Association between new markers of cardiovascular risk and hepatic insulin resistance in those at high risk of developing type 2 diabetes.

AIM/HYPOTHESIS: Hepatic insulin resistance (HIR) is considered to be an independent predictor of metabolic disorders and plays an important role in systemic inflammation, which contributes to abnormalities in cardiovascular disease (CVD) risk factors. The aim of this study was to investigate the relationship between HIR and new markers of cardiovascular risks, including leptin/adiponectin ratio (L/A), lipoprotein(a) [Lp(a)], and tumor necrosis factor alpha (TNF-α), at comparable whole body insulin sensitivity in non-diabetic individuals with or without CVD and at high risk of developing type 2 diabetes. METHODS: The HIR index, L/A, Lp(a), and TNF-α were measured in 50 participants with CVD and in 200 without CVD (1:4 ratio). These were also matched for the homeostatic model assessment for insulin resistance (HOMA-IR) and Matsuda-insulin sensitivity index (ISI) in an observational study design. RESULTS: The HIR index (1.52 ± 0.14 vs. 1.45 ± 0.17, p < 0.02), L/A (3.22 ± 3.10 vs. 2.09 ± 2.27, p < 0.004), and levels of Lp(a) (66.6 ± 49.5 vs. 37.9 ± 3 6.8 mg/dL, p < 0.0001) and TNF-α (18.9 ± 21.8 vs. 5.4 ± 7.1 pg/mL, p < 0.0001) were higher in those with CVD than those without CVD. HOMA-IR and ISI were not significantly different (p = 0.88 and p = 0.35, respectively). The HIR index was directly correlated with L/A (r = 0.41, p < 0.0001), Lp(a) (r = 0.20, p < 0.002), TNF- α (r = 0.14, p < 0.03), and diastolic blood pressure (DBP) (r = 0.13, p < 0.03). The stepwise model analysis showed that L/A, Lp(a), and TNF-α explained about 20% of the variation in the HIR indices of all the participants (p < 0.02). CONCLUSIONS/INTERPRETATIONS: Our results suggest a positive association between HIR and new markers of cardiovascular risk [L/A, Lp(a), and TNF- α] at comparable whole body insulin sensitivity in those with or without CVD and at high risk of developing type 2 diabetes.

Long lasting protective effects of early l-arginine treatment on endothelium in an in vitro study.

BACKGROUND & AIMS: Excess nutrient supply, such as high fat and high glucose intake, promotes oxidative stress and advanced glycation end products accumulation. Oxidative stress and AGE accumulation cause pathological elevation of arginase activity and pro-inflammatory signaling implicated in endothelial dysfunction. Several studies showed positive effects of l-arginine supplementation in endothelial function but little is currently known about the role of l-arginine as prevention of endothelial dysfunction caused by excessive nutrient supply (overfeeding). Our aim was to evaluate a possible protective effect of l-arginine on endothelial dysfunction caused by excessive nutrient supply (overfeeding), using human endothelial cells line in an in vitro study. METHODS: Endothelial EA.hy926 cells were pre-treated with 1.72 mM of l-arginine for 24 h and afterwards subjected to nutritional stress (high lipid, high insulin and high glucose concentrations) for further 24 h. After treatment discontinuation, the cells were kept in culture for 48 h, in physiological condition, to evaluate the effects of treatments after normalization. RESULTS: Excess nutrient supply in EA.hy926 cell line showed an increase of oxidative and nitrosative stress, a rise of AGEs production, high arginase activity, leading the cells to acidosis and to cell death. l-arginine pretreatment protects the cells by reducing apoptosis, acidosis, oxidative and nitrosative stress, arginase activity and AGE accumulation. l-arginine pretreatment reduces AGEs generation and accumulation by regulating STAB1 and RAGE gene expression levels. STAB1, acting as receptor scavenger of AGEs, interferes with AGE-RAGE binding and thus prevents activation of intracellular signaling pathways leading to cell damage. Moreover the reduction of oxidative stress promotes a decrease of excessive activation of arginase involved in endothelial dysfunction. The effects of pretreatment with l-arginine last even in the absence of stimuli and despite after treatment discontinuation. CONCLUSIONS: An early l-arginine treatment is able to prevent oxidative stress and AGEs accumulation caused by overfeeding in human endothelial cell line by regulating STAB1/RAGE gene expression and by reducing excess arginase activity. The positive effects of l-arginine pretreatment continue even after treatment discontinuation in normal conditions.

Associations of statins and antiretroviral drugs with the onset of type 2 diabetes among HIV-1-infected patients.

BACKGROUND: Statin use is associated with a modest increase in the incidence of type 2 diabetes mellitus (DM) among the general population. However, HIV-infected patients have a higher risk of developing DM, and it is unclear whether statins have a diabetogenic effect in these patients. Therefore, we investigated the associations of statin use and exposure to antiretroviral drugs with type 2 DM onset in a cohort of HIV-infected patients. METHODS: This retrospective, controlled, cohort study identified HIV-1-infected patients who did not have DM and were not receiving statins at their antiretroviral treatment (ART) initiation. Follow-up was accrued from ART initiation to the earliest instance of a DM diagnosis, loss to follow-up, death, or last available visit. The incidence of DM was estimated according to statin use, which was adjusted for periods without statin treatment. The Fine-Gray competing risk model was used in the multivariate analysis to identify risk factors for developing DM. RESULTS: The analyses evaluated 6,195 patients followed for 9.8 years (interquartile range: 4.3-16.3 years). During 64,149 person-years of follow-up (PYFU), 235 patients developed DM (crude incidence: 3.66 [95%CI: 3.20-4.13] per 1,000 PYFU), and 917 (14%) patients used statins. After adjusting for potential confounders, statin use was associated with a non-significant increase in the risk of DM (AHR: 1.21, 95% CI: 0.71-2.07; P = 0.47). DM was more likely among patients who were ever treated with stavudine, and less likely among those ever treated using emtricitabine, tenofovir, abacavir, efavirenz, nevirapine, atazanavir or darunavir. CONCLUSIONS: A higher risk of diabetes mellitus was not associated with statin treatment but with traditional risk factors and stavudine use while a reduced risk of DM was associated with the use of emtricitabine, tenofovir, abacavir, efavirenz, nevirapine, atazanavir or darunavir.

Benefits of LixiLan, a Titratable Fixed-Ratio Combination of Insulin Glargine Plus Lixisenatide, Versus Insulin Glargine and Lixisenatide Monocomponents in Type 2 Diabetes Inadequately Controlled on Oral Agents: The LixiLan-O Randomized Trial.

OBJECTIVE: To evaluate efficacy and safety of LixiLan (iGlarLixi), a novel titratable fixed-ratio combination of insulin glargine (iGlar) and lixisenatide (Lixi), compared with both components, iGlar and Lixi, given separately in type 2 diabetes inadequately controlled on metformin with or without a second oral glucose-lowering drug. RESEARCH DESIGN AND METHODS: After a 4-week run-in to optimize metformin and stop other oral antidiabetic drugs, participants (N = 1,170, mean diabetes duration ∼8.8 years, BMI ∼31.7 kg/m2) were randomly assigned to open-label once-daily iGlarLixi or iGlar, both titrated to fasting plasma glucose <100 mg/dL (<5.6 mmol/L) up to a maximum insulin dose of 60 units/day, or to once-daily Lixi (20 µg/day) while continuing with metformin. The primary outcome was HbA1c change at 30 weeks. RESULTS: Greater reductions in HbA1c from baseline (8.1% [65 mmol/mol]) were achieved with iGlarLixi compared with iGlar and Lixi (-1.6%, -1.3%, -0.9%, respectively), reaching mean final HbA1c levels of 6.5% (48 mmol/mol) for iGlarLixi versus 6.8% (51 mmol/mol) and 7.3% (56 mmol/mol) for iGlar and Lixi, respectively (both P < 0.0001). More subjects reached target HbA1c <7% with iGlarLixi (74%) versus iGlar (59%) or Lixi (33%) (P < 0.0001 for all). Mean body weight decreased with iGlarLixi (-0.3 kg) and Lixi (-2.3 kg) and increased with iGlar (+1.1 kg, difference 1.4 kg, P < 0.0001). Documented symptomatic hypoglycemia (≤70 mg/dL) was similar with iGlarLixi and iGlar (1.4 and 1.2 events/patient-year) and lower with Lixi (0.3 events/patient-year). iGlarLixi improved postprandial glycemic control versus iGlar and demonstrated considerably fewer nausea (9.6%) and vomiting (3.2%) events than Lixi (24% and 6.4%, respectively). CONCLUSIONS: iGlarLixi complemented iGlar and Lixi effects to achieve meaningful HbA1c reductions, close to near normoglycemia without increases in either hypoglycemia or weight, compared with iGlar, and had low gastrointestinal adverse effects compared with Lixi.

Pharmacogenetic influence of eNOS gene variant on endothelial and glucose metabolism responses to L-arginine supplementation: Post hoc analysis of the L-arginine trial.

