that miR-126 levels are associated with vascular complications of diabetes, particularly with proliferative retinopathy.

Is the choice of the statistical model relevant in the cost estimation of patients with chronic diseases? An empirical approach by the Piedmont Diabetes Registry.

BACKGROUND: Chronic diseases impose large economic burdens. Cost analysis is not straightforward, particularly when the goal is to relate costs to specific patterns of covariates, and to compare costs between diseased and healthy populations. Using different statistical methods this study describes the impact on results and conclusions of analyzing health care costs in a population with diabetes. METHODS: Direct health care costs of people living in Turin were estimated from administrative databases of the Regional Health System. Patients with diabetes were identified through the Piedmont Diabetes Registry. The effect of diabetes on mean annual expenditure was analyzed using the following multivariable models: 1) an ordinary least squares regression (OLS); 2) a lognormal linear regression model; 3) a generalized linear model (GLM) with gamma distribution. Presence of zero cost observation was handled by means of a two part model. RESULTS: The OLS provides the effect of covariates in terms of absolute additive costs due to the presence of diabetes (€ 1,832). Lognormal and GLM provide relative estimates of the effect: the cost for diabetes would be six fold that for non diabetes patients calculated with the lognormal. The same data give a 2.6-fold increase if calculated with the GLM. Different methods provide quite different estimated costs for patients with and without diabetes, and different costs ratios between them, ranging from 3.2 to 5.6. CONCLUSIONS: Costs estimates of a chronic disease vary considerably depending on the statistical method employed; therefore a careful choice of methods to analyze data is required before inferring results.

Zinc and Other Metals Deficiencies and Risk of Type 1 Diabetes: An Ecological Study in the High Risk Sardinia Island.

BACKGROUND: Type 1 diabetes incidence presents a decreasing gradient in Europe from the Nordic countries to the Mediterranean ones. Exception to this gradient is represented by Sardinia, the second largest Mediterranean island whose population shows the highest incidence in Europe, after Finland. The genetic features of this population have created a fertile ground for the epidemic of the disease, however, as well as being strikingly high, the incidence rate has suddenly presented a continuous increase from the '50s, not explainable by accumulation of new genetic variants. Several environmental factors have been taken into account, possibly interacting with the genetic/epigenetic scenario, but there are no strong evidences to date. METHODS: The present study investigated the hypothesis that geochemical elements could create permissive environmental conditions for autoimmune diabetes. An ecological analysis was performed to test possible correlations between the values of eight elements in stream sediments and type 1 diabetes incidence rate in Sardinia. RESULTS: Analyses revealed negative associations between elements, such as Co, Cr, Cu, Mn, Ni, Zn, and type 1 diabetes incidence. CONCLUSIONS: The results suggest a possible protective role of some elements against the onset of the disease.

Prevalence of metabolic syndrome in the clinical practice of general medicine in Italy.

BACKGROUND: Prevalence of metabolic syndrome (MS) in the clinical practice is still debated, due to different diagnostic criteria, target populations and clinical settings. Thus, the main purposes of the study were: (I) to evaluate prevalence of MS; (II) to estimate prevalence of additional cardiovascular (CV) risk factors and concomitant conditions in patients with MS followed by general practitioners (GPs) in Italy. METHODS: GPs from three different macro-areas were asked to evaluate the first and the last three outpatients, consecutively seen during 20 consecutive weeks in 2007, whatever the reason for clinical consultation. MS was defined according to Adult Treatment Panel (ATP) III definition. Clinical data were collected locally and centrally analysed. RESULTS: The overall population sample included 4,513 outpatients, among which 1,574 (34.9%) from Regione Lazio, 1,498 (33.2%) from Regione Piemonte, and 1,441 (31.9%) from Regione Umbria. The population analysis included 4,418 (97.9%) adult outpatients [52.1% females, (mean age, 58.0±11.8 years); mean body mass index (BMI), 26.7±4.7 kg/m(2)]. MS was diagnosed in 1,456 (33.0%) outpatients. High-normal blood pressure (BP) was the most common risk factor for MS (n=1,382; 94.9%), followed by abdominal obesity (n=1,229; 84.4%), hypertriglyceridemia (n=1,032; 70.9%), abnormal fasting glucose (n=819; 56.3%) and low high-density lipoprotein (HDL) cholesterol levels (n=730; 50.1%). CONCLUSIONS: Using this sample of outpatients followed by GPs in Italy, our study reports a relatively high prevalence of MS and a high prevalence of associated CV and metabolic risk factors in patients with than in those without MS.

