Insulin Treatment Is Associated With Improved Fetal Placental Vascular Circulation in Obese and Non-obese Women With Gestational Diabetes Mellitus.

Objective: The present study was designed to investigate the impact of carbohydrate restriction and insulin treatment on placental maternal and fetal vascular circulation in obese and non-obese women with gestational diabetes mellitus (GDM). Design and methods: One Hundred Ninety-One women with GDM who gave birth and underwent a placental histopathological examination at Wolfson Medical Center, Israel, were included in the study: 122 women who were treated with carbohydrate/calorie restriction diet (Group 1) and 69 women who were treated with diet plus insulin (Group 2). Additionally, each group was divided into two subgroups according to pre-pregnancy BMI: non-obese and obese. Results: Maternal vascular malperfusion lesions did not differ significantly between groups. Vascular lesions related to fetal malperfusion were significantly lower in GDM women treated by insulin and diet compared to women with diet alone (p = 0.027). Among fetal malperfusion lesions, villous changes consistent with fetal thrombo-occlusive disease (FTOD) were significantly lower in women treated with diet plus insulin and lowest in GDM women with pre-pregnancy BMI < 30 kg/m2 (p = 0.009). In the logistic regression analysis, insulin treatment was significantly associated with a decreased rate of villous changes consistent with FTOD (OR 0.97, 95% CI 0.12-0.80, p = 0.03). Prevalence of gestational hypertension was higher in obese women of both treatment groups (p = 0.024). Conclusion: Combination of obesity and GDM increased rate of FTOD and prevalence of gestational hypertension. Carbohydrate restriction diet plus insulin treatment was associated with improved fetal placental vascular circulation, especially in GDM women with pre-pregnancy BMI < 30 kg/m2.

Effect of Vitamin D Supplementation on Markers of Vascular Function: A Systematic Review and Individual Participant Meta-Analysis.

BACKGROUND: Low 25-hydroxyvitamin D levels are associated with an increased risk of cardiovascular events, but the effect of vitamin D supplementation on markers of vascular function associated with major adverse cardiovascular events is unclear. METHODS AND RESULTS: We conducted a systematic review and individual participant meta-analysis to examine the effect of vitamin D supplementation on flow-mediated dilatation of the brachial artery, pulse wave velocity, augmentation index, central blood pressure, microvascular function, and reactive hyperemia index. MEDLINE, CINAHL, EMBASE, Cochrane Central Register of Controlled Trials, and http://www.ClinicalTrials.gov were searched until the end of 2016 without language restrictions. Placebo-controlled randomized trials of at least 4 weeks duration were included. Individual participant data were sought from investigators on included trials. Trial-level meta-analysis was performed using random-effects models; individual participant meta-analyses used a 2-stage analytic strategy, examining effects in prespecified subgroups. 31 trials (2751 participants) were included; 29 trials (2641 participants) contributed data to trial-level meta-analysis, and 24 trials (2051 participants) contributed to individual-participant analyses. Vitamin D3 daily dose equivalents ranged from 900 to 5000 IU; duration was 4 weeks to 12 months. Trial-level meta-analysis showed no significant effect of supplementation on macrovascular measures (flow-mediated dilatation, 0.37% [95% confidence interval, -0.23 to 0.97]; carotid-femoral pulse wave velocity, 0.00 m/s [95% confidence interval, -0.36 to 0.37]); similar results were obtained from individual participant data. Microvascular function showed a modest improvement in trial-level data only. No consistent benefit was observed in subgroup analyses or between different vitamin D analogues. CONCLUSIONS: Vitamin D supplementation had no significant effect on most markers of vascular function in this analysis.

The role of ferritin and adiponectin as predictors of cartilage damage assessed by arthroscopy in patients with symptomatic knee osteoarthritis.

The aim of the present study was to evaluate whether circulating serum ferritin and adiponectin (ADP) in the serum and synovial fluid correlate with cartilage damage severity assessed by arthroscopy in patients with knee osteoarthritis. The 40 subjects with symptomatic knee osteoarthritis were divided into four groups according to arthroscopy assessed cartilage damage, using Outerbridge (OB) grading. Group I included minor damage while Group IV included severe damage. Metabolic parameters, bone homeostasis, and insulin resistance markers were determined. Synovial fluid of the affected knee joint was obtained and assessed for synovial adiponectin levels. Parameters of bone homeostasis in the serum including levels of PTH, alkaline phosphatase, 25OH vitamin D, serum calcium and phosphorus were similar in the four groups. A significant difference in the level of serum ferritin was found: ferritin levels increased from Group 1 to Group 4 in a continuous fashion (p < 0.035). In General linear model (GLM) analysis significant by-group differences in circulating ferritin persisted even after adjustment (p = 0.030). Although all groups were similar in terms of serum ADP levels, between groups difference in synovial fluid ADP was found (p < 0.037). However, after controlling for the age, there was no between-group difference in terms of synovial ADP levels. Serum ferritin levels were associated with cartilage damage severity assessed by arthroscopy. This association was independent of age, sex, BMI, and CRP levels suggesting that ferritin may be actively involved in the progression of cartilage damage in patients with symptomatic knee OA.

The relationship between hypertensive disorders in pregnancy and placental maternal and fetal vascular circulation.

We examined the impact of chronic hypertension (HTN), gestational HTN, and preeclampsia on placental maternal and fetal vascular circulation. Of the 1047 women who gave birth and underwent a placental histopathologic examination between 2007 and 2013 at Wolfson Medical Center, 140 women were included in the present study: 34 women with preeclampsia, 25 women with chronic HTN, 28 women with gestational HTN, and 53 women without hypertensive disorder, matched by age, gravidity, parity, and mode of delivery.Placental lesions related to maternal vascular malperfusion (MVM) differed significantly across groups (P < .0001) and were highest in subjects with chronic HTN and preeclampsia (72% and 65%, respectively) and lowest in women without hypertensive disorder (26%). Placental fetal vascular malperfusion rate did not differ significantly between groups (P = .767). In the logistic regression analysis, chronic HTN emerged as a significant predictor of placental MVM and increased the risk of this outcome more than sixfold (odds ratio 6.614, 95% confidence interval 2.047-21.37, P = .002). Preeclampsia emerged as a significant predictor of MVM and more than tripled the risk of this outcome (odds ratio 3.468, 95% confidence interval 1.083-11.103, P = .036). Gestational HTN was not significantly associated with increased MVM rate. We demonstrated that chronic HTN and preeclampsia were associated with an increased rate of vascular placental maternal malperfusion and emerged as significant independent predictors of this outcome.

Circulating osteoprotegerin in postmenopausal osteoporotic women: marker of impaired glucose regulation or impaired bone metabolism.

OBJECTIVE: Osteoprotegerin (OPG) is closely related to insulin resistance and bone remodeling. However, no studies have examined the role of OPG in postmenopausal women with coexistent impaired glucose and bone regulation. The present study investigated the relationship of OPG to glucose homeostasis and insulin resistance in postmenopausal osteoporotic women with different types of glucose tolerance. METHODS: In all, 114 postmenopausal osteoporotic women were divided into three groups according to glucose tolerance status: 51 with normal glucose tolerance (NGT, group 1), 31 with impaired glucose tolerance (IGT, group 2), and 32 with type 2 diabetes mellitus (DM, group 3). Study participants were evaluated for metabolic parameters, OPG, Homeostasis Model Assessment of Insulin Resistance (HOMA-IR), and bone mineral density parameters. RESULTS: The OPG levels differed significantly across groups and increased from group 1 to group 3 in a continuous fashion (analysis of variance, P < 0.0001). In post-hoc analysis, OPG was significantly lower in osteoporotic women with NGT, than participants with IGT and DM (P < 0.05 and P < 0.0001, respectively). OPG was positively associated with HOMA-IR (P < 0.0001). No association between serum OPG levels and measures of BMD was observed. In a multiple regression analysis, OPG emerged as an independent predictor of HOMA-IR even after controlling for age, body mass index, and creatinine. CONCLUSIONS: OPG is significantly higher in postmenopausal osteoporotic women with impaired glucose regulation (IGT and DM) than women with NGT. OPG was independently associated with insulin resistance assessed by HOMA-IR. Thus, measurement of OPG may potentially be considered as a prediabetic state screening in postmenopausal osteoporotic women.

Does a First-Degree Family History of Diabetes Impact Placental Maternal and Fetal Vascular Circulation and Inflammatory Response?

Context: Heritability of diabetes is associated with hyperinsulinemia, impaired endothelial function, and inflammatory up-regulation. However, no studies have examined whether a family history of diabetes (FHD) effects placental vascular circulation. Objective: The current study was designed to investigate the impact of a first-degree FHD on placental vascular circulation and inflammatory lesions. Design: Observational cohort study. Setting: Pregnant women who gave birth at Edith Wolfson Medical Center. Patients: Three hundred thirty-nine pregnant women were divided into two groups according to presence of FHD: group 1 included 225 subjects without FHD, and group 2 included 114 subjects with FHD. Intervention: Placental histopathological examination. Main Outcome Measures: Placental vascular supply abnormalities of maternal and fetal origin. Results: Maternal vascular supply (MVS) abnormalities of the placenta were significantly higher in subjects with FHD, compared with subjects without FHD (P < 0.005). Fetal vascular supply abnormalities, as well as maternal and fetal inflammatory response did not differ significantly between groups. In the general linear modeling analysis, FHD was an independent and significant predictor of MVS abnormalities and more than doubled the risk of this outcome. Gestational diabetes mellitus (GDM) incidence was significantly higher in subjects with FHD (P < 0.0001). Significant by-group differences in GDM persisted even after adjustment for age and body mass index. Although incidence of gestational hypertensive disorders was significantly higher in individuals with FHD, after adjustment FHD did not significantly predict this outcome. Conclusions: A first-degree FHD is significantly and independently associated with an increased rate of maternal vascular perfusion abnormalities and risk of GDM.

Placental maternal and fetal vascular circulation in healthy non-obese and metabolically healthy obese pregnant women.

BACKGROUND AND AIMS: We investigated placental histopathology for lesions that are associated with maternal and fetal circulation abnormalities in obese pregnant women with and without metabolic alterations. METHODS: 332 pregnant women were divided into three groups: Group 1 included 163 non-obese metabolically healthy (NOMH), Group 2 106 obese metabolically healthy (OMH), and Group 3 63 obese metabolically abnormal (OMA) subjects, respectively. RESULTS: Fetal vascular supply (FVS) abnormalities and Willous maturation defect (WMD) rate were higher in obese subjects without metabolic abnormalities, compared to NOMH subjects (p < 0.021 and p < 0.018, respectively). In the logistic regression analysis, obesity emerged as a significant independent predictor of FVS abnormalities (OR 1.54, 95% CI 1.193-1.992, p = 0.001) and WMD (OR 2.004, 95% CI 1.173-3.422, p = 0.011). Although maternal vascular supply (MVS) abnormalities differed significantly across groups (31%, 38% and 54% respectively, p < 0.005), in the logistic regression analysis, obesity was not significantly associated with MVS abnormalities. CONCLUSIONS: We demonstrated that obesity, per se, is associated with an increased rate of placental vascular supply abnormalities and has a more adverse effect on fetal vascular circulation than on maternal vascular supply.

Effect of metformin treatment on circulating osteoprotegerin in patients with nonalcoholic fatty liver disease.

PURPOSE/INTRODUCTION: Growing evidence suggests complex interplay between nonalcoholic fatty liver disease (NAFLD) and bone health. The present study's aim was to examine the impact of metformin treatment on circulating osteoprotegerin (OPG) in patients with NAFLD, a population in which this relationship has not yet been studied. METHODS: In a randomized, placebo-controlled study, 63 patients with NAFLD were assigned to one of two groups: Group 1 received daily metformin; Group 2 received a placebo. Metabolic parameters, insulin resistance markers and OPG levels were examined at baseline and at the end of the study. RESULTS: In the placebo group, liver function and OPG levels did not change during the study. Among metformin-treated patients, significant declines in OPG and alkaline phosphatase were observed. CRP and ALT decreased marginally during the 4-month treatment period. While at baseline circulating OPG levels did not differ significantly between the groups, by the end of the study OPG was significantly lower in patients treated with metformin than in the placebo group (p < 0.0001). Delta OPG was significantly greater in the metformin group than the placebo group (p = 0.001). In the general linear model, metformin treatment was the only significant independent predictor of endpoint and delta OPG. CONCLUSIONS: Metformin treatment was associated with a significant decrease in OPG levels in patients with NAFLD. The effect on OPG was associated with exposure to metformin per se. CLINICAL TRIAL REGISTRATION NUMBER: NCT01084486.

Effects of long-term risedronate treatment on serum ferritin levels in postmenopausal women with osteoporosis: the impact of cardiovascular risk factor load.

OBJECTIVE: Although ferritin has been considered as a possible link between accelerated bone loss and atherosclerosis, the long-term impact of therapeutic agents widely used to treat osteoporosis, such as bisphosphonates, on ferritin levels has not been investigated. The present study investigated the effects of risedronate on serum ferritin levels in postmenopausal women with osteoporosis. METHODS: In an open-label, prospective, uncontrolled study, 68 postmenopausal women with osteoporosis were evaluated. Study participants received risedronate orally at a dose of 35 mg/week during a 6-month treatment period. Blood sampling for lipid profile, hemoglobin A1c, insulin, fibrinogen, C-reactive protein, osteoprotegerin, and ferritin was performed at baseline and after 6 months of treatment. Pulse-wave velocity and augmentation index at baseline were determined using SphygmoCor version 7.1 (AtCor Medical, Sydney, Australia). RESULTS: Mean (SD) serum ferritin decreased significantly from 62.1 (44.8) to 46.7 (29.4) µg/dL (P < 0.0001) during the treatment period. On multiple linear regression analysis, the significant predictors of Δferritin were pulse-wave velocity (P = 0.04; effect size, 0.188), C-reactive protein (P = 0.021; effect size, 0.043), insulin (P = 0.011; effect size, 0.100), and high-density lipoprotein cholesterol (P = 0.046; effect size, 0.132) at baseline. CONCLUSIONS: Risedronate treatment is associated with significantly decreased serum ferritin levels in postmenopausal women with osteoporosis and cardiovascular risk factors.

Vascular Impact of Metabolic Syndrome in Subjects with Normal Weight, Overweight, or Obesity: Is Normal Weight Sufficient for Vascular Health?

OBJECTIVE: Obesity appears to be one of the major risk factors for metabolic complications. However, no direct relationship between body weight and metabolic abnormalities exists. The present study was designed to investigate the impact of body mass index (BMI) and the presence of metabolic syndrome (MS) on early vascular atherosclerotic changes, as determined by augmentation index (AI) and pulse wave velocity (PWV). DESIGN AND METHODS: The 285 study participants were divided into four groups according to BMI and the presence of MS. Subjects without MS were defined as metabolically normal, while subjects with MS were defined as metabolically obese. Group 1 included 71 metabolically normal, normal-weight subjects (MNNW), Group 2 included 69 metabolically obese, normal-weight subjects (MONW), Group 3 included 66 metabolically obese, overweight subjects (MOOW), and Group 4 included 79 metabolically obese, obese subjects (MOOB). RESULTS: AI and PWV differed significantly between groups, such that they increased from Group 1 to Group 4 in a continuous fashion. AI was significantly lower in normal-weight subjects without MS than in normal-weight subjects with MS (p < 0.001). In univariate general linear model (GLM) analysis, significant by-group differences in AI persisted even after adjustment for age, sex, and blood pressure. CONCLUSIONS: AI was significantly higher in normal-weight subjects with MS than in normal-weight metabolically benign individuals. Thus, even in patients with normal weight (BMI ≤ 25), presence of metabolic syndrome was associated with significant deterioration in terms of arterial stiffness.

Adiponectin as an independent predictor of left ventricular hypertrophy in nondiabetic patients with hypertension.

We evaluated novel and traditional biomarkers as well as hemodynamic parameters associated with the development of left ventricular hypertrophy (LVH) in nondiabetic patients with hypertension. Nondiabetic patients with hypertension (n = 86) were evaluated for lipids, glucose, insulin, homeostasis model assessment-insulin resistance (HOMA-IR), adiponectin, aldosterone, renin, matrix metalloproteinase 2, and endothelin. Arterial elasticity was evaluated using pulse wave contour. The LVH parameters were assessed echographically. Adiponectin was significantly and inversely associated with left ventricular mass (LVM; P = .032). The aldosterone-renin ratio (ARR) was significantly, positively associated with LVM (P = .031). Fasting insulin as well as HOMA-IR was significantly, positively associated with LVM (P = .036 and P = .025, respectively). In multiple linear regression analysis, adiponectin and ARR remained a significant predictor of LVM. The present study found that adiponectin and ARR are important independent determinants of LVH in nondiabetic patients with hypertension.

Role of RAAS and adipokines in cardiovascular protection: effect of different doses of angiotensin II receptor blocker on adipokines level in hypertensive patients.

The present study was designed to determine the effect of different doses of the angiotensin II receptor blocker (ARB), candesartan, on circulating adiponectin and leptin levels as well as leptin adiponectin ratio (LAR) in hypertensive patients with multiple cardiovascular risk factors.Sixty-nine hypertensive patients were randomized to three groups: group 1 included patients treated with high doses of Candesartan (32 mg); group 2 included patients treated with conventional doses of Candesartan (16 mg); and group 3 included patients that received antihypertensive treatment other than ARBs or angiotensin-converting-enzyme inhibitors. Patients were evaluated for lipid profile, HbA1C, insulin, C-peptide, c-reactive protein, aldosterone, renin, Homeostasis model assessment-insulin resistance, leptin, adiponectin and LAR. Baseline adiponectin, leptin, and LAR levels did not differ significantly between the three groups. After 6 months of treatment, LAR was significantly higher in group 3 than group 1 (P = .007) or group 2 (P = .023). Differences between effects of high (32 mg) and conventional doses (16 mg) of Candesartan on LAR were not observed (P = .678). Marginal across-group differences were detected for posttreatment circulating adiponectin level (P = .064). Univariate general linear model (GLM) analysis of posttreatment LAR detected significant by-group differences even after adjustment for age, gender, baseline values of LAR, and blood pressure. In this model, group was the only significant predictor of LAR after controlling for these variables. Treatment with high doses of the ARB, candesartan, is associated with significantly reduced LAR and marginally increased circulating adiponectin levels in hypertensive patients with multiple cardiovascular risk factors.

Normal weight diabetic patients versus obese diabetics: relation of overall and abdominal adiposity to vascular health.

OBJECTIVE: The present study investigated the impact of overall obesity defined by BMI and abdominal obesity defined by WC on vascular atherosclerotic changes in obese and normal weight diabetic subjects. DESIGN AND METHODS: 285 subjects were divided according to presence diabetes mellitus (DM) and obesity: Group 1 included 144 nonobese subjects without DM; Group 2 consisted of 141 type 2 diabetic patients. Then diabetic patients were divided into two groups according to presence of overall obesity, defined by BMI and furthermore, abdominal obesity, defined by waist circumference (WC). Pulse wave velocity (PWV) and augmentation index (AI) were performed using SphygmoCor (version 7.1, AtCor Medical, Sydney, Australia). RESULTS: Between Group Comparisons by BMI: Diabetic subjects with and without overall obesity did not differ from one another in terms of AI and PWV. CONCLUSIONS: Abdominal obesity defined by WC was associated with significantly higher AI and PWV in in both diabetic men and women; whereas overall obesity defined by BMI did not predict adverse vascular changes in this study population. Abdominal obesity was associated with an adverse effect on blood vessels, independently of age, sex, blood pressure, fasting glucose and BMI.

Adiponectin is better predictor of subclinical atherosclerosis than liver function tests in patients with nonalcoholic fatty liver disease.

Adiponectin has recently been considered as a possible link between liver dysfunction and atherosclerosis in patients with nonalcoholic fatty liver disease (NAFLD). The present study was designed to evaluate the relation between circulating adiponectin and arterial stiffness parameters, such as pulse wave velocity (PWV) and aortic augmentation index (AI), in patients with hepatic steatosis. The study group consisted of 52 subjects with NAFLD. PWV and AI were performed using SphygmoCor (version 7.1, AtCor Medical, Sydney, Australia). Metabolic parameters, homeostasis model assessment-insulin resistance, and adiponectin levels were determined. Adiponectin was significantly, positively associated with AI (r = 0.467; P < .0001) and with PWV (r = 0.348; P = .011). No association between arterial stiffness parameters and liver function tests was observed. In a multiple linear regression analysis, adiponectin remained a significant predictor of PWV even after controlling for age, gender, and MAP. Serum adiponectin levels were significantly associated with indices of subclinical atherosclerosis, such as PWV and AI in patients with NAFLD. This association was independent of age, gender, and blood pressure level and suggests an active role of adiponectin in the pathophysiology of vascular disease in this particular population group.

Diabetes and menopause aggravate age-dependent deterioration in arterial stiffness.

OBJECTIVE: The present study was designed to evaluate the effects of menopause status and diabetes on arterial stiffness, metabolic parameters, and inflammatory parameters in premenopausal and postmenopausal women with and without type 2 diabetes mellitus. METHODS: In the present study, 186 women were divided into three groups: group 1 includes 42 premenopausal women without type 2 diabetes mellitus, group 2 includes 85 postmenopausal women without diabetes, and group 3 includes 59 postmenopausal women with diabetes. Blood glucose, hemoglobin A1c, insulin, lipids, C-reactive protein, homeostasis model assessment-insulin resistance, aldosterone, and renin were measured. Pulse wave velocity (PWV) and augmentation index (AI) were determined using SphygmoCor (version 7.1; AtCor Medical, Sydney, Australia). RESULTS: PWV and AI values increased from group 1 to group 3 in a continuous fashion. Postmenopausal women with and without diabetes exhibited significantly increased AI compared with premenopausal women without diabetes (P < 0.0001 and P < 0.0001, respectively). PWV was significantly higher in postmenopausal women with diabetes mellitus than in premenopausal and postmenopausal women without diabetes mellitus (P = 0.007 and P = 0.002, respectively). CONCLUSIONS: Postmenopausal women without diabetes have significantly higher AI compared with premenopausal women without type 2 diabetes mellitus. The combination of diabetes and postmenopause status is associated with further deterioration of AI and PWV independently of age, body mass index, and other cardiovascular risk factors.

Determinants of left ventricular hypertrophy in hypertensive patients: identification of high-risk patients by metabolic, vascular, and inflammatory risk factors.

Left ventricular hypertrophy (LVH) is recognized as an independent predictor of cardiovascular morbidity and mortality in hypertensive patients. Thus, it is critical to understand the mechanisms underlying the development of LVH for formulation screening and treatment strategies. This study was designed to determine the association between echographically determined LVH measures and markers of inflammation, neurohormonal activity, glomerular function, oxidative stress, insulin resistance, and vascular endothelial function. In this study, 129 hypertensive subjects were evaluated for lipids, glucose, HbA1C, insulin, homeostasis model assessment-insulin resistance, C-reactive protein (CRP), urinary microalbumin, homocysteine, aldosterone, renin, and endothelin. LVH parameters including interventricular septum thickness, posterior wall thickness (PWT), and left ventricular mass index (LVMI) were assessed echographically. Serum aldosterone levels were significantly positively associated with left ventricular mass (LVM) and marginally positively associated with LVMI and PWT. Both LVM and LVMI were significantly elevated in subjects with high versus normal serum aldosterone levels (p = 0.018 for LVM and p = 0.050 for LVMI). Serum endothelin was positively associated with LVM and LVMI. In multiple linear regression analysis, aldosterone remained a significant predictor of LVM (standardized ß = 0.229, p = 0.024), and endothelin a marginally significant predictor of LVM (standardized ß = 0.178, p = 0.077). Among serum lipids, high-density lipoprotein cholesterol only had a significant inverse association with LVM and PWT. Homocysteine as well as CRP were significantly positively associated with LVM and LVMI in females. This study found that aldosterone and endothelin levels are the most important independent determinants of LVH in hypertensive subjects. These markers may be useful to identify asymptomatic hypertensive subjects at risk for heart failure.

Relation between augmentation index and adiponectin during one-year metformin treatment for nonalcoholic steatohepatosis: effects beyond glucose lowering?

BACKGROUND: Insulin resistance (IR) is the major driving force behind development and progression of atherosclerosis in patients with nonalcoholic fatty liver disease (NAFLD). Therefore, correction of IR is a relevant therapeutic target.We performed the current trial to evaluate whether 12- month metformin therapy improves vascular stiffness in patients with NAFLD and to assess if this improvement is associated with change in glucose control, insulin resistance or circulating adiponectin. METHODS: In randomized, placebo controlled study, 63 patients with NAFLD were assigned to one of two groups: Group 1 received daily metformin; Group 2 received placebo. Central aortic augmentation index (AI) was performed using SphygmoCor (version 7.1, AtCor Medical, Sydney, Australia) at baseline, at 4-and 12-month treatment period. Metabolic parameters, insulin resistance markers and serum adiponectin levels were determined. RESULTS: In placebo group: AI did not improve during the treatment period. Liver function and adiponectin levels did not change during the study.In multiple linear regression analysis, the independent predictors of arterial stiffness improvement were metformin treatment and increase in circulating adiponectin levels.Among metformin treated patients: AI decreased significantly during the study. ALP and ALT decreased during initial 4-month treatment period, however raised to the pretreatment levels after 12 months. Serum adiponectin level tended to increase during treatment period with metformin. CONCLUSIONS: Metformin treatment was associated with significant decrease in AI during one year treatment in NAFLD patients. These beneficial vascular effects was associated with exposure to metformin per se as well as change in adiponectin levels suggesting that metformin may mediate its vascular effects via glycemic control-independent mechanisms.

Treatment with insulin sensitizer metformin improves arterial properties, metabolic parameters, and liver function in patients with nonalcoholic fatty liver disease: a randomized, placebo-controlled trial.

Insulin resistance has an important role in the development of nonalcoholic fatty liver disease (NAFLD) and is involved in both pathological processes: hepatic steatosis and atherosclerosis. Therefore, treatment of NAFLD with insulin sensitizers is likely to have a favorable effect toward hepatic steatosis and cardiovascular outcomes. The present study investigated the effect of metformin on arterial properties, metabolic parameters, and liver function in patients with NAFLD. In a randomized, placebo-controlled study, 63 patients with NAFLD were assigned to 1 of 2 groups: Group 1 received daily metformin; group 2 received placebo. Pulse wave velocity (PWV) and augmentation index (AI) were measured using SphygmoCor (version 7.1; AtCor Medical, Sydney, Australia) at baseline and at the end of the 4-month treatment period. Metabolic measures and serum adiponectin levels were determined. Among metformin-treated patients, PWV and AI decreased significantly during the study. Significant declines in fasting glucose, triglyceride, and alkaline phosphatase and a significant increase in high-density lipoprotein cholesterol were observed. Alanine aminotransferase decreased and serum adiponectin increased marginally. In the placebo group, neither PWV nor AI improved significantly during the treatment period. Alanine aminotransferase, aspartate aminotransferase, and adiponectin did not change in the placebo group. Metformin treatment was associated with significant decrease in PWV and AI in NAFLD patients. This beneficial vascular effect was accompanied by an improvement in glucose and lipid metabolism as well as liver enzymes.

Effect of long-term treatment with antioxidants (vitamin C, vitamin E, coenzyme Q10 and selenium) on arterial compliance, humoral factors and inflammatory markers in patients with multiple cardiovascular risk factors.

BACKGROUND: Antioxidant supplementations have the potential to alleviate the atherosclerotic damage caused by excessive production of reactive oxygen species (ROS). The present study evaluated the effects of prolonged antioxidant treatment on arterial elasticity, inflammatory and metabolic measures in patients with multiple cardiovascular risk factors. METHODS: Study participants were randomly assigned to two groups. Group 1 received oral supplementation with 2 capsules per day of Mid Life Guard, SupHerb, Israel. In each capsule vitamin C (500 mg) vitamin E (200 iu), co-enzyme Q10 (60 mg) and selenium (100 mcg), Group 2 received matching placebo(SupHerb) for 6 months. Patients were evaluated for lipid profile, HbA1C, insulin, C-peptide, hs-CRP, endothelin, aldosterone, plasma renin activity and Homeostasis model assessment-insulin resistance (HOMA-IR). Arterial elasticity was evaluated using pulse wave contour analysis (HDI CR 2000, Eagan, Minnesota). RESULTS: Antioxidant-treated patients exhibited significant increases in large arterial elasticity index (LAEI) as well as small arterial elasticity index (SAEI). A significant decline HbA1C and a significant increase in HDL-cholesterol were also observed. In the placebo group, significant changes in LAEI, SAEI or metabolic measures were not observed. CONCLUSIONS: Antioxidant supplementation significantly increased large and small artery elasticity in patients with multiple cardiovascular risk factors. This beneficial vascular effect was associated with an improvement in glucose and lipid metabolism as well as decrease in blood pressure.

Effect of Long-Term L-Arginine Supplementation on Arterial Compliance and Metabolic Parameters in Patients with Multiple Cardiovascular risk Factors: Randomized, Placebo-Controlled Study.

OBJECTIVES:: This study was designed to determine the effect of long-term L-arginine supplementation on arterial compliance, inflammatory and metabolic parameters in patients with multiple cardiovascular risk factors. METHODS:: In this randomized, placebo-controlled trial, 90 patients were randomly assigned to two groups: Group 1 received daily oral L-arginine, Group 2 received matching placebo capsules. Patients were evaluated for lipid profile, glucose, HbA1C, insulin, hs-CRP, renin and aldosterone .Arterial elasticity was evaluated using pulse wave contour analysis (HDI CR 2000, Eagan, Minnesota). RESULTS:: Although large artery elasticity index (LAEI) did not differ significantly between the groups at baseline (10.64.3 vs.11.64.5 ml/mm HgX100, p=0.346), at the end of the study LAEI was significantly greater in patients treated with L-arginine than in the placebo group (12.73.4 vs. 8.02.8 ml/mm HgX10, p<0.0001). Systemic vascular resistance was significantly lower in patients treated with L-arginine than in the placebo group after 6 months. Small artery elasticity index (SAEI) did not differ significantly between the groups at baseline or at the end of the study. Serum aldosterone decreased significantly in Group 1 from 10.76.3 to 8.45.0 ng/ml (p=0.008), but did not change in the placebo group. CONCLUSION:: L-arginine supplementation improves LAEI in patients with multiple cardiovascular risk factors. This improvement was associated with a decrease in systolic blood pressure, peripheral vascular resistance as well as a decrease in aldosterone levels. The results suggest that long term L-arginine supplementation has beneficial vascular effects in pathologic disease states associated with endothelial dysfunction.