OBJECTIVE: To evaluate whether variants of the eNOS gene are associated with endothelial and metabolic responses to L-arginine (L-arg) supplementation. MATERIAL AND METHODS: We examined a single nucleotide polymorphism of the eNOS gene (rs753482-A>C) to investigate the effects of this variant on endothelial function (EF), colony-forming unit-endothelial cell (CFU-EC) number, asymmetric-dimethylarginine (ADMA) level, insulin sensitivity index (ISI), and insulin secretion (IS) in a post hoc analysis of the L-arg trial. The L-arg trial (6.4 g/day for 18 months) was a single-center, randomized, double-blind, parallel-group, placebo-controlled, phase III trial in individuals with impaired glucose tolerance and metabolic syndrome. followed by a 12-month extended follow-up period after termination of the study drug (NCT 00917449). RESULTS: At baseline, EF, CFU-EC numbers, ADMA levels, and ISI were impaired in subjects carrying minor allele C (both heterozygotes, AC and homozygotes, CC) as compared to subjects carrying major allele A (homozygotes, AA) (p<0.01). Compared to placebo, L-arg increased EF, CFU-EC numbers, and ISI, and improved ADMA levels and IS (p<0.01). The greatest improvements were found in AA subjects treated with L-arg, while the worst results were found in AC+CC subjects treated with placebo. In the placebo-treated subjects, EF, CFU-EC, ISI, and IS were significantly lower and ADMA was significantly higher in AC+CC subjects than in AA subjects. CONCLUSIONS: Treatment with L-arg induced similar improvements in EF, CFU-EC numbers, ADMA levels, ISI, and IS in both AA subjects and AC+CC subjects. The presence of minor allele resulted in the worst prognosis in terms of EF, CFU-EC numbers, ADMA levels, ISI, and IS during the 30-month observation period.

Smoking is associated with impaired glucose regulation and a decrease in insulin sensitivity and the disposition index in first-degree relatives of type 2 diabetes subjects independently of the presence of metabolic syndrome.

The aim of this study was to investigate glucose tolerance, insulin secretion and insulin resistance according to smoking habits in first-degree relatives of type 2 diabetes patients, a population at high risk for developing diabetes. One thousand three hundred (646 females and 654 males) subjects underwent an oral glucose tolerance test (OGTT) to investigate their glucose metabolism and answered questionnaires about their lifestyle habits. Smoker subjects showed significant impairment compared with non-smoker subjects in 2-h post-oral glucose tolerance test (2hOGTT, 129.3 ± 40.2 vs. 117.7 ± 37.6 mg/dl, p < 0.001), the OGTT insulin sensitivity (386.3 ± 54.9 vs. 400.5 ± 53.4 ml min(-1) m(2), p < 0.01) method and the insulin sensitivity and secretion index-2 (ISSI-2, 1.7 ± 0.8 vs. 2.0 ± 1.0, p < 0.005). Metabolic syndrome (MS) was higher in the smoker than in the non-smoker group (46.5 vs. 29.7 %, p < 0001), and smokers were more sedentary than non-smokers (3.94 ± 3.77 vs. 4.86 ± 4.41 h/week, p < 0.001). Smokers showed an increased risk of impaired glucose regulation (IGR: impaired glucose tolerance or diabetes mellitus) with a hazard ratio (HR) adjusted by gender, metabolic syndrome and physical activity of 1.78, 95 % CI 1.27-2.47 (p < 0.001). The association between smoking and MS conferred a risk of IGR that was five times higher (HR 5.495, 95 % CI 4.07-7.41, p < 0.001). Smoking habit was a significant explanatory variable in a multiple forward stepwise regression analysis performed using 2hOGTT and ISSI-2 as dependent variables (p < 0.0001, R = 0.313 and p < 0.0001, R = 0.347, respectively). In conclusions, our results show that tobacco smoking is tightly associated with impairments in glucose metabolism and insulin sensitivity and insulin secretion.

A novel truncated form of eNOS associates with altered vascular function.

AIMS: Nitric oxide (NO) plays a key role in vascular homeostasis and is produced by endothelial NO synthase (eNOS), encoded by NOS3 gene. We previously reported the genetic association between NOS3 rs753482-A>C polymorphism on intron 19 and coronary artery disease (CAD). In the attempt of conferring functional implication to the rs753482-A>C polymorphism, we investigated its influence on transcript maturation. METHODS AND RESULTS: A transcript variant skipping exons 20-21 is prevalent in carriers of the rs753482-C allele and is translated in a novel truncated form of eNOS. The truncated eNOS displays increased basal NO production, is insensitive to calcium stimulation, and, upon heterodimerization with the full-length eNOS protein, exerts a dominant-negative effect on NO production. CAD patients and healthy subjects' carriers of the rs753482-C genotype are characterized by increased NO basal levels in peripheral blood and platelets, and negatively respond to oral glucose load by failing to increase NO synthesis following insulin wave. Furthermore, forearm vasodilation after reactive hyperaemia is dramatically impaired in rs753482-C carriers. CONCLUSIONS: We demonstrated that subjects carrying the rs753482-C genotype express a novel stable truncated form of eNOS with altered enzymatic activity that influences NO production and endothelial function. These findings open to new intriguing perspectives to several diseases involving vascular response to NO.

L-arginine enriched biscuits improve endothelial function and glucose metabolism: a pilot study in healthy subjects and a cross-over study in subjects with impaired glucose tolerance and metabolic syndrome.

OBJECTIVE: The aim of this study was to evaluate the effects of a new L-arginine-enriched biscuit on endothelial function, insulin sensitivity/secretion and body composition. MATERIALS/METHODS: The project was composed of two studies. The first study was an acute pilot postprandial study in 7 healthy subjects that evaluated bio-availability and vascular effects of L-arginine-enriched biscuits that contained 6.6 gL-arginine, 21.9 g carbohydrates, 3.6 g protein, 7.5 g fat and 4.3 g dietary fiber compared with placebo biscuits and 6.6 g powdered L-arginine. Subjects underwent the tests in random order, in at least 14-day intervals. The second study was a double-blind crossover study in 15 obese subjects with IGT and MS. These subjects consumed 6.6 g of L-arginine-enriched biscuits or placebo biscuits in a 1600 kcal diet. Each study period lasted 2 weeks with a 2-week washout in between. Endothelial function, glucose tolerance, insulin sensitivity and insulin secretion were evaluated at the end of each intervention period. RESULTS: In the first study, the groups that received the L-arginine-enriched biscuits and the powdered L-arginine had similarly increased L-arginine, NOx and cGMP levels and post-ischemic blood flow (PI-BF). In both cases, these levels were significantly higher than those in the placebo biscuit recipient group. In the second study, the L-arginine-enriched biscuit recipient group displayed increased L-arginine, NOx, cGMP, PI-BF, and Matsuda index levels, whereas their circulating glucose, proinsulin/insulin ratio and fat mass were decreased compared with the placebo biscuit recipient group. CONCLUSIONS: L-Arginine-enriched biscuits with low sugar and protein content enhance endothelial function and improve glucose metabolism, insulin sensitivity and insulin secretion in subjects with IGT and MS.

Effects of saxagliptin added to sub-maximal doses of metformin compared with uptitration of metformin in type 2 diabetes: the PROMPT study.

OBJECTIVE: The PROMPT study compared efficacy and tolerability of two treatment intensification strategies: adding saxagliptin or uptitrating metformin monotherapy, in patients with type 2 diabetes (T2D) and inadequate glycaemic control on a sub-maximal metformin dose. RESEARCH DESIGN AND METHODS: In this double-blind, 24-week study, metformin-tolerant patients with T2D on metformin monotherapy were randomised to receive fixed-dose metformin 1500 mg/day, plus either add-on saxagliptin 5 mg/day (SAXA-MET) or a two-step metformin uptitration (MET-UP) to a maximum dose (2500 mg/day). CLINICAL TRIAL REGISTRATION: NCT01006590. MAIN OUTCOME MEASURES: Primary: absolute change from baseline in glycated haemoglobin A(1c) (HbA(1c)) (Week 24). Secondary: proportion of patients achieving a therapeutic glycaemic response (Week 24); change from baseline in fasting plasma glucose (Week 24); safety and tolerability. Exploratory analyses comprised three patient-related questionnaires, including the validated 5-dimension Digestive Health Status Index (DHSI). RESULTS: A total of 286 patients were randomised: (SAXA-MET: 147; MET-UP: 139). Baseline mean (SD) HbA(1c): 7.71 (0.85; SAXA-MET); 7.80 (0.82; MET-UP). Adjusted mean reductions from baseline in HbA(1c) (Week 24): -0.47% (SAXA-MET); -0.38% (MET-UP); mean (95% CI) difference in treatment effect, -0.10% (-0.26, 0.07); p = 0.260. The proportion of patients (95% CI) achieving a therapeutic glycaemic response (HbA(1c) < 7%): 43.8% (34.8, 49.6) (SAXA-MET) vs. 35.0% (29.0, 43.8) (MET-UP). Of the five DHSI domains, mean (95% CI) differences were observed for diarrhoea-predominant score (+0.8 [-2.5, 4.0] vs. +7.9 [4.6, 11.2]) and dysmotility score (-0.5 [-2.0, 1.0] vs. +1.9 [0.3, 3.4]), (SAXA-MET and MET-UP, respectively). The most common adverse event was diarrhoea: 6.1% (SAXA-MET) vs. 12.2% (MET-UP). CONCLUSIONS: In metformin-tolerant patients with T2D (inadequately controlled on sub-maximal metformin monotherapy), saxagliptin was well tolerated. Although HbA(1c) reduction was not significantly different between treatment groups, the lower occurrence of gastrointestinal symptoms in the SAXA-MET group suggests that saxagliptin add-on treatment may be a suitable alternative treatment strategy to metformin uptitration.

Long-term glucose tolerance in highly experienced HIV-infected patients receiving nucleoside analogue-sparing regimens.

Thirty-nine HIV-1-infected patients treated for 156 weeks with a new nucleoside analogue-sparing regimen [raltegravir, etravirine and maraviroc (REM) or raltegravir, etravirine and darunavir/ritonavir (RED)] showed a uniform increase in fasting glucose levels and a uniform decrease in insulin secretory capacity. Diabetes mellitus occurred in one RED-treated and four REM-treated patients. A worsening glucose tolerance was observed in highly treatment-experienced HIV-infected patients receiving effective antiretroviral therapy after virological failure.

Risk of type 2 diabetes among HIV-infected and healthy subjects in Italy.

Type 2 diabetes mellitus is a growing problem in HIV population and a comparison with the general population may help screening and prevention. In this cross-sectional study the authors determined the prevalence of type 2 diabetes mellitus in 4,249 HIV-infected subjects attending the San Raffaele Infectious Diseases Department compared with 9,148 healthy controls recruited in 15 Italian regions, and identified risk factors associated with of type 2 diabetes mellitus. Type 2 diabetes mellitus was defined as reported diabetes, a fasting plasma glucose concentration ≥7.0 mmol/l, or current use of anti-diabetic medication. Prevalence of type 2 diabetes mellitus was higher in HIV-infected than healthy subjects (4.1 vs. 2.5 %; P < 0.0001). At multivariable analysis, HIV-infected subjects (odds ratio 1.70, 95 % CI, 1.12-2.51; P = 0.009), older age (P < 0.0001), higher BMI (P < 0.0001) and hypertension (P = 0.039) were associated with a higher risk of diabetes. Among HIV-infected patients, the risk of type 2 diabetes mellitus increased with older age (P < 0.0001), higher BMI (P = 0.003), higher triglycerides (P = 0.015) lower total cholesterol (P = 0.008), longer duration of HIV infection (P = 0.036) lower nadir CD4 (P = 0.027). Prevalence of type 2 diabetes mellitus in HIV-infected subjects was almost two-fold increased than healthy subjects and it was associated with the typical risk factors of the general population and also to longer duration of HIV infection and lower nadir CD4.

Aerobic and resistance training effects compared to aerobic training alone in obese type 2 diabetic patients on diet treatment.

AIMS: The study was designed to compare a combined aerobic and resistance training (ART) with an aerobic training (AT) over hemodynamic, glucose metabolism and endothelial factors, adipokines and pro-inflammatory marker release in a population of obese type 2 diabetic patients. METHODS: Forty-seven patients were randomly assigned to aerobic (27 patients) or aerobic plus resistance (20 patients) exercise trainings, on the top of a diet regime. Anthropometric, metabolic, hormonal and inflammatory variables were measured at hospitalization and discharge. RESULTS: Both exercise programs equally improved body weight and fructosamine levels however ART only partially decreased HOMA index compared with AT (ART: -25% vs AT: -54%, p<0.01). Mean blood pressure (AT: -3.6 mmHg vs ART: +0.6 mmHg, p<0.05) and endothelin-1 (ET-1) incremental areas during walking test (AT: -11% vs ART: +30%, p<0.001) decreased after AT while increased after ART. Adiponectin levels increased by 54% after AT while decreased by 13% after ART (p<0.0001) and matrix metalloproteinase-2 (MMP-2), tumor necrosis factor-alpha (TNF-alpha) and monocyte chemoattractan protein-1 (MCP-1) levels significantly decreased in AT while increased in ART group. CONCLUSIONS: Compared with AT, ART similarly enhanced body weight loss but exerted less positive effects on insulin sensitivity and endothelial factors, adipokines and pro-inflammatory marker release.

Body weight, not insulin sensitivity or secretion, may predict spontaneous weight changes in nondiabetic and prediabetic subjects: the RISC study.

