A meta-analysis of randomized trials for the treatment of nonalcoholic fatty liver disease.

UNLABELLED: Nonalcoholic fatty liver disease (NAFLD) encompasses a histological spectrum ranging from simple steatosis to nonalcoholic steatohepatitis (NASH). NAFLD carries a higher risk of cardio-metabolic and liver-related complications, the latter being confined to NASH and demanding specific treatment. We assessed the efficacy of proposed treatments for NAFLD/NASH by reviewing reports of randomized controlled trials (RCTs) on online databases and national and international meeting abstracts through January 2010. Primary outcome measure was histological improvement; secondary outcome was biochemical improvement; improvement in radiological steatosis was also evaluated. Two reviewers extracted articles using predefined quality indicators, independently and in duplicate. Main outcomes of randomized controlled trials (RCTs) were pooled using random-effects or fixed-effects models. Publication bias was assessed by funnel plots. Forty-nine RCTs (30 in NASH) were included: 23 RCTs (22 in NASH, 1 in NAFLD) had post-treatment histology. Most RCTs were small and did not exceed 1-year duration. Weight loss, thiazolidinediones (especially pioglitazone), and antioxidants were most extensively evaluated. Weight loss was safe and dose-dependently improved histological disease activity in NASH, but more than 50% of patients failed to achieve target weight loss. Thiazolidinediones improved steatosis and inflammation but yielded significant weight gain. RCTs with antioxidants yielded conflicting results and were heterogeneous with respect to type and dose of drug, duration, implementation of lifestyle intervention. Among the other agents, pentoxifylline, telmisartan and L-carnitine improved liver histology in at least 1 RCT in NASH; polyunsaturated fatty acid (PUFA) ameliorated biochemical and radiological markers of NAFLD. Other approaches yielded negative results. CONCLUSION: Well-designed RCTs of adequate size and duration, with histological endpoints, are needed to assess long-term safety and efficacy of proposed treatments on patient-oriented clinical outcomes.

Transcription factor 7-like 2 polymorphism modulates glucose and lipid homeostasis, adipokine profile, and hepatocyte apoptosis in NASH.

UNLABELLED: Genetic factors underlying the association of NAFLD with diabetes and atherosclerosis are unknown. Recent human studies suggest transcription factor 7-like 2 (TCF7L2) polymorphism predisposes to diabetes through modulation of beta-cell function and modulates lipid levels in familial dyslipidemia. Emerging experimental evidence connects TCF7L2 to adipocyte metabolism and lipid homeostasis, as well. We tested if TCF7L2 polymorphism is a risk factor for nonalcoholic fatty liver disease (NAFLD) and if it modulates liver injury, glucose homeostasis, lipoprotein, and adipokine profiles in NASH. TCF7L2 genotype and dietary habits of 78 nondiabetic normolipidemic NAFLD subjects and 156 age-, body mass index-, sex-matched healthy controls were assessed. In 39 biopsy-proven nonalcoholic steatohepatitis (NASH) and matched controls TCF7L2 polymorphism was correlated to liver histology and oral glucose tolerance test-derived parameters of glucose homeostasis. Patients with NASH and controls consumed a high-fat meal and TCF7L2 genotype was correlated to postprandial circulating lipoproteins, adipokines, and cytokeratin-18 fragments. The TCF7L2 CT/TT genotype was more frequent in NAFLD and predicted the presence and severity of liver disease, of beta-cell dysfunction, of reduced incretin effect and hepatic insulin resistance in NASH; it also modulated postprandial hepatocyte apoptosis, lipoproteins, and adipokine profiles in both groups. CONCLUSION: TCF7L2 polymorphism predisposes to NAFLD and significantly impacts liver injury, glucose homeostasis, and postprandial lipoprotein and adipokine responses to fat ingestion. This polymorphism also modulates a fat-induced increase in circulating markers of hepatocyte apoptosis in NASH. Targeting postprandial lipemia, at least in at-risk TCF7L2 genotypes, may improve liver disease and glucose dysmetabolism in these patients.

Uncoupling protein 2 G(-866)A polymorphism: a new gene polymorphism associated with C-reactive protein in type 2 diabetic patients.

