A novel approach to control hyperglycemia in type 2 diabetes: sodium glucose co-transport (SGLT) inhibitors: systematic review and meta-analysis of randomized trials.

BACKGROUND: Current treatment of hyperglycemia in type 2 diabetes (T2DM) is often ineffective and has unwanted effects. Therefore, novel antidiabetic drugs are under development. OBJECTIVE: To assess efficacy and safety of the new antidiabetic drugs sodium glucose co-transport-2 (SGLT2) inhibitors in T2DM. Design and setting. Among 151 articles published on MEDLINE, Cochrane Library, EMBASE, PubMed, International meeting abstracts through December 2010, 13 randomized placebo-controlled trials (RCT) were included. MEASUREMENTS: Two reviewers retrieved articles and evaluated study quality by appropriate scores. Main outcomes were pooled using random- or fixed-effects models. RESULTS: Dapagliflozin significantly reduced HbA1c (weighted mean difference (WMD) -0.52%; 95% CI -0.46, -0.57%; P < 0.00001) fasting plasma glucose (WMD -18.28 mg/dL; 95% CI -20.66, -15.89; P < 0.00001), body mass index (WMD -1.17%; -1.41, -0.92%; P < 0.00001), systolic (WMD -4.08 mmHg; -4.91, -3.24), and diastolic (WMD -1.16 mmHg; -1.67, -0.66) blood pressure, and serum uric acid (WMD -41.50 µmol/L; -47.22, -35.79). Other SGLT2 inhibitors showed similar results. Dapagliflozin treatment increased the risk of urinary (OR 1.34; 1.05-1.71) and genital (OR 3.57; 2.59-4.93) tract infection; it also mildly increased the risk of hypoglycemia (OR 1.27; 1.05-1.53) when co-administered with insulin. LIMITATIONS: Limitations of the literature include the small number, size, and duration of RCTs. CONCLUSIONS: Pending confirmation from larger RCTs, this analysis shows SGLT2 inhibitors are safe and effective for hyperglycemia treatment in T2DM.

Loxin polymorphism is associated with increased resistin levels and with oxidative status.

OBJECTIVES: We hypothesized that LOX-1 polymorphism may impact on inflammation and cardiovascular risk by modulating systemic resistin expression. DESIGN AND METHODS: 276 men were randomly selected from a population-based cohort. Metabolic and inflammatory markers were evaluated at baseline and after 6-years follow-up, OLR1 (loxin) IVS4-14 A>G polymorphism was assessed. RESULTS: Mean plasma resistin and nitrotyrosine values were significantly higher, and TAS was significantly lowered in homozygous for the G allele. The G allele was significantly and directly associated with resistin and nitrotyrosine values. CONCLUSION: Enhanced oxidized-LDL uptake by LOX-1 G-allele carriers is associated with increased pro-oxidant status and resistin levels, suggesting a major uptake of ox-LDL by macrophages, smooth muscle cells, and monocytes.

Meta-analysis: natural history of non-alcoholic fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver disease severity.

BACKGROUND. NAFLD ranges from simple steatosis (SS) to non-alcoholic steatohepatitis (NASH). The natural history of NAFLD and the optimal strategy to identify subjects with progressive liver disease are unclear. Objectives. To assess the evidence in: (1) natural history of NAFLD; and (2) non-invasive methods to differentiate NAFLD histological subtypes. DESIGN AND SETTING. Among 4185 articles published on MEDLINE, Cochrane Library, EMBASE, Pubmed, national and International meeting abstracts through July 2010, 40 articles assessing the natural history of NAFLD and 32 articles evaluating the diagnostic accuracy of non-invasive tests against liver biopsy (LB) were included. MEASUREMENTS. Two reviewers retrieved articles and evaluated study quality by appropriate scores. Main outcomes were pooled using random- or fixed-effects models. RESULTS. NAFLD has an increased overall mortality (OR: 1.57, 95% CI: 1.18-2.10), deriving from liver-related and cardiovascular disease, and a 2-fold risk of diabetes. Compared to SS, NASH has a higher liver-related (OR for NASH: 5.71, 2.31-14.13; OR for NASH with advanced fibrosis: 10.06, 4.35-23.25), but not cardiovascular mortality (OR: 0.91, 0.42-1.98). Three non-invasive methods received independent validation: pooled AUROC, sensitivity and specificity of cytokeratin-18 for NASH are 0.82 (0.78-0.88), 0.78 (0.64-0.92), 0.87 (0.77-0.98). For NASH with advanced fibrosis, pooled AUROC, sensitivity and specificity of NAFLD fibrosis score and Fibroscan are 0.85 (0.80-0.93), 0.90 (0.82-0.99), 0.97 (0.94-0.99) and 0.94 (0.90-0.99), 0.94 (0.88-0.99) and 0.95 (0.89-0.99). CONCLUSIONS. NAFLD warrants screening for cardio-metabolic risk and for progressive liver disease. The combination of three noninvasive tests with LB may optimally individuate patients with NASH, with or without advanced fibrosis.

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.

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 (TCF7L2) polymorphism and hyperglycemia in an adult Italian population-based cohort.

OBJECTIVE: To assess whether TCF7L2 polymorphism has a role in the deterioration of glycemic control. RESEARCH DESIGN AND METHODS: Metabolic variables were evaluated at baseline and after 6-year follow-up in 1,480 Caucasian subjects from a population-based cohort. RESULTS: At baseline, T-allele carriers showed significantly lower BMI and homeostasis model assessment for beta-cell function (HOMA-B) values and higher fasting glycemia and diabetes prevalence. At follow-up, fasting glucose and HOMA-B index were increased and reduced, respectively, in carriers of the T-allele. Incident impaired fasting glucose (IFG) and incident diabetes were 5.7, 10.7, 16.9% and 1.6, 1.7, 3.0% in the CC, CT, and TT genotypes, respectively. In a multiple logistic regression model, the association between incident IFG and the T-allele was significant (odds ratio [OR] 2.08 [95% CI 1.35-3.20] and 3.56 [2.11-5.98] in CT and TT genotypes, respectively). CONCLUSIONS: The T-allele of TCF7L2 rs7903146 polymorphism was independently associated with increasing fasting glucose values toward hyperglycemia in the follow-up.

Effects of TCF7L2 polymorphisms on glucose values after a lifestyle intervention.

BACKGROUND: TCF7L2 is the strongest locus linked to type 2 diabetes that has been identified thus far, and rs7903146 is the most significantly associated variant. Few intervention studies have shown that it has negative effects on metabolic improvement after lifestyle programs. OBJECTIVE: Our objective was to assess the effects of this variant on lifestyle intervention-induced changes in glucose values and metabolic variables at 1- and 4-y follow-ups. DESIGN: The rs7903146 variant was genotyped in 335 nondiabetic, dysmetabolic participants in a randomized lifestyle intervention trial. RESULTS: Subjects with the unfavorable TT genotype showed higher values of fasting glucose and lower homeostasis model assessment of beta cell function at baseline. Lifestyle modifications were successful in the amelioration of metabolic traits in all genetic subgroups after 1 y. At 4-y follow-up most of the metabolic benefits had disappeared. In a multiple regression model, values for glucose and homeostasis model assessment of beta cell function at 4 y were significantly associated with the T allele (for glucose and homeostasis model assessments, respectively: beta = 6.6; 95% CI: 2.5, 10.7; P = 0.001; and beta = -0.37; 95% CI: -0.54, -0.20; P < 0.001) but not with intervention. There was no interaction between genotype and intervention. After 1 y, impaired fasting glucose and diabetes incidence were inversely associated with intervention. After 4 y, the presence of a T allele was associated with impaired fasting glucose (odds ratio: 3.04; 95% CI: 1.53, 6.04; P = 0.001) and diabetes (odds ratio: 2.63; 95% CI: 1.00, 6.96; P = 0.05) but not with intervention. CONCLUSIONS: Lifestyle modifications improved the metabolic pattern in all genetic subgroups. At the end of the trial, however, weight gain occurred, and carriers of the T allele developed first hyperglycemia and decreased insulin secretion, which suggests the need for different "after-care" preventive approaches tailored to each genotype's metabolic risk.

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.

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.

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.

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.

Diet or exercise: what is more effective in preventing or reducing metabolic alterations?

OBJECTIVE/DESIGN: The influence of diet and exercise on metabolic syndrome is controversial since fit individuals might also eat healthier foods. We evaluated the association of diet/exercise variation with reductions in metabolic variables and C-reactive protein (CRP) values in the experimental and control arms of a 1-year randomized lifestyle intervention trial performed in patients with multiple metabolic abnormalities. METHODS: A prospective study of 169 cases and 166 controls after a lifestyle intervention was performed. RESULTS: In the intervention group, 15/169 (8.9%), 63/169 (37.3%), and 70/169 (41.4%) reached only dietary, only exercise, and dietary/exercise targets respectively. Reductions in weight, body mass index (BMI), and waist were significant only in patients who increased exercise. Most controls did not reach any target (131/166, 78.9%), while only few patients reached only dietary (13/166, 7.8%), only exercise (5/166, 3.0%), and dietary/exercise targets (17/166, 10.2%). Weight, BMI, and waist reduction was more pronounced in those reaching the exercise target. In the whole cohort, increased exercise was inversely associated with weight, BMI, waist, and CRP, increased saturated fat was directly associated with weight, BMI, waist, and diastolic pressure variations, while increased fiber intake was inversely associated with glucose values in a multiple regression model. After adjusting for waist changes, the associations between exercise and CRP (beta=-0.023; 95% CI -0.028 -0.017; P<0.001) and the associations between fiber and glucose (beta=-0.022; -0.031 -0.013; P<0.001) remained significant. CONCLUSIONS: Independent of weight reduction, exercise level and fiber intake are inversely associated with CRP and fasting glucose values respectively. Change in lifestyle may lower inflammation and prevent metabolic deterioration.

Association of liver disease with postprandial large intestinal triglyceride-rich lipoprotein accumulation and pro/antioxidant imbalance in normolipidemic non-alcoholic steatohepatitis.

BACKGROUND: Dietary fat excess and antioxidant deficiency, altered lipid metabolism, and increased lipoperoxidation have been associated with non-alcoholic steatohepatitis (NASH), but the relative importance of each of these factors is unclear. AIMS: To assess acute intestinal and hepatic very-low-density lipoprotein (VLDL) subfraction metabolism, lipid peroxidation, and pro/antioxidant imbalance after a fat load in NASH. METHODS: Dietary habits, circulating adipokines, fasting and postprandial lipids, intestinal and hepatic VLDL, oxidized low-density lipoproteins (oxLDL), and total antioxidant status (TAS) were correlated to postprandial liver enzymes and to liver histology in 28 non-obese non-diabetic normolipidemic patients with NASH and 28 healthy controls. RESULTS: Despite similar fasting profiles, NASH had more pronounced intestinal and hepatic VLDL1 accumulation, LDL lipid peroxidation and TAS fall postprandially. Postprandial intestinal VLDL1 independently predicted oxLDL and TAS responses in NASH. In NASH, hepatic steatosis was independently associated with postprandial intestinal VLDL1 and TAS; necroinflammation with postprandial serum gamma-glutamyltransferase, oxLDL and TAS responses; and fibrosis with adiponectin and postprandial TAS and oxLDL responses. CONCLUSIONS: Postprandial intestinal VLDL1 accumulation is associated with a pro-oxidant imbalance in normolipidemic non-diabetic NASH, and both correlate with the severity of liver disease. Modulating postprandial lipoprotein metabolism may be beneficial in NASH, even if normolipidemic.

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.

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.

Should nonalcoholic fatty liver disease be included in the definition of metabolic syndrome? A cross-sectional comparison with Adult Treatment Panel III criteria in nonobese nondiabetic subjects.

OBJECTIVE: The ability of the Adult Treatment Panel III (ATP III) criteria of metabolic syndrome to identify insulin-resistant subjects at increased cardiovascular risk is suboptimal, especially in the absence of obesity and diabetes. Nonalcoholic fatty liver disease (NAFLD) is associated with insulin resistance and is emerging as an independent cardiovascular risk factor. We compared the strength of the associations of ATP III criteria and of NAFLD to insulin resistance, oxidative stress, and endothelial dysfunction in nonobese nondiabetic subjects. RESEARCH DESIGN AND METHODS: Homeostasis model assessment of insulin resistance (HOMA-IR) >2, oxidative stress (nitrotyrosine), soluble adhesion molecules (intracellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin), and circulating adipokines (tumor necrosis factor-alpha, leptin, adiponectin, and resistin) were cross-sectionally correlated to ATP III criteria and to NAFLD in 197 unselected nonobese nondiabetic subjects. RESULTS: NAFLD more accurately predicted insulin resistance than ATP III criteria: sensitivity 73 vs. 38% (P = 0.0001); positive predictive value: 81 vs. 62% (P = 0.035); negative predictive value 87 vs. 74% (P = 0.012); positive likelihood ratio 4.39 vs. 1.64 (P = 0.0001); and negative likelihood ratio 0.14 vs. 0.35 (P = 0.0001). Adding NAFLD to ATP III criteria significantly improved their diagnostic accuracy for insulin resistance. Furthermore, NAFLD independently predicted HOMA-IR, nitrotyrosine, and soluble adhesion molecules on logistic regression analysis; the presence of NAFLD entailed more severe oxidative stress and endothelial dysfunction, independent of adiposity or any feature of the metabolic syndrome in insulin-resistant subjects. CONCLUSIONS: NAFLD is more tightly associated with insulin resistance and with markers of oxidative stress and endothelial dysfunction than with ATP III criteria in nonobese nondiabetic subjects and may help identify individuals with increased cardiometabolic risk in this population.

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.

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.

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.