Vitamin D levels at birth and risk of type 1 diabetes in childhood: a case-control study.

AIMS: To assess whether vitamin D levels at birth were associated with risk of having type 1 diabetes up to 10 years of age and the potential modifier effect of ethnic group. METHODS: The Piedmont Diabetes Registry and the Newborn Screening Regional data were linked to identify cases (n = 67 incident children aged ≤10 years at diabetes onset, 2002-2012) and up to five controls (n = 236) matched for birthday and ethnic group. Cards with neonatal blood spot were used and 25-hydroxyvitamin D(3) assessed with tandem mass spectroscopy. RESULTS: In conditional logistic regression, OR for unit increment of log vitamin D was 0.78 (95 % CI 0.56-1.10). Vitamin D was significantly lower in migrant than in Italian control newborn babies (p < 0.0001), and interaction between vitamin D and migrant status was statistically significant (p = 0.04). Compared to migrant newborns babies with vitamin D ≥ 2.14 ng/ml, migrants with lower levels had an OR of 14.02 (1.76-111.70), whereas no association was evident in Italians. CONCLUSIONS: Our case-control study within the Piedmont Diabetes Registry showed no association between vitamin D levels at birth and risk of having type 1 diabetes up to 10 years of age, apart from the subgroup of migrant babies, which might have clinical implications if confirmed.

What is the impact of sleeve gastrectomy and gastric bypass on metabolic control of diabetes? A clinic-based cohort of Mediterranean diabetic patients.

BACKGROUND: Effectiveness of sleeve gastrectomy and gastric bypass on glycemic, blood pressure, and lipids control in obese type 2 diabetic patients is poorly known. OBJECTIVE: To assess the effectiveness of bariatric surgery on obese patients with type 2 diabetes. SETTING: University hospital, Italy. METHODS: Diabetes remission and metabolic changes over postoperative follow-up were assessed in 135 obese patients with type 2 diabetes who underwent bariatric surgery in 2007-2011 (gastric bypass, n = 100; sleeve gastrectomy, n = 35). Repeated-measures analysis of variance and logistic regression were used. RESULTS: Diabetes remission was observed in 22% and 21.5% of the patients, respectively, 1 and 2 years after surgery. Compared with the remaining patients, patients in diabetes remission were significantly younger, had lower diabetes duration, hemoglobin A1c (HbA1c), fasting plasma glucose, and frequency of insulin treatment. Trends of HbA1c, body mass index (BMI), blood pressure, and plasma triglycerides revealed a significant decrease over time and the trend of HDL-cholesterol revealed a significant increase over time in both treatment groups (P<.001). Patients reaching target levels for at least 3 out of 5 indicators of intermediate outcomes of care (composite indicator of good diabetes control) were 25.5% at the baseline and 66.1% at final follow-up visit (P<.001). In logistic regression, age (OR = .89, 95% CI .84-.95), HbA1c (OR = .67, 95% CI .49-0.91) and diabetes duration (OR = .87, 95% CI .77-1.00) were independent predictors of diabetes remission. CONCLUSIONS: Bariatric surgery is an effective approach to optimize glucose, lipids, and blood pressure control in obese type 2 diabetic patients. Bariatric surgery should be offered earlier over the natural course of diabetes to increase the likelihood of diabetes remission in obese patients.

Investigating obesity among professional drivers: the high risk professional driver study.

OBJECTIVE: The aim of this study is to detect the main individual and transportation factors associated with obesity and its prevalence among Italian professional drivers (PDs). METHODS: We performed a cross-sectional questionnaire survey. Data from PDs (n = 497) were used for analyses. RESULTS: Sixty-one percent of participants were either overweight or obese according to their body mass index. Predictive factors for obesity were traveling more than 40,000 miles per year (odds ratio [OR] 4.20, confidence interval [CI] 1.41-12.56) and hours spent behind the wheel per day (OR 1.27, CI 1.02-1.58). Bus drivers had half the risk of being obese compared to truck drivers (OR 0.45, CI 0.23-0.87). An inverse association was detected between educational attainment and obesity (OR 0.32, CI 0.11-0.90). CONCLUSIONS: PDs with high number of driving hours per day, miles driven per year, and low educational level should be subject to special educational programs to reduce and prevent obesity.

Levels of N-terminal pro brain natriuretic peptide are enhanced in people with the uncomplicated metabolic syndrome: a case-cohort analysis of the population-based Casale Monferrato study.

BACKGROUND: Both metabolic syndrome (MetS) and N-amino terminal fragment of the prohormone B-type natriuretic peptide (NT-proBNP) confer increased risk of cardiovascular diseases (CVD). We assessed if NT-proBNP levels were greater in people with uncomplicated MetS, who had neither CVD/chronic kidney disease (CKD) nor diabetes, as compared with subjects who met none of the defining criteria of the MetS. METHODS: A case-cohort study from the non-diabetic population-based Casale Monferrato study was performed, after exclusion of all subjects with established CVD, CKD [estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m(2)], and CRP values ≥3 mg/L. Cases (n = 161) with MetS were compared with all subjects within the cohort (n = 124) who were completely free of any component of the MetS. Serum NT-proBNP was centrally measured by immunoenzymatic assay. RESULTS: NT-proBNP levels were significantly higher in cases than in control subjects [35.4 (15.5-98.2) vs 24.4 (11.7-49.6) pg/mL, p = 0.014]. In logistic regression analysis, compared with NT-proBNP values in the lower quartiles (≤49.64 pg/mL), higher values conferred odds ratio 4.17 (1.30-13.44) of having the MetS, independently of age, sex, microalbuminuria, CRP, eGFR, and central obesity. This association was evident even after the exclusion of hypertensive subjects. Further adjustment for log-HOMA and diastolic blood pressure did not modify the strength of the association, while central obesity was a negative confounder. CONCLUSIONS: Compared with people without any component of the MetS, those with uncomplicated MetS, who had neither CVD/CKD nor diabetes, had increased NT-proBNP values, even if they were normotensive and although absolute values were still in the low range. The insulin resistance state did not mediate this association, while central obesity was a negative confounder.

Inflammation in diabetic nephropathy: moving toward clinical biomarkers and targets for treatment.

Diabetic nephropathy (DN) is a leading cause of end stage renal failure and there is an urgent need to identify new clinical biomarkers and targets for treatment to effectively prevent and slow the progression of the complication. Many lines of evidence show that inflammation is a cardinal pathogenetic mechanism in DN. Studies in animal models of experimental diabetes have demonstrated that there is a low-grade inflammation in the diabetic kidney. Both pharmacological and genetic strategies targeting inflammatory molecules have been shown to be beneficial in experimental DN. In vitro studies have cast light on the cellular mechanisms whereby diabetes triggers inflammation and in turn inflammation magnifies the kidney injury. Translation of this basic science knowledge into potential practical clinical applications is matter of great interest for researchers today. This review focuses on key pro-inflammatory systems implicated in the development of DN: the tumor necrosis factor(TNF)-α/TNF-α receptor system, the monocyte chemoattractant protein-1/CC-chemokine receptor-2 system, and the Endocannabinoid system that have been selected as they appear particularly promising for future clinical applications.