BACKGROUND: This study evaluated the relationship between the G(-866)A polymorphism of the uncoupling protein 2 (UCP2) gene and high-sensitivity C reactive protein (hs-CRP) plasma levels in diabetic patients. METHODS: We studied 383 unrelated people with type 2 diabetes aged 40-70 years. Anthropometry, fasting lipids, glucose, HbA1c, and hs-CRP were measured. Participants were genotyped for the G (-866)A polymorphism of the uncoupling protein 2 gene. RESULTS: Hs-CRP (mg/L) increased progressively across the three genotype groups AA, AG, or GG, being respectively 3.0 ± 3.2, 3.6 ± 5.0, and 4.8 ± 5.3 (p for trend = 0.03). Since hs-CRP values were not significantly different between AA and AG genotype, these two groups were pooled for further analyses. Compared to participants with the AA/AG genotypes, homozygotes for the G allele (GG genotype) had significantly higher hs-CRP levels (4.8 ± 5.3 vs 3.5 ± 4.7 mg/L, p = 0.01) and a larger proportion (53.9% vs 46.1%, p = 0.013) of elevated hs-CRP (> 2 mg/L). This was not explained by major confounders such as age, gender, BMI, waist circumference, HbA1c, smoking, or medications use which were comparable in the two genotype groups. CONCLUSIONS: The study shows for the first time, in type 2 diabetic patients, a significant association of hs-CRP levels with the G(-866)A polymorphism of UCP2 beyond the effect of major confounders.

High-normal blood pressure is associated with a cluster of cardiovascular and metabolic risk factors: a population-based study.

OBJECTIVE: A Few population-based studies have shown that high-normal blood pressure clusters with other cardiovascular risk factors. Increased inflammation, endothelial dysfunction, oxidative stress, and reduced adiponectin values have sporadically been reported in these patients. METHODS: We cross-sectionally compared blood pressure categories with cardiovascular risk factors in an adult population-based cohort (n = 1658) and evaluated the relationships between C-reactive-protein, nitrotyrosine, total antioxidant status, E-selectin, vascular adhesion molecule-1, intercellular adhesion molecule-1, resistin, adiponectin values and blood pressure categories in a subgroup of healthy lean individuals from this cohort (n = 107) in order to exclude the impact of obesity/insulin resistance on these variables. RESULTS: Glucose, triglyceride, low-density lipoprotein-cholesterol, alanine aminotranferase, gamma-glutamyl transferase values, and diabetes and metabolic syndrome prevalence were significantly higher in high-normal compared with the optimal blood pressure category. In the healthy subgroup, adiponectin (beta = - 4315.3; 95% confidence interval - 5916.4 -2654.2), total antioxidant status (-0.15; -0.3 -0.04) were significantly lower, and nitrotyrosine (1.2; 0.3 2.1), E-selectin (11.7; 1.8 21.6), vascular adhesion molecule-1 (0.3; 0.1 0.5), and intercellular adhesion molecule-1 (0.3; 0.1 0.5) were higher in high-normal compared with the optimal blood pressure category, at multiple regression analyses. CONCLUSIONS: Individuals with high-normal blood pressure had a higher prevalence of cardiovascular and metabolic risk factors than those with optimal, and, even if healthy, they showed reduced adiponectin values, early signs of endothelial dysfunction, and oxidative stress. Further research is needed to determine whether they will benefit from blood pressure reduction.

Adiponectin gene polymorphisms modulate acute adiponectin response to dietary fat: Possible pathogenetic role in NASH.

UNLABELLED: Factors underlying the independent association of nonalcoholic steatohepatitis (NASH) with increased cardiovascular risk are unknown. Adiponectin polymorphisms predict cardiometabolic risk in the general population. This association is not always mediated by low fasting adiponectin levels, adipose tissue accumulation, or traditional risk factors. Adiponectin modulates lipid metabolism and liver injury in nonalcoholic fatty liver disease (NAFLD) even in the absence of obesity, dyslipidemia, and diabetes. We hypothesized adiponectin polymorphisms may predispose to NAFLD and may increase cardiovascular risk by modulating circulating lipoprotein and adiponectin response postprandially. The prevalence of adiponectin single-nucleotide polymorphisms (SNPs) 45GT and 276GT was assessed in 70 nonobese, nondiabetic, normolipidemic NAFLD patients and 70 healthy matched controls; the impact of the adiponectin SNPs was subsequently correlated to liver histology and postprandial adiponectin and lipoprotein responses to oral fat load in a subgroup of 30 biopsy-proven patients with NASH and 30 controls. The 45TT and 276GT/TT genotypes were more prevalent in NAFLD patients than in controls and independently predicted the severity of liver disease in NASH. In both patients and controls, these genotypes exhibited a blunted postprandial adiponectin response and higher postprandial triglycerides (Tg), free fatty acids (FFA), oxidized LDL (oxLDL), and VLDL levels than their counterparts, despite comparable fasting adipokines, lipids, dietary habits, adiposity, and insulin resistance. They were also independently associated, together with dietary polyunsaturated fatty acid intake, with postprandial adiponectin response. IAUC adiponectin independently predicted postprandial Tg, FFA, oxLDL, and intestinal and hepatic VLDL subfraction responses in NASH. CONCLUSION: The at-risk adiponectin SNPs 45TT and 276GT are significantly more prevalent in NAFLD than in the general population; they are associated with severity of liver disease, with blunted postprandial adiponectin response, and with an atherogenic postprandial lipoprotein profile in NASH independently of fasting adipokine and lipid levels.

Type 1 autoimmune hepatitis and adipokines: new markers for activity and disease progression?

PURPOSE: Cytokines may play an important role as inflammatory factors in liver diseases. There is some evidence suggesting a link between adiponectin-biliary function and liver disease. The aim of this study was to clarify the behavior of adipokines in autoimmune hepatitis type 1. METHODS: We assessed the circulating levels of adiponectin, tumor necrosis factor-alpha, resistin and leptin in 42 patients with autoimmune hepatitis, comparing them with 42 healthy subjects who were matched for age and sex and with 31 patients with nonalcoholic steatohepatitis (NASH), evaluating the associations with markers of cytolysis, cholestasis, and histological severity. RESULTS: Adiponectin and TNF-alpha values were higher in patients compared to controls. The patients showed significantly higher Homeostasis Model Assessment values, suggesting an increased insulin resistance and serum levels of adiponectin positively correlated with gamma-glutamyltranspeptidase and alkaline phosphatase values after a simple regression analysis. Serum levels of resistin positively correlated with elevated aminotransferases and bilirubin values, and serum levels of TNF-alpha positively correlated with elevated alanine-aminotransferase and resistin values. The concentration of adiponectin increased significantly with staging of the disease. Patients with NASH showed lower levels of adiponectin and higher levels of resistin than AIH patients and controls. CONCLUSIONS: Patients with AIH showed significantly higher adiponectin concentrations than controls despite their higher HOMA-IR values. The significant correlation between adiponectin levels and serological features of cholestasis suggested an association with biliary function. Our results indicate that adiponectin may be a possible marker for disease progression in AIH.

Phytosterol-enriched yogurt increases LDL affinity and reduces CD36 expression in polygenic hypercholesterolemia.

Dietary enrichment with phytosterols (plant sterols similar to cholesterol) is able to reduce plasma cholesterol levels due to reduced intestinal absorption. The aim of this study was to investigate the effect of phytosterol-enriched yogurt consumption on the major serum lipid parameters, low density lipoprotein (LDL) receptor activity, LDL-receptor affinity, and CD36 expression in hypercholesterolemic subjects. Fifteen patients affected by polygenic hypercholesterolemia were evaluated in a single-blind randomized crossover study after a 4 weeks treatment with a phytosterol-enriched yogurt containing 1.6 g esterefied phytosterols (equivalent to 1.0 g free phytosterol). Lipid parameters were compared with a phytosterol-free placebo-controlled diet. The effect of the two treatments on each variable, measured as percentage change, was compared by paired samples t test and covariance analysis. The treatment induced a modest but significant decrease in LDL-cholesterol levels (4.3%, P = 0.03) and a significant increase in high density lipoprotein (HDL) 3-cholesterol (17.1%, P = 0.01). Phytosterol consumption had no effect on LDL-receptor activity whereas patient LDL-receptor affinity significantly increased (9.7%, P = 0.01) and CD36 expression showed a marked significant decrease (18.2%, P = 0.01) in the phytosterol-enriched yoghurt patients. Our data show that the oral administration of a phytosterol-enriched yogurt has modest but significant effects on commonly measured lipid parameters. The improvement of LDL-receptor affinity and the reduction in CD36 expression may reflect an important antiatherogenic effect.

Associations of dietary and serum copper with inflammation, oxidative stress, and metabolic variables in adults.

There are conflicting data on the associations between copper and glycemia, plasma lipids, and atherosclerotic diseases. Copper has both pro-oxidant and antioxidant effects. We performed a cross-sectional analysis to investigate the associations between dietary copper intake and metabolic variables and serum high-sensitivity C-reactive protein (hs-CRP) in asymptomatic subjects from a population-based cohort (n = 1197) and between serum copper concentration and markers of oxidative stress, including plasma nitrotyrosine (NT) and total antioxidant status (TAS), hs-CRP, and metabolic variables in a subgroup of men from this cohort (n = 231). In all subjects, diastolic blood pressure and circulating glucose, uric acid, and total and LDL-cholesterol concentrations significantly decreased, whereas the hs-CRP concentration increased, from the lowest to the highest tertile of copper intake. In the male subgroup, glucose and total and LDL-cholesterol and TAS decreased, whereas hs-CRP and NT concentrations increased from the lowest to the highest tertile of serum copper concentration. In multiple regression models, dietary copper intake was inversely associated with diastolic blood pressure (P = 0.002), fasting glucose (P < 0.001), total cholesterol (P < 0.001), LDL-cholesterol (P < 0.001), and uric acid (P < 0.001) and was directly associated with the hs-CRP concentration (P < 0.001). Serum copper concentrations were inversely associated with glucose (P < 0.001), total cholesterol (P < 0.001), LDL-cholesterol (P < 0.001), and TAS (P < 0.001) and were directly associated with hs-CRP (P < 0.001) and NT concentrations (P < 0.001). Marginal copper deficiency is associated with an unfavorable metabolic pattern, but copper supplementation might not be recommended in view of its association with inflammation and markers of oxidative stress.

Changes over time in the prevalence and quality of care of type 2 diabetes in Italy: the Casale Monferrato surveys, 1988 and 2000.

BACKGROUND AND AIMS: In this study we assessed the prevalence of diagnosed type 2 diabetes and the quality of care during the period 1988-2000 in an Italian population. METHODS AND RESULTS: Two population-based surveys, using similar methods and centralized measurements, were conducted in 1988 and 2000 in a representative Italian area to identify people with known diabetes. The adjusted prevalence (reference, 2001 Italian population) was computed. The age- and sex-adjusted prevalence rates of diabetes in the population of Casale Monferrato were 2.13% (2.05-2.22) in 1988 and 3.07% (2.97-3.17) in 2000. In comparison with diabetic persons recruited in 1988 and independently of age and sex, persons recruited in 2000 had a lower likelihood of having HbA1c > or = 7.0% (OR=0.48; 0.42-0.56), diastolic blood pressure > or = 80 mmHg (OR=0.61; 0.49-0.75), LDL cholesterol > or = 2.59 mmol/l (OR=0.77; 0.63-0.93) and AER > or = 20 microg/min (OR=0.53; 0.45-0.61; they had a higher likelihood of having BMI > or = 25 kg/m(2) (OR=1.49; 1.2-1.74). However, 45.4% of patients still had HbA1c > or = 7.0%, 80% blood pressure > or = 130/80 mmHg and 79% LDL-cholesterol values > or =2.59 mmol/l. CONCLUSION: More than two-thirds of Italians with diabetes are now aged 65 years and more. The quality of control of glycemia, lipids and blood pressure improved and the prevalence of diabetic nephropathy decreased over time, although complete adherence to international guidelines has not yet been achieved.

Nitrosative stress predicts the presence and severity of nonalcoholic fatty liver at different stages of the development of insulin resistance and metabolic syndrome: possible role of vitamin A intake.

BACKGROUND: Although nonalcoholic fatty liver disease (NAFLD) is associated with the metabolic syndrome, the mechanisms responsible for the development of NAFLD at different stages of the development of insulin resistance are unknown. Diet, adipokines, and nitrosative stress have been linked to both NAFLD and insulin resistance. OBJECTIVE: We aimed to identify the factors that are specifically associated with NAFLD at different stages in the development of insulin resistance and the metabolic syndrome. DESIGN: Circulating concentrations of adipokines (ie, tumor necrosis factor-alpha, adiponectin, resistin, leptin, and interleukin-6), markers of nitrosative stress (nitrotyrosine), dietary habits, and MTP -493G/T polymorphism were cross-sectionally related to the presence and severity of insulin resistance (homeostasis model assessment index for insulin resistance: >or=2), the metabolic syndrome, and fatty liver in 64 nonobese nondiabetic patients with NAFLD (33 insulin-sensitive and 31 insulin-resistant subjects) and 74 control subjects without liver disease who were matched for sex, BMI, homeostasis model assessment index for insulin resistance status, and the various features of the metabolic syndrome. RESULTS: Persons with NAFLD had greater systemic nitrosative stress and a lower intake of vitamins A and E than did control subjects, but the 2 groups did not differ significantly in any other features. Nitrotyrosine and adiponectin concentrations and vitamin A intakes independently predicted alanine aminotransferase concentrations in NAFLD patients and liver histology in a subgroup of 29 subjects with biopsy-proven nonalcoholic steatohepatitis. CONCLUSIONS: Oxidative stress is operating in NAFLD and nonalcoholic steatohepatitis, even in the absence of insulin resistance, the metabolic syndrome, and hypoadiponectinemia, which aggravate liver histology at more severe stages of metabolic disease. The possible pathogenetic role of reduced vitamin A intake in NAFLD warrants further investigation.

Diabetic LDL inhibits cell-cycle progression via STAT5B and p21(waf).

Modified LDL is a major cause of injury to the endothelium in diabetes. In the present study, we analyzed the effects on endothelial cells of LDL recovered from type 2 diabetic patients (dm-LDL) or from nondiabetic subjects (n-LDL). Treatment of human umbilical vein endothelial cells with dm-LDL, but not n-LDL, led to the accumulation of cells in G1. To dissect the molecular mechanisms of this effect, we analyzed the expression and function of the cyclin-dependent kinase inhibitor p21(waf), a cell cycle regulator known to be a target of the signal transducers and activators of transcription (STATs). dm-LDL led to transient STAT5 phosphorylation and the formation of a STAT5-containing complex and activated p21(waf) expression at the transcriptional level. Expression of the dominant-negative form of STAT5B, but not of STAT5A, significantly decreased both p21(waf) expression and the fraction of cells in G1. Finally, immunofluorescence analysis demonstrated that activated STAT5 is expressed in newly formed intraplaque vessels and in endothelial cells lining the luminal side of the plaque. Similarly, p21(waf) immunoreactivity was found in the neointimal vasculature. Our results suggest a role of STAT5B as a regulator of gene expression in diabetes-associated vascular disease.

Effectiveness of a lifestyle intervention on metabolic syndrome. A randomized controlled trial.

BACKGROUND: Intensive lifestyle intervention significantly reduces the progression to diabetes in high-risk individuals. OBJECTIVE: It is not known whether a program of moderate intervention might effectively reduce metabolic abnormalities in the general population. DESIGN: Two-arm randomized controlled 1-year trial. PATIENTS: Three hundred and thirty-five patients participated from a dysmetabolic population-based cohort of 375 adults aged 45-64 years in northwestern Italy. MEASUREMENTS: We compared the effectiveness of a general recommendation-based program of lifestyle intervention carried out by trained professionals versus standard unstructured information given by family physicians at reducing the prevalence of multiple metabolic and inflammatory abnormalities. RESULTS: At baseline, clinical/anthropometric/laboratory and lifestyle characteristics of the intervention (n = 169) and control (n = 166) groups were not significantly different. The former significantly reduced total/saturated fat intake and increased polyunsaturated fat/fiber intake and exercise level compared to the controls. Weight, waist circumference, high-sensitivity C-reactive protein, and most of the metabolic syndrome components decreased in the intervention group and increased in the controls after 12 months. Lifestyle intervention significantly reduced metabolic syndrome (odds ratio [OR] = 0.28; 95% CI 0.18-0.44), with a 31% (21-41) absolute risk reduction, corresponding to 3.2 (2-5) patients needing to be treated to prevent 1 case after 12 months. The intervention significantly reduced the prevalence of central obesity (OR = 0.33; 0.20-0.56), and hypertriglyceridemia (OR = 0.48; 0.31-0.75) and the incidence of diabetes (OR = 0.23; 0.06-0.85). CONCLUSION: A lifestyle intervention based on general recommendations was effective in reducing multiple metabolic/inflammatory abnormalities. The usual care by family physicians was ineffective at modifying progressive metabolic deterioration in high-risk individuals.

Microsomal triglyceride transfer protein 493-T variant is associated with resistin levels and C-reactive protein.

BACKGROUND: The microsomal triglyceride transfer protein (MTP) is a heterodimeric lipid transfer protein that consists of a large unique 97-kDA subunit and protein disulfide isomerase. MTP is involved in the assembly of apoB-containing lipoprotein and enables the secretion of VLDLs by the liver and chylomicrons by the intestine. The MTP gene is highly polymorphic. The less common T variant has been associated with the reduction of plasma LDL-cholesterol levels and with an increased risk in coronary heart disease. We hypothesized that MTP polymorphism could be associated to LDL-cholesterol levels and proinflammatory cytokines, such as resistin. METHODS AND RESULTS: The -493G/T MTP gene polymorphism was investigated in 290 subjects. Subjects carrying the TT genotype had lower level of LDL-cholesterol and higher serum resistin levels than individual carrying one or two copies of the -493G allele. After adjustments for age, BMI, waist circumference, alcohol intake and exercise levels, a significant direct association was evident between hs-CRP and resistin levels and the presence of the TT genotype in a multiple regression model. CONCLUSION: This study supports the notion that the rare MTP-493T/T genotype is associated both with higher levels of inflammatory parameters and with low levels of LDL-cholesterol. Prospective data are needed to investigate if the association between CVD and the MTP-493T/T genotype might be due to the increased sub-clinical proinflammatory state associated with this mutation.

Prevalence of undiagnosed metabolic syndrome in a population of adult asymptomatic subjects.

BACKGROUND: To evaluate in the general population the prevalence of undiagnosed metabolic syndrome (MS), defined according to the National Cholesterol Education Program (NCEP) and International Diabetes Federation (IDF) criteria. METHODS: A population-based cross-sectional study of 1175 asymptomatic adults in North-Western Italy. RESULTS: The prevalence of undiagnosed MS was 16.4% (95% CI=14.4-18.6) (NCEP) and 28.0% (25.4-30.6) (IDF), respectively, 5.2% (3.6-7.3) and 8.9% (6.6-11.3) in normal-BMI and 26.6% (23.3-30.2) and 45.3% (41.3-49.2) in overweight/obese individuals. Of the total cohort, 52% were overweight/obese and they accounted for 85% of the cases of MS; a further 19% were normal weight with light physical activity and accounted, respectively, for 12% (NCEP) and 13% (IDF) of the cases. Only 25% (NCEP) and 14% (IDF) of participants showed no component of the MS (respectively, 40 and 26% of those not-overweight and 11 and 3% of those overweight/obese). CONCLUSIONS: More than 97% of unknown MS cases would be identified among apparently healthy individuals when overweight/obese, and normal-BMI subjects with low physical activity were screened. These two criteria might, therefore, be used to prioritise screening programmes in asymptomatic subjects, since even apparently healthy individuals, who are not-overweight, frequently show one or more metabolic abnormalities, whose co-existence has been demonstrated to be hazardous.

Dietary magnesium and fiber intakes and inflammatory and metabolic indicators in middle-aged subjects from a population-based cohort.

BACKGROUND: Type 2 diabetes (DM), metabolic syndrome (MetS), and inflammation are linked to reduced magnesium and fiber intakes; these associations are attenuated by adjustment for each of these nutrients. OBJECTIVE: We investigated the association among magnesium and fiber intakes, metabolic variables, and high-sensitivity C-reactive protein (hs-CRP) values. DESIGN: Cross-sectional analyses were performed in a representative cohort of 1653 adults and in a subgroup with normal body mass index without dysmetabolisms (n = 205). A validated semiquantitative food-frequency questionnaire was used; magnesium intake was computed by multiplying its content in each food by the frequency of food consumption. RESULTS: The prevalence of DM, MetS, and hs-CRP >/= 3 mg/L significantly decreased from the lowest to the highest tertile of magnesium and fiber intakes. Subjects within the lowest tertiles of magnesium and fiber intakes were 3-4 times as likely to have DM, MetS, and hs-CRP >/= 3 mg/L, after multiple adjustments. After the analysis was additionally controlled for fiber intake, associations with hs-CRP >/= 3 mg/L proved to be significant (odds ratio: 2.05; 95% CI: 1.30, 3.25), whereas reduced magnesium intake and DM and MetS were no longer significant. The lowest tertile of fiber intake remained associated with DM, hs-CRP >/= 3 mg/L, and MetS after adjustments for multiple confounders and magnesium intake. In the lean, healthy subject subgroup, hs-CRP values were inversely associated with magnesium and fiber intakes in a multivariate model (P < 0.001). CONCLUSIONS: Reduced fiber intake was significantly associated with metabolic abnormalities; the magnesium effect might be confounded by fiber being in foods that also provided magnesium. Lower magnesium and fiber intakes were linked to hs-CRP >/= 3 mg/L in both the entire cohort and healthy persons.

Alterations of seminal and hormonal parameters: An extrahepatic manifestation of HCV infection?

AIM: To evaluate the possible influences of HCV infection and relative antiviral treatment on seminal parameters and reproductive hormonal serum levels. METHODS: Ten male patients with HCV-related chronic hepatitis and 16 healthy male volunteers were studied. In all subjects seminal parameters (nemaspermic concentration, progressive motility, morphology) and hormonal levels were determined. Seminal parameters and inhibin B, follicle-stimulating hormone, luteinizing hormone, total and free testosterone, estradiol, prolactine in patients were measured after six and twelve months of antiviral combined (interferon+ribavirin) treatment. RESULTS: Patients before treatment showed a significantly lower nemaspermic motility and morphology as well as lower inhibin B and free testosterone levels than controls. Inhibin B levels in cases were improved six and 12 mo after treatment in five responders (161.9+/-52.8 pg/mL versus 101.7+/-47.0 pg/mL and 143.4+/-46.1 pg/mL versus 95.4+/-55.6 pg/mL, respectively). Hormonal pattern of patients did not significantly change after treatment, with the exception of estradiol levels with an initial reduction and an overall subsequent increment (19.7+/-6.4 pg/mL versus 13.6+/-5.0 pg/mL versus 17.3+/-5.7 pg/mL). However in 1-year responders a significant increment of free testosterone (14.2+/-2.54 pg/mL versus 17.1+/-2.58 pg/mL) occurred. An impairment of nemaspermic morphology occurred, while other seminal parameters did not change significantly during antiviral treatment. CONCLUSION: Patients with HCV infection show worse spermatic parameters than controls, suggesting a possible negative influence of virus on spermatogenesis, with further mild impairment during antiviral treatment. However therapy could improve the spermatic function, as suggested by the increased inhibin B levels and improved hormonal pattern in responders. Further studies are needed to confirm these preliminary intriguing results.

Incidence of type 1 and type 2 diabetes in adults aged 30-49 years: the population-based registry in the province of Turin, Italy.

OBJECTIVE: Incidence of type 1 diabetes is considered to be low in adults, but no study has been performed in Mediterranean countries. RESEARCH DESIGN AND METHODS: We extended the study base of the registry of the province of Turin, Italy, to subjects aged 30-49 years in the period 1999-2001 to estimate the incidences of type 1 and type 2 diabetes. Diagnosis of type 1 diabetes was based on permanent insulin treatment or a fasting C-peptide level < or =0.20 nmol/l or islet cell (ICA) or GAD (GADA) antibody positivities. RESULTS: We identified 1,135 case subjects with high completeness of ascertainment (99%), giving an incidence rate of 58.0 per 100,000 person-years (95% CI 54.7-61.5). The incidence of type 1 diabetes was 7.3 per 100,000 person-years (6.2-8.6), comparable with the rates in subjects aged 0-14 and 15-29 years (10.3 [9.5-11.2] and 6.8 [6.3-7.4]). Male subjects had a higher risk than female subjects for both type 1 (rate ratio [RR] 1.70 [95% CI 1.21-2.38]) and type 2 (2.10 [1.84-2.40]) diabetes. ICA and/or GADA positivities were found in 16% of the cohort. In logistic regression, variables independently associated with autoimmune diabetes were age 30-39 years (odds ratio [OR] 2.39 [95% CI 1.40-4.07]), fasting C-peptide <0.60 nmol/l (3.09 [1.74-5.5]), and BMI <26 kg/m2 (2.17 [1.22-3.85]). CONCLUSIONS: Risk of type 1 diabetes between age 30 and 49 years is similar to that found in the same area between age 15 and 29 years. Further studies are required to allow geographical comparisons of risks of both childhood and adulthood autoimmune diabetes, the latter being probably higher than previously believed.

Residual beta-cell function and male/female ratio are higher in incident young adults than in children: the registry of type 1 diabetes of the province of Turin, Italy, 1984-2000.