OBJECTIVE: Previous studies have found that high insulin sensitivity predicts weight gain; this association has not been confirmed. Our aim was to systematically analyze metabolic predictors of spontaneous weight changes. RESEARCH DESIGN AND METHODS: In 561 women and 467 men from the Relationship Between Insulin Sensitivity and Cardiovascular Disease (RISC) cohort (mean age 44 years, BMI range 19-44 kg/m(2), 9% impaired glucose tolerance) followed up for 3 years, we measured insulin sensitivity (by a euglycemic clamp) and ß-cell function (by modeling of the C-peptide response to oral glucose and by acute insulin response to intravenous glucose). RESULTS: Insulin sensitivity was similar in weight gainers (top 20% of the distribution of BMI changes), weight losers (bottom 20%), and weight stable subjects across quartiles of baseline BMI. By multiple logistic or linear regression analyses controlling for center, age, sex, and baseline BMI, neither insulin sensitivity nor any ß-cell function parameter showed an independent association with weight gain; this was true in normal glucose tolerance, impaired glucose tolerance, and whether subjects progressed to dysglycemia or not. Baseline BMI was significantly higher in gainers (26.1 ± 4.1 kg/m(2)) and losers (26.6 ± 3.7 kg/m(2)) than in weight stable subjects (24.8 ± 3.8 kg/m(2), P<0.0001 for both gainers and losers). Baseline waist circumference (or equivalently, BMI or weight) was a positive, independent predictor of both weight gain and weight loss (odds ratio 1.48 [95% CI 1.12-1.97]) in men and (1.67 [1.28-2.12]) in women. In men only, better insulin sensitivity was an additional independent predictor of weight loss. CONCLUSIONS: Neither insulin sensitivity nor insulin secretion predicts spontaneous weight gain. Individuals who have attained a higher weight are prone to either gaining or losing weight regardless of their glucose tolerance.

Fasting hyperinsulinemia associates with increased sub-clinical inflammation in first-degree relatives normal glucose tolerant women independently of the metabolic syndrome.

BACKGROUND: To evaluate the influence of gender on the relationship between inflammation and hyperinsulinemia in first-degree relatives of type 2 diabetic patients independently of metabolic syndrome. METHODS: Study group consisted in 217 first-degree relatives with normal glucose tolerance after an oral glucose tolerance test. A logistic analysis, adjusted for age, sex and all the components of the metabolic syndrome, was used to determine the relationship between interleukin-6 (IL-6) and leptin and tertiles of fasting insulin, and to take into account the influence of gender. RESULTS: In the whole cohort, IL-6 and leptin were significantly higher and adiponectin significantly lower in the III tertile when corrected for age, body mass index (BMI) and metabolic syndrome components. In women, but not in men, IL-6 and leptin remained significantly higher when corrected for metabolic syndrome. In the whole cohort and in women, univariate correlations between IL-6 concentrations and the parameters under evaluation showed that IL-6 and leptin were positively correlated with age, BMI, waist, systolic blood pressure (SBP), diastolic blood pressure (DBP), fasting glucose, fasting insulin, Delta AUC insulin area, triglyceride (TG), free fatty acids (FFA) and monocyte chemoattractant protein-1 (MCP-1) and inversely correlated with HDL cholesterol (HDL-C) and adiponectin. In women a forward stepwise linear regression analysis in a model including age, BMI, features of metabolic syndrome, fasting insulin, Delta AUC insulin and insulin sensitivity index (ISI) index revealed that only IL-6 and leptin were independently associated with fasting insulin levels. CONCLUSIONS: In first-degree relatives normal glucose tolerant women, fasting hyperinsulinemia, independently of the presence of metabolic syndrome, is associated with elevated IL-6 and leptin levels, suggesting an increased cardiovascular risk.

Oral L-arginine supplementation improves endothelial function and ameliorates insulin sensitivity and inflammation in cardiopathic nondiabetic patients after an aortocoronary bypass.

It is known that L-arginine treatment can ameliorate endothelial dysfunction and insulin sensitivity in type 2 diabetes mellitus patients, but little is known on L-arginine effects on these variables in nondiabetic patients with stable cardiovascular disease (coronary artery disease). We evaluated the effects of long-term oral L-arginine treatment on endothelial dysfunction, inflammation, adipokine levels, glucose tolerance, and insulin sensitivity in these patients. Sixty-four patients with cardiovascular disease previously submitted to an aortocoronary bypass and not known for type 2 diabetes mellitus had an oral glucose load to define their glucose tolerance. Thirty-two patients with nondiabetic response were eligible to receive, in a double-blind randomized parallel order, L-arginine (6.4 g/d) or placebo for 6 months. An evaluation of insulin sensitivity index during the oral glucose load, markers of systemic nitric oxide bioavailability and inflammation, and blood flow was performed before and at the end of the treatment in both groups. Compared with placebo, L-arginine decreased asymmetric dimethylarginine levels (P < .01), indices of endothelial dysfunction, and increased cyclic guanosine monophosphate (P < .01), L-arginine to asymmetric dimethylarginine ratio (P < .0001), and reactive hyperemia (P < .05). Finally, L-arginine increased insulin sensitivity index (P < .05) and adiponectin (P < .01) and decreased interleukin-6 and monocyte chemoattractant protein-1 levels. In conclusion, insulin resistance, endothelial dysfunction, and inflammation are important cardiovascular risk factors in coronary artery disease patients; and L-arginine seems to have anti-inflammatory and metabolic advantages in these patients.

Effects of growth hormone treatment on arginine to asymmetric dimethylarginine ratio and endothelial function in patients with growth hormone deficiency.

Patients with growth hormone deficiency (GHD) are known to have reduced life expectancy due to increased cardiovascular and cerebrovascular events. An increase in asymmetric dimethylarginine (ADMA) levels previously found in GHD patients could promote premature atherosclerosis. The aim of this study was to determine whether 6-month growth hormone (GH) replacement therapy was able to decrease ADMA levels and ameliorate endothelial dysfunction. Thirty-one GHD patients were studied before and after 6 months of GH (4 microg/[kg d], daily) replacement therapy. Reduced pretreatment levels of serum insulin-like growth factor (IGF) 1 were normalized during GH treatment (88.2 +/- 62.5 to 191.7 +/- 80.3 ng/mL, P < .0001). After 6 months of GH replacement, plasma cyclic guanosine monophosphate levels significantly increased (2.14 +/- 0.52 to 3.54 +/- 1.2 ng/mL, P < .0001), serum ADMA levels were significantly decreased (0.65 +/- 0.1 vs 0.59 +/- 0.11 mumol/L, P < .05), and arganine (Arg) to ADMA ratio was significantly higher (155 +/- 53 vs 193 +/- 61, P < .01). No changes were observed for plasma nitric oxide end products (nitrite and nitrate) levels after GH treatment (21.9 +/- 14.9 vs 24.1 +/- 19.0 mumol/L, not significant). Basal forearm blood flow remained unchanged, whereas reactive hyperemia increased from 7.30 +/- 5.31 mL/100 mL forearm per minute before GH therapy to 13.18 +/- 7.30 mL/100 mL forearm per minute after 6 months of therapy (P < .001). There was a positive correlation between IGF-1 and cyclic guanosine monophosphate (r = 0.73, P < .0001), IGF-1 and reactive hyperemia (r = 0.63, P < .0001), and IGF-1 and Arg/ADMA ratio (r = 0.44, P < .01). Conversely, a negative correlation was found between IGF-1 and ADMA levels (r = -0.41, P < .02). At the end of the study period, fat-free mass, plasma glucose, and hemoglobin A(1c) levels significantly increased, even if they were still in the reference range, suggesting moderate alteration of glucose metabolism. In conclusion, in GHD patients, GH replacement contributes to decreased, to some extent, cardiovascular risk, reducing ADMA levels and improving Arg/ADMA ratio and endothelial dysfunction.

Food selection based on total antioxidant capacity can modify antioxidant intake, systemic inflammation, and liver function without altering markers of oxidative stress.

BACKGROUND: It is unknown whether diets with a high dietary total antioxidant capacity (TAC) can modify oxidative stress, low-grade inflammation, or liver dysfunction, all of which are risk factors for type 2 diabetes and cardiovascular disease. OBJECTIVE: We studied the effect of high- and low-TAC (HT and LT, respectively) diets on markers of antioxidant status, systemic inflammation, and liver dysfunction. DESIGN: In a crossover intervention, 33 healthy adults (19 men, 14 women) received the HT and LT diets for 2 wk each. Dietary habits were checked with a 3-d food record during both diet periods and the washout period. RESULTS: Fruit and vegetable, macronutrient, dietary fiber, and alcohol intakes did not differ significantly between the 2 diets, whereas dietary TAC, alpha-tocopherol, and ascorbic acid were significantly (P < 0.001) higher during the HT diet. Plasma alpha-tocopherol rose during the HT and decreased during the LT diet (P < 0.02 for difference) without changes in markers of oxidative stress except plasma malondialdehyde, which decreased unexpectedly during the LT diet (P < 0.05). Plasma high-sensitivity C-reactive protein, alanine aminotransferase, gamma-glutamyltranspeptidase, and alkaline phosphatase concentrations decreased during the HT compared with the LT diet (mean +/- SEM for pre-post changes: -0.72 +/- 0.37 compared with 1.05 +/- 0.60 mg/L, P < 0.01; -1.73 +/- 1.02 compared with 2.33 +/- 2.58 U/L, P < 0.01; -2.12 +/- 1.45 compared with 5.15 +/- 2.98 U/L, P < 0.05; and 1.36 +/- 1.34 compared with 5.06 +/- 2.00 U/L, P < 0.01, respectively). CONCLUSION: Selecting foods according to their TAC markedly affects antioxidant intake and modulates hepatic contribution to systemic inflammation without affecting traditional markers of antioxidant status.

Hyperinsulinemia and impaired leptin-adiponectin ratio associate with endothelial nitric oxide synthase polymorphisms in subjects with in-stent restenosis.

Little is known about the association of endothelial nitric oxide synthase (NOS3) gene polymorphisms and the presence of insulin resistance and the early evolution of atherosclerosis in nondiabetic subjects with cardiovascular disease (CAD) and stent implantation. The present study was performed in an attempt to better understand whether metabolic, endothelial, and angiographic findings characteristic of subjects with cardiovascular disease and in-stent restenosis are related to NOS3 variants. This is a case-control study performed from 2002 to 2006. All subjects admitted to the study were recruited in the Nord-Centre of Italy, most from Milan and its surrounding towns. Measures of glucose tolerance, insulin sensitivity, markers of endothelial dysfunction, forearm vasodilation, and adipokine levels were determined and associated to the frequency of two single-nucleotide polymorphisms of NOS3, i.e., Glu298Asp (rs1799983, G/T) and rs753482 (intron 18 A/C). A total of 747 subjects, not known to have diabetes, were evaluated: 333 subjects had asymptomatic CAD, 106 subjects had unstable angina and were evaluated for in-stent restenosis 6 mo after stent placement, and 308 were control subjects. The presence of TT and CC minor alleles was significantly greater in case groups compared with control subjects. At phenotypic level, subjects with the polymorphisms were characterized by hyperinsulinemia and reduced reactive hyperemia, whereas increased leptin and decreased adiponectin levels were present in subjects with restenosis in the presence of reduced minimal lumen diameter and length of stenosis almost doubled. Hyperinsulinemia, endothelial dysfunction, and a more atherogenic profile seem to be peculiar features of subjects with asymptomatic CAD and restenosis carrying NOS3 gene variants.

Increased insulin-stimulated endothelin-1 release is a distinct vascular phenotype distinguishing Cushing's disease from metabolic syndrome.

OBJECTIVE: Although much is known about the anti-inflammatory effects of an acute corticosteroid therapy, little is known about the effects on chronic hypercortisolism on endothelial dysfunction and proinflammatory alterations in patients with Cushing's disease (CD). PATIENTS AND METHODS: We studied 9 patients with CD, 10 patients with metabolic syndrome and 27 normal controls. The tests consisted of an intravenous bolus of 0.1 U/kg insulin combined with a euglycaemic clamp technique with an arterialized forearm and assessment of the training parameters deep-venous balance of forearm glucose uptake (as an index of insulin sensitivity); NO(x) (nitric oxide end-products), c-GMP (second messenger of nitric oxide) and endothelin-1 release, as indices of endothelial function and proinflammatory systemic markers. RESULTS: Forearm glucose uptake incremental area was significantly lower in Cushing's disease and in the metabolic syndrome than in controls, suggesting a state of severe insulin resistance. Compared to controls and to the metabolic syndrome, basal and insulin-stimulated NO(x) release incremental areas were significantly reduced in Cushing's disease, while forearm c-GMP release was similarly decreased in CD and metabolic syndrome. By contrast, endothelin-1 incremental areas after insulin bolus were significantly higher in CD than in controls and the metabolic syndrome, in the presence of increased TNF-alpha, IL-6 and CRP levels. Forearm glucose uptake incremental area significantly correlated with NO(x) incremental area, forearm c-GMP release incremental area, TNF-alpha levels and ET-1 incremental area. CONCLUSIONS: In patients with CD, supraphysiological insulin levels are not able to overcome the insulin resistance due to chronic hypercortisolism. Furthermore, an increased proatherogenic risk profile is characterized by decreased nitric oxide synthesis and activity, enhanced endothelin-1 levels and increased proinflammatory markers.