Protective effect of the tunneling nanotube-TNFAIP2/M-sec system on podocyte autophagy in diabetic nephropathy.

Podocyte injury leading to albuminuria is a characteristic feature of diabetic nephropathy (DN). Hyperglycemia and advanced glycation end products (AGEs) are major determinants of DN. However, the underlying mechanisms of podocyte injury remain poorly understood. The cytosolic protein TNFAIP2/M-Sec is required for tunneling nanotubes (TNTs) formation, which are membrane channels that transiently connect cells, allowing organelle transfer. Podocytes express TNFAIP2 and form TNTs, but the potential relevance of the TNFAIP2-TNT system in DN is unknown. We studied TNFAIP2 expression in both human and experimental DN and the renal effect of tnfaip2 deletion in streptozotocin-induced DN. Moreover, we explored the role of the TNFAIP2-TNT system in podocytes exposed to diabetes-related insults. TNFAIP2 was overexpressed by podocytes in both human and experimental DN and exposre of podocytes to high glucose and AGEs induced the TNFAIP2-TNT system. In diabetic mice, tnfaip2 deletion exacerbated albuminuria, renal function loss, podocyte injury, and mesangial expansion. Moreover, blockade of the autophagic flux due to lysosomal dysfunction was observed in diabetes-injured podocytes both in vitro and in vivo and exacerbated by tnfaip2 deletion. TNTs allowed autophagosome and lysosome exchange between podocytes, thereby ameliorating AGE-induced lysosomal dysfunction and apoptosis. This protective effect was abolished by tnfaip2 deletion, TNT inhibition, and donor cell lysosome damage. By contrast, Tnfaip2 overexpression enhanced TNT-mediated transfer and prevented AGE-induced autophagy and lysosome dysfunction and apoptosis. In conclusion, TNFAIP2 plays an important protective role in podocytes in the context of DN by allowing TNT-mediated autophagosome and lysosome exchange and may represent a novel druggable target.Abbreviations: AGEs: advanced glycation end products; AKT1: AKT serine/threonine kinase 1; AO: acridine orange; ALs: autolysosomes; APs: autophagosomes; BM: bone marrow; BSA: bovine serum albumin; CTSD: cathepsin D; DIC: differential interference contrast; DN: diabetic nephropathy; FSGS: focal segmental glomerulosclerosis; HG: high glucose; KO: knockout; LAMP1: lysosomal-associated membrane protein 1; LMP: lysosomal membrane permeabilization; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; PI3K: phosphoinositide 3-kinase; STZ: streptozotocin; TNF: tumor necrosis factor; TNFAIP2: tumor necrosis factor, alpha-induced protein 2; TNTs: tunneling nanotubes; WT: wild type.

Reversal of albuminuria by combined AM6545 and perindopril therapy in experimental diabetic nephropathy.

BACKGROUND AND PURPOSE: The endocannabinoid (EC) system has been implicated in the pathogenesis of diabetic nephropathy (DN). We investigated the effects of peripheral blockade of the cannabinoid CB1 receptor as an add-on treatment to ACE-inhibition in type 1 diabetic mice (DM) with established albuminuria. EXPERIMENTAL APPROACH: Renal functional parameters (albumin excretion rate, creatinine clearance), tubular injury, renal structure, both EC and CB receptor levels and markers of podocyte dysfunction, fibrosis and inflammation were studied in streptozotocin-induced DM treated for 14 weeks with vehicle, the ACE-inhibitor perindopril (2 mg·kg-1 ·day-1 ), peripherally-restricted CB1 receptor antagonist AM6545 (10 mg·kg-1 ·day-1 ) or both. Treatments began at 8 weeks after diabetes onset, when early DN is established. KEY RESULTS: CB1 receptors were overexpressed in DM and neither perindopril nor AM6545 altered this effect, while both drugs abolished diabetes-induced overexpression of angiotensin AT1 receptors. Single treatment with either AM6545 or perindopril significantly reduced progression of albuminuria, down-regulation of nephrin and podocin, inflammation and expression of markers of fibrosis. However, reversal of albuminuria was only observed in mice administered both treatments. The ability of the combination therapy to completely abolish slit diaphragm protein loss, monocyte infiltration, overexpression of inflammatory markers and favour macrophage polarization towards an M2 phenotype may explain this greater efficacy. In vitro experiments confirmed that CB1 receptor activation directly inhibits retinoic acid-induced nephrin expression in podocytes and IL-4-induced M2 polarization in macrophages. CONCLUSION AND IMPLICATIONS: Peripheral CB1 receptor blockade used as add-on treatment to ACE-inhibition reverses albuminuria, nephrin loss and inflammation in DM.

Impaired taste sensation in type 2 diabetic patients without chronic complications: a case-control study.

PURPOSE: Few and contradictory data suggest changes in taste perception in type 2 diabetes (T2DM), potentially altering food choices. We, therefore, analyzed taste recognition thresholds in T2DM patients with good metabolic control and free of conditions potentially impacting on taste, compared with age-, body mass index-, and sex-matched normoglycemic controls. METHODS: An ascending-concentration method was used, employing sucrose (sweet), sodium chloride (salty), citric acid (sour), and quinine hydrochloride (bitter), diluted in increasing concentration solutions. The recognition threshold was the lowest concentration of correct taste identification. RESULTS: The recognition thresholds for the four tastes were higher in T2DM patients. In a multiple regression model, T2DM [ß = 0.95; 95% CI 0.32-1.58; p = 0.004 (salty); ß = 0.61; 0.19-1.03; p = 0.006 (sweet); ß = 0.78; 0.15-1.40; p = 0.016 (sour); ß = 0.74; 0.22-1.25; p = 0.006 (bitter)] and waist circumference [ß = 0.05; 0.01-0.08; p = 0.012 (salty); ß = 0.03; 0.01-0.05; p = 0.020 (sweet); ß = 0.04; 0.01-0.08; p = 0.020 (sour); ß = 0.04; 0.01-0.07; p = 0.007 (bitter)] were associated with the recognition thresholds. Age was associated with salty (ß = 0.06; 0.01-0.12; p = 0.027) and BMI with sweet thresholds (ß = 0.06; 0.01-0.11; p = 0.019). CONCLUSIONS: Taste recognition thresholds were higher in uncomplicated T2DM, and central obesity was significantly associated with this impairment. Hypogeusia may be an early sign of diabetic neuropathy and be implicated in the poor compliance of these patients to dietary recommendations.

The acute impact of the intake of four types of bread on satiety and blood concentrations of glucose, insulin, free fatty acids, triglyceride and acylated ghrelin. A randomized controlled cross-over trial.

The purpose of the present study is to compare the effects of four different breads (one commercial par-baked wheat bread, three sourdough breads prepared with commercial wheat flour, organic wheat flour, organic einkorn flour) in 16 healthy subjects. The primary outcome of this randomized cross-over trial was evaluating intra-individual changes in glycemic areas-under-the-curve (AUCs) after 50g carbohydrate portions of each bread; secondary outcomes were changes in insulin, fatty free acids (FFA), triglyceride, acylated ghrelin and satiety AUCs. Blood samples and satiety ratings were collected every 30-min for 2-h after the consumption of each bread. The einkorn flour showed the lowest amylase activity, the commercial flour the highest; commercial bread had the highest carbohydrate content and the lowest dietary fiber content. Glucose AUCs were significantly lower after the consumption of sourdough breads made with organic (12,754±1433mg/dL×h) and einkorn flour (12,216±1210mg/dL×h), with respect to the commercial bread (13,849±2193mg/dL×h). Insulin AUCs decreased after the consumption of all sourdough breads when compared to commercial bread. FFA and triglyceride AUCs did not differ by kind of breads. Median ghrelin AUC was significantly lower and satiety higher after the einkorn bread (3710pg/mL×h; 3225±2414, respectively) than after commercial bread consumption (4140pg/mL×h; 1706±1766, respectively), but not with other sourdough breads. In conclusion, the use of sourdough may improve the nutritional features of breads; einkorn bread induced the least disturbance in carbohydrate homeostasis and the greater satiety. If confirmed by further research, these results might have implications in the approach towards chronic dysmetabolic diseases.

Effects of 6 months of resveratrol versus placebo on pentraxin 3 in patients with type 2 diabetes mellitus: a double-blind randomized controlled trial.

AIMS: The anti-inflammatory effects of the polyphenol resveratrol in patients with type 2 diabetes mellitus (T2DM) are controversial. Its role on pentraxin 3 (PTX3) concentrations, a human acute phase protein, has never been evaluated. Our aim was to determine whether a two-dosage resveratrol supplementation (500 and 40 mg/day) has an impact on PTX3 values in T2DM patients from a double-blind randomized placebo-controlled trial. Variations in total antioxidant status (TAS) were evaluated too. METHODS: A total of 192 T2DM patients were randomized to receive resveratrol 500 mg/day (Resv 500 arm), resveratrol 40 mg/day (Resv 40 arm) or placebo for 6 months. At baseline and at the trial end, PTX3 and TAS values were determined. RESULTS: A dose-dependent increase in PTX3 concentrations of 4.7% (Resv 40 arm) and 26.3% (Resv 500 arm), and 8.0% reduction after placebo were found. Adjusted mean differences of change versus placebo were 0.16 (95% CI 0.01-0.32) and 0.25 (0.09-0.42) in the Resv 40 and Resv 500 arms, respectively. At subgroup analyses, lower diabetes duration, aspirin, alcohol use, younger age, female gender, smoking (Resv 500 arm) and female gender and aspirin use (Resv 40 arm) were associated with higher PTX3 increments. A dose-dependent increment in TAS values in the resveratrol arms (1.4 and 6.4% for Resv 40 and Resv 500, respectively), and a reduction in placebo arm (-8.9%) were observed. Adjusted mean differences of change were 28.5 (95% CI 10.1-46.8) and 44.8 (25.4-64.1) in the Resv 40 and Resv 500 arms, respectively. CONCLUSION: Resveratrol supplementation increased PTX3 and TAS levels in a dose-dependent manner in T2DM patients. At present, potential clinical implications of these results remain unclear. CLINICALTRIALS. GOV IDENTIFIER: NCT02244879.

Six months of resveratrol supplementation has no measurable effect in type 2 diabetic patients. A randomized, double blind, placebo-controlled trial.

The polyphenol resveratrol is considered to exert many beneficial actions, such as antioxidant, anti-inflammatory, insulin-sensitizer and anticancer effects. Its benefits in patients with type 2 diabetes mellitus (T2DM) are controversial. Our aims were to determine whether resveratrol supplementation at two different dosages (500 and 40mg/day) for 6 months i) reduced the concentrations of C-reactive-protein (CRP) and ii) ameliorated the metabolic pattern of T2DM patients. In the present double-blind, randomized, placebo-controlled trial, 192 T2DM patients were randomized to receive resveratrol 500mg/day (Resv500arm), resveratrol 40mg/day (Resv40arm) or placebo for 6-months. At baseline and at the trial end, CRP values, anthropometric, metabolic and liver parameters were determined. No serious adverse event occurred. A dose-dependent, though not significant, CRP decrease of 5.6% (Resv40arm) and 15.9% (Resv500arm) was observed vs placebo. We failed to detect significant differences in weight, BMI, waist circumference, and values of arterial blood pressure, fasting glucose, glycated hemoglobin, insulin, C-peptide, free fatty acids, liver transaminases, uric acid, adiponectin, interleukin-6, in both the Resv500 and Resv40 arms vs placebo. Total cholesterol and triglycerides slightly increased in the Resv500arm. Subgroup analyses revealed that lower diabetes duration (in both Resv500 and Resv40arms), and, in the Resv500arm, younger age, aspirin use and being a smoker were associated with a significantly higher CRP reduction vs placebo. The supplementations with 40mg/day or 500mg/day resveratrol did neither reduce CRP concentrations, nor improve the metabolic pattern of T2DM patients.

High-normal blood pressure and impaired renal function. A prospective study in a population-based cohort.

AIM: The association between high-normal blood pressure and the impairment of renal function is highly controversial. We analysed the contribution of high-normal blood pressure on incident impaired renal function. METHODS: The study was performed in a population-based cohort of 1307 subjects free of diabetes, cardiovascular and renal disease at baseline, who attended both at baseline and after 6-year follow-up a metabolic screening. The outcome was incident impaired renal function, defined as a glomerular filtration rate <60 mL/min/1.73 m2. RESULTS: Incidence of impaired renal function was 2.5%, 4.5%, 8.7% and 10.8% in optimal, normal, high-normal blood pressure and hypertension, respectively. Adjusted relative odds ratio (OR) of impaired renal function were modelled using logistic regression analyses including multiple confounders. The adjusted OR were 1.6 (95% CI 0.5-5.0) for normal blood pressure, 3.4 (1.2-10.3) for high-normal blood pressure and 3.7 (1.3-10.7) for hypertension. Results were similar after excluding overweight or obese patients. CONCLUSION: High-normal blood pressure is an independent predictor of impaired renal function. Trials are warranted to test if therapeutic intervention on blood pressure is justified also in subjects with high-normal blood pressure to preserve renal function.

Simple lifestyle recommendations and the outcomes of gestational diabetes. A 2 × 2 factorial randomized trial.

The benefits of exercise and behavioural recommendations in gestational diabetes mellitus (GDM) are controversial. In a randomized trial with a 2 × 2 factorial design, we examined the effect of exercise and behavioural recommendations on metabolic variables, and maternal/neonatal outcomes in 200 GDM patients. All women were given the same diet: group D received dietary recommendations only; group E was advised to briskly walk 20-min/day; group B received behavioural dietary recommendations; group BE was prescribed the same as B + E. Dietary habits improved in all groups. In a multivariable regression model, fasting glucose did not change. Exercise, but not behavioural recommendations, was associated with the reduction of postprandial glucose (p < 0001), glycated haemoglobin (HbA1c; p < 0.001), triglycerides (p = 0.02) and C-reactive protein (CRP; p < 0.001) and reduced any maternal/neonatal complications (OR = 0.50; 95%CI=0.28-0.89;p = 0.02). In GDM patients a simple exercise programme reduced maternal postprandial glucose, HbA1c, CRP, triglycerides and any maternal/neonatal complications, but not fasting glucose values.

Diabetes-specific variables associated with quality of life changes in young diabetic people: the type 1 diabetes Registry of Turin (Italy).

BACKGROUND AND AIMS: Type 1 diabetes (T1DM) affects young people during the most active years of their life. Our aim was to assess quality of life (QoL) and associated variables in a large cohort of adults with childhood-onset and adult-onset T1DM. METHODS: A cohort of adult patients (18 years and older) from the T1DM Registry of Turin, Italy, was recruited. Clinical characteristics and Diabetes QoL (DQOL) questionnaire were assessed by standardized procedures. RESULTS: 310 adults completed the questionnaire. Age and diabetes duration at assessment (mean ± SD) were 32.8 ± 7.3 years and 17.3 ± 6.3 years, respectively. DQOL and its subscores were in the lower quartiles of their distributions, indicating a good level of QoL. However, scores were significantly higher in females than in males, particularly for the subscale of diabetes-related worries. In multivariate analysis, lower QoL was independently associated with female sex (ß = 1.07, 95% CI 1.03-1.11, p = 0.003), higher age at onset (ß = 1.03, 1.00-1.05, p = 0.009), lower schooling (ß = 1.05, 1.00-1.09, p = 0.02), higher fasting plasma glucose (ß = 1.03, 1.01-1.05, p = 0.008), daily SMBG >4 (ß = 1.06, 1.01-1.10, p = 0.01), severe hypoglycemia over the last year (ß = 1.06, 1.01-1.11, p = 0.02), lower numbers of diabetologic visits (ß = 1.07, 1.01-1.13, p = 0.02) and hypertension (ß = 1.06, 1.02-1.10, p = 0.005). Autonomic neuropathy was associated with diabetes impact. Female sex (ß = 4.36, 2.43-7.83) and daily SMBG >4 (ß = 3.77, 1.72-8.30) were independently associated with worst level and CSII with better level (ß = 0.22, 0.07-0.68) of diabetes-related worries. CONCLUSIONS: The impact of T1DM on QoL may depend on demographic, metabolic control-related variables, presence of complications and insulin delivery modality.

Variations of serum levels of adiponectin and resistin in chronic viral hepatitis.

BACKGROUND AND AIMS: Several studies investigated the possible role of adipokines during chronic viral hepatitis, not producing defined results neither clearly establishing their behavior in course of anti-viral treatment. Our study evaluated blood concentrations of adiponectin and resistin in patients with chronic hepatitis C (CHC), B (CHB), and D (CHD) receiving anti-viral treatment, at baseline and after therapy. METHODS: We examined 122 subjects, divided into two groups: 64 patients with chronic hepatitis C virus (HCV) infection (38 males and 26 females, mean age 47.25 yr) and 58 patients including 39 ones with chronic hepatitis B virus (HBV) infection (26 males and 13 females, mean age 48.46 yr) and 19 ones with chronic HBV-hepatitis D virus (HDV) infection (15 males and 4 females, mean age 45.79 yr). Serum levels of adiponectin and resistin were assayed by enzyme-linked immunosorbent assay. RESULTS: In the group of CHC patients we observed a significant decrease in resistin after therapy (p=0.006), while not a significant increase in adiponectin after treatment (p=0.32). Evaluation of changes in adiponectin and resistin levels after anti-viral treatment, both in responders and non-responders, revealed no significant variations. In the group of HBV+ and HBV-HDV+ patients, we found a decrease in resistin after therapy (p=0.0016) and a not significant reduction in adiponectin after treatment (p=0.13). Furthermore, we noticed a significant reduction of resistin (p=0.006) in the sub-group of responders. CONCLUSIONS: Our data suggested the possible marker role of adiponectin and resistin in the inflammatory process in course of chronic viral hepatitis.

Association of obstructive sleep apnoea with the presence and severity of non-alcoholic fatty liver disease. A systematic review and meta-analysis.

Obstructive sleep apnoea syndrome (OSAS) and non-alcoholic fatty liver disease (NAFLD) are common in clinical practice. NAFLD encompasses simple steatosis and non-alcoholic steatohepatitis (NASH): both confer an increased risk of cardiovascular disease and diabetes; NASH increases also liver-related risk. Growing experimental evidence connects chronic intermittent hypoxia of OSAS to NAFLD. We reviewed English and non-English articles and international meeting abstracts through December 2012. Observational studies were included if they assessed OSAS by polysomnography and NAFLD by histological, radiological or biochemical criteria. Two reviewers evaluated retrieved articles by appropriate quality scores. Main outcomes were pooled using random- or fixed-effects models. The effect of age, sex and body mass index (BMI) on effect estimates was assessed by meta-regression. Eighteen cross-sectional studies (2,183 participants) were included. Pooled odds ratios (ORs) of OSAS for the presence of NAFLD, as defined by histology, radiology, and AST or ALT elevation, were 2.01(95% CI: 1.36-2.97), 2.99(1.79-4.99), 2.36(1.46-3.82) and 2.60(1.88-3.61), respectively. Pooled ORs of OSAS for NASH, fibrosis-any stage, or advanced fibrosis in biopsy-proven NAFLD patients were 2.37(1.59-3.51), 2.16(1.45-3.20) and 2.30(1.21-4.38). The magnitude and direction of effects were unaffected by age, sex and BMI. In conclusion, OSAS is associated with an increased risk of NAFLD, NASH and fibrosis. OSAS patients should be screened for the presence and severity of NAFLD.

Anti-inflammatory and antioxidant effects of resveratrol in healthy smokers a randomized, double-blind, placebo-controlled, cross-over trial.

OBJECTIVE: Smokers are characterized by a low-grade systemic inflammatory state and an oxidant-antioxidant imbalance. Few human studies were conducted on the effects of resveratrol, a natural compound with anti-inflammatory and antioxidant properties, and no trial on smokers has been performed to date. We evaluated whether resveratrol has beneficial effects on markers of inflammation and oxidative stress in smokers. METHODS AND RESULTS: A randomized, double- blind, cross-over trial was performed in 50 healthy adult smokers: 25 were randomly allocated to "resveratrol-first" (30-days: 500mg resveratrol/day, 30-days wash-out, 30-days placebo) and 25 to "placebo-first" (30-days placebo, 30-days wash-out, 30-days 500mg resveratrol/day). Resveratrol significantly reduced C-reactive protein (CRP) and triglyceride concentrations, and increased Total Antioxidant Status (TAS) values. After analyzing data with general linear models to assess period and carry-over effects, the ratios of the values after resveratrol to those after placebo were respectively: 0.47 (95%CI 0.38-0.59) -CRP- and 0.71 (95%CI 0.65-0.78) -triglycerides-, while TAS increased by 74.2 µmol/L (95%CI 60.8-87.6). Uric acid, glucose, insulin, cholesterol, liver enzyme concentrations, and weight, waist circumference, and blood pressure values did not significantly change after resveratrol supplementation. CONCLUSIONS: Because resveratrol has anti-inflammatory, anti-oxidant, and hypotriglyceridemic effects, its supplementation may beneficially affect the increased cardiovascular risk of healthy smokers.

Impact of current treatments on liver disease, glucose metabolism and cardiovascular risk in non-alcoholic fatty liver disease (NAFLD): a systematic review and meta-analysis of randomised trials.

AIMS/HYPOTHESIS: Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum ranging from simple steatosis to non-alcoholic steatohepatitis (NASH): NAFLD causes an increased risk of cardiovascular disease, diabetes and liver-related complications (the latter confined to NASH). The effect of proposed treatments on liver disease, glucose metabolism and cardiovascular risk in NAFLD is unknown. We reviewed the evidence for the management of liver disease and cardio-metabolic risk in NAFLD. METHODS: Publications through November 2011 were systematically reviewed by two authors. Outcomes evaluated though standard methods were: histological/radiological/biochemical features of NAFLD, variables of glucose metabolism and cardiovascular risk factors. Seventy-eight randomised trials were included (38 in NASH, 40 in NAFLD): 41% assessed post-treatment histology, 71% assessed glucose metabolism and 88% assessed cardiovascular risk factors. Lifestyle intervention, thiazolidinediones, metformin and antioxidants were most extensively evaluated. RESULTS: Lifestyle-induced weight loss was safe and improved cardio-metabolic risk profile; a weight loss ≥7% improved histological disease activity, but was achieved by <50% patients. Statins and polyunsaturated fatty acids improved steatosis, but their effects on liver histology are unknown. Thiazolidinediones improved histological disease activity, glucose, lipid and inflammatory variables and delayed fibrosis progression. Pioglitazone also improved blood pressure. Weight gain (up to 4.8%) was common. Antioxidants yielded mixed histological results: vitamin E improved histological disease activity when administered for 2 years, but increased insulin resistance and plasma triacylglycerols. CONCLUSIONS/INTERPRETATION: Weight loss is safe, and improves liver histology and cardio-metabolic profile. For patients not responding to lifestyle intervention, pioglitazone improves histological disease activity, slows fibrosis progression and extensively ameliorates cardio-metabolic endpoints. Further randomised controlled trials (RCTs) of adequate size and duration will assess long-term safety and efficacy of proposed treatments on clinical outcomes.

The rs553668 polymorphism of the ADRA2A gene predicts the worsening of fasting glucose values in a cohort of subjects without diabetes. A population-based study.

AIMS: Single-nucleotide polymorphisms in the human ADRA2A gene have been associated with increased risk of Type 2 diabetes. The associations between the rs553668 polymorphism and fasting glucose concentrations both cross-sectionally and longitudinally after 6-year follow-up were evaluated in an adult Caucasian population-based cohort. METHODS: From a cohort of 1658 individuals, after excluding patients with diabetes, those who died and those whose blood samples were not available for genotyping, data of 1345 individuals were analysed. RESULTS: Subjects homozygous for the A allele showed significantly increased baseline fasting glucose values and a significant worsening of fasting glucose (ß = 0.48; 95% CI 0.10-0.86) and insulin secretion (ß =-20.75; -32.67 to -8.82 for homeostasis model assessment for ß-cell function) at follow-up by using generalized estimating equations. Incidence of impaired fasting glucose and diabetes was almost twofold higher in subjects homozygous for the A allele (respectively: incident impaired fasting glucose 7.6-8.2, 16.1%, incident diabetes 1.7-2.3, 3.2% in GG, AG, AA carriers). CONCLUSIONS: Our results suggested that the rs553668 polymorphism is associated with glucose worsening in subjects without diabetes at baseline.

Is left ventricular hypertrophy a low-level inflammatory state? A population-based cohort study.

BACKGROUND AND AIMS: Cross-sectional studies have shown that chronic sub-clinical inflammation is associated with left ventricular hypertrophy (LVH), but results are conflicting. We investigated the association between baseline LVH and high-sensitivity C-reactive protein (CRP) values, both cross-sectionally and after a six-year-follow-up, in a population-based cohort (n = 1564) and a subgroup from this cohort (n = 515), without obesity, diabetes, metabolic syndrome or any drugs. METHODS AND RESULTS: ECG tracings at baseline were interpreted according to the Cornell voltage-duration product criteria: 166/1564 subjects (10.6%) showed LVH. Patients with baseline LVH showed increased BMI, waist circumference, blood pressure, and a worse metabolic pattern. Their CRP values both at baseline and at follow-up were almost two-fold higher than in patients without LVH. Similar results were found in the healthier sub-sample. In a multiple regression model, CRP at follow-up was directly associated with baseline LVH (expressed as Cornell voltage-duration product) in the whole cohort (ß = 0.0003; 95%CI 0.0002-0.0006; p < 0.001) and in the sub-sample (ß = 0.0003; 0.0002-0.0004; p < 0.001), after adjusting for age, sex, BMI, waist circumference, smoking, exercise levels, blood pressure and baseline CRP values. CONCLUSION: Baseline LVH, which is associated with systemic inflammation, predicts increased CRP values at follow-up, independently of cardiovascular and metabolic risk factors, both in a population-based cohort and a healthier sub-sample. The inflammatory consequences of LVH might be an intriguing subject for further researches.

Contributors to the obesity and hyperglycemia epidemics. A prospective study in a population-based cohort.

OBJECTIVE: Relatively unexplored contributors to the obesity and diabetes epidemics may include sleep restriction, increased house temperature (HT), television watching (TW), consumption of restaurant meals (RMs), use of air conditioning (AC) and use of antidepressant/antipsychotic drugs (ADs). DESIGN AND SUBJECTS: In a population-based cohort (n=1597), we investigated the possible association among these conditions, and obesity or hyperglycemia incidence at 6-year follow-up. Subjects with obesity (n=315) or hyperglycemia (n=618) at baseline were excluded, respectively, 1282 and 979 individuals were therefore analyzed. RESULTS: At follow-up, 103/1282 became obese; these subjects showed significantly higher body mass index, waist circumference, saturated fat intake, RM frequency, TW hours, HT, AC and AD use, and lower fiber intake, metabolic equivalent of activity in h per week (METS) and sleep hours at baseline. In a multiple logistic regression model, METS (odds ratio=0.94; 95% confidence interval (CI) 0.91-0.98), RMs (odds ratio=1.47 per meal per week; 1.21-1.79), being in the third tertile of HT (odds ratio=2.06; 1.02-4.16) and hours of sleep (odds ratio=0.70 per h; 0.57-0.86) were associated with incident obesity. Subjects who developed hyperglycemia (n=174/979; 17.8%) had higher saturated fat intake, RM frequency, TW hours, HT, AC and AD use at baseline and lower METS and fiber intake. In a multiple logistic regression model, fiber intake (odds ratio=0.97 for each g per day; 0.95-0.99), RM (1.49 per meal per week; 1.26-1.75) and being in the third tertile of HT (odds ratio=1.95; 1.17-3.26) were independently associated with incident hyperglycemia. CONCLUSIONS: Lifestyle contributors to the obesity and hyperglycemia epidemics may be regular consumption of RM, sleep restriction and higher HT, suggesting potential adjunctive non-pharmacological preventive strategies for the obesity and hyperglycemia epidemics.

Non-alcoholic fatty liver disease from pathogenesis to management: an update.

Non-alcoholic fatty liver disease (NAFLD), the most common chronic liver disease in the Western world, is tightly associated with obesity and metabolic syndrome. NAFLD entails an increased cardiometabolic and liver-related risk, the latter regarding almost exclusively non-alcoholic steatohepatitis (NASH), the progressive form of NAFLD. Pathogenetic models encompass altered hepatic lipid partitioning and adipokine action, increased oxidative stress, free fatty acid lipotoxicity. On this basis, lifestyle-, drug- or surgically induced weight loss, insulin sensitizers, antioxidants, lipid-lowering drugs have been evaluated in NAFLD/NASH. Most trials are small, of short duration, nonrandomized, without histological end points, thus limiting assessment of long-term safety and efficacy of proposed treatments. All NAFLD patients should be evaluated for their metabolic, cardiovascular and liver-related risk. Liver biopsy remains the gold standard for staging NAFLD, but non-invasive methods are under intense development. Weight loss through lifestyle intervention is the initial approach, because of established efficacy on NAFLD-associated cardiometabolic abnormalities, and to emerging benefits on necroinflammation and overall disease activity in NASH. Bariatric surgery warrants further evaluation before it can be routinely considered in morbidly obese NASH. Larger- and longer-duration randomized trials assessing safety and benefits of drugs on patient-oriented outcomes are needed before pharmacological treatment can be routinely recommended for NASH.

What predicts the occurrence of the metabolic syndrome in a population-based cohort of adult healthy subjects?

BACKGROUND: Metabolic syndrome (MS), the concurrence of hyperglycaemia, dyslipidaemia, hypertension and visceral obesity, increases cardiovascular risk and mortality. Predictors of MS were previously evaluated in patients without the full syndrome, but with some of its traits. This might confound the resulting associations. METHODS: The relationship between baseline variables and MS development was evaluated in healthy middle-aged subjects without any MS component at baseline, over a 4.5-year follow-up. RESULTS: From a population-based cohort of 1658 subjects, 241 individuals showed no MS components and 201 (83.4%) of them participated in a follow-up screening. At baseline, patients who developed the MS (n = 28/201; 13.9%) showed significantly higher Homeostasis Model Assessment-Insulin Resistance score (HOMA-IR) and C-reactive protein (CRP) values, and lower exercise level than subjects who did not. In a multiple logistic regression analysis, after multiple adjustments, the only baseline variable significantly (p < 0.01) associated with the MS was CRP (OR = 4.05; 95% CI 2.23-7.38; p < 0.001). Results did not change after adjusting for weight gain. The area under the receiver-operating curve was 0.83 for CRP after multiple adjustments. The optimal cut-off point of baseline CRP values was 2.1 mg/L, with 86% (95% CI 81-90) sensitivity and 75% (69-81) specificity in predicting the MS. Baseline CRP resulted associated with after-study glucose values in a multiple regression model (beta = 0.14; 0.08-0.20; p < 0.001). CONCLUSIONS: Higher baseline CRP values confer a significant increased risk of developing the MS in healthy subjects, independently of weight gain.

Plasma visfatin concentrations after a lifestyle intervention were directly associated with inflammatory markers.

BACKGROUND AND AIMS: The biological activity and regulation of the novel adipokine visfatin are still largely unknown. Our aim was to evaluate if visfatin plasma concentrations may be influenced by a lifestyle intervention. METHODS AND RESULTS: Out of 335 dysmetabolic patients from a population-based cohort, randomized to receive a lifestyle intervention program (intervention group) or family physician usual care (controls), 20 patients per group were randomly selected for plasma visfatin determination. The before-after variation (Delta) in visfatin concentration at 1-year from randomization, and the correlations between (Delta)visfatin and intervention-induced changes in waist circumference, fasting glucose, markers of inflammation, and oxidative stress were evaluated. The intervention group showed a significant improvement in waist circumference, and many metabolic/inflammatory variables, while the controls worsened. Visfatin concentrations slightly decreased in the former and significantly increased in the controls ((Delta)visfatin=-2.4 vs 66.0 ng/ml, p<0.001). In robust regression models, the following variables resulted associated with (Delta)visfatin: (Delta)waist circumference, (Delta)fasting glucose, (Delta)hs-CRP (high-sensitivity C-reactive protein) and (Delta)TNFalpha (tumor necrosis factor-alpha). Significant effects on (Delta)visfatin of (Delta)TNFalpha (beta=16.8; 6.1-25.6; p=0.003) and, modified by group, of (Delta)hs-CRP (beta=29.8; 95% CI 15.4-44.2; p<0.001 and beta=4.2; 2.9-5.5; p<0.001 in the control and intervention group, respectively) were detected. By controlling for (Delta)waist, the effects of (Delta)TNFalpha and of (Delta)hs-CRP on (Delta)visfatin by group did not change, while (Delta)waist was no longer associated. The association between (Delta)visfatin and (Delta)glucose was no longer significant, after adjusting for (Delta)hs-CRP. CONCLUSION: Visfatin values increased with waist circumference and were associated with variations of inflammatory markers, suggesting participation in inflammatory mechanisms.