OBJECTIVE: The hypothesis of age-dependent variations in epidemiologic and clinical features at onset of type 1 diabetes has been assessed in the registry of the province of Turin, Italy. RESEARCH DESIGN AND METHODS: The study base is the population 0-29 years of age of the province of Turin, in the period from 1984 to 2000. Islet cell antibody (ICA), GAD antibody (GADA), antibodies to protein tyrosine phosphatase (IA2), and C-peptide were measured in subgroups of the cohort. RESULTS: One thousand fifty-six incident cases have been identified (completeness of ascertainment 98.1%). Rates per 100,000 person-years were similar in males and females in the age-group 0-14 years (10.7, 95% CI 9.5-12.0 vs. 9.8, 8.6-11.1). In the age-group 15-29 years, males had higher risk than females (7.7, 6.9-8.6 vs. 5.3, 4.6-6.1; rate ratio, 1.46, 95% CI 1.23-1.74; P = 0.00002). Fasting plasma C-peptide values (n = 575) were twofold lower in the age-group 0-14 years than in the age-group 15-29 years (0.10 vs. 0.23 nmol/l; P < 0.0001). Frequencies of ICA and IA2 positivities (n = 183) decreased with increasing age, whereas frequency of GADA positivity increased. Idiopathic cases were 12.6% and had higher mean values of fasting (0.28 vs. 0.14 nmol/l; P = 0.043) and stimulated C-peptide (0.59 vs. 0.34 nmol/l; P = 0.05). In logistic regression analyses, subjects with fasting C-peptide values in the upper quartile had higher likelihood of being older (odds ratio 1.20 for year, 95% CI 1.11-1.28), ICA negative (0.26, 0.10-0.70), and female (1.29, 0.48-3.42). CONCLUSIONS: This study shows 1) sex differences in incidence rates in young adults; 2) better preserved beta-cell function in young adults, in idiopathic cases (12%), and in ICA-negative cases; and 3) lower frequencies of ICA and IA2 positivities and higher frequency of GADA positivity in young adults than in children.

STAT5 activation induced by diabetic LDL depends on LDL glycation and occurs via src kinase activity.

Advanced glycation end products (AGEs) have been implicated in the accelerated vascular injury occurring in diabetes. We recently reported that LDL prepared from type 2 diabetic patients (dm-LDL), but not normal LDL (n-LDL) triggered signal transducers and activators of transcription STAT5 activation and p21(waf) expression in endothelial cells (ECs). The aims of the present study were to investigate the role of LDL glycation in dm-LDL- mediated signals and to analyze the molecular mechanisms leading to STAT5 activation. We found that glycated LDL (gly-LDL) triggered STAT5 activation, the formation of a prolactin inducible element (PIE)-binding complex containing STAT5, and increased p21(waf) expression through the activation of the receptor for AGE (RAGE). We also demonstrated that dm-LDL and gly-LDL, but not n-LDL treatment induced the formation of a stable complex containing the activated STAT5 and RAGE. Moreover, gly-LDL triggered src but not JAK2 kinase activity. Pretreatment with the src kinase inhibitor PP1 abrogated both STAT5 activation and the expression of p21(waf) induced by gly-LDL. Consistently, gly-LDL failed to activate STAT5 in src(-/-) fibroblasts. Collectively, our results provide evidence for the role of glycation in dm-LDL-mediated effects and for a specific role of src kinase in STAT5-dependent p21(waf) expression.

RAGE- and TGF-beta receptor-mediated signals converge on STAT5 and p21waf to control cell-cycle progression of mesangial cells: a possible role in the development and progression of diabetic nephropathy.

The molecular events associated with acute and chronic exposure of mesangial cells (MC) to hyperglycemia were evaluated. We found that, unlike high glucose (HG) and Amadori adducts, advanced glycation end products (AGE) and transforming growth factor-beta (TGF-beta) induced p21waf expression and accumulation of MC in G0/G1. TGF-beta1 blockade inhibited AGE-mediated collagen production but only partially affected AGE-induced p21waf expression and cell-cycle events, indicating that AGE by binding to AGE receptor (RAGE) per se could control MC growth. Moreover, AGE and TGF-beta treatment led to the activation of the signal transduction and activators of transcription (STAT)5 and the formation of a STAT5/p21SIE2 complex. The role of STAT5 in AGE- and TGF-beta-mediated p21waf expression and growth arrest, but not collagen production, was confirmed by the expression of the dominant negative STAT5 (DeltaSTAT5) or the constitutively activated STAT5 (1*6-STAT5) constructs. Finally, in p21waf-/- fibroblasts both AGE and TGF-beta failed to inhibit cell-cycle progression. A potential in vivo role of these mechanisms was sustained by the increasing immunoreactivity for the activated STAT5 and p21(waf) in kidney biopsies from early to advanced stage of diabetic nephropathy. Our data indicate that AGE- and TGF-beta-mediated signals, by converging on STAT5 activation and p21waf expression, may regulate MC growth.