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Background: Genetic analysis from patients participated in the randomized trials reported that the increased risk of type 2 diabetes noted with statins is at least partially explained by HMG-coenzyme A reductase inhibition. We investigated vascular and metabolic phenotypes of different dosages of rosuvastatin in hypercholesterolemic patients., Methods: A randomized, single-blind, placebo-controlled, parallel study was conducted in 48 patients on placebo, and in 47, 48, and 47 patients given daily rosuvastatin 5, 10, and 20mg, respectively during a 2month treatment period., Results: Rosuvastatin 5, 10, and 20mg improved flow-mediated dilation (34, 40, and 46%) after 2months therapy when compared with baseline (P<0.001 by paired t-test) and when compared with placebo (P<0.001 by ANOVA). Rosuvastatin 5,10, and 20mg dose-dependently and significantly increased insulin (mean % changes; 19, 29, and 31%, respectively) and glycated hemoglobin levels (mean % changes; 2, 2, and 3%, respectively), and decreased adiponectin levels (mean % changes; 3, 9, and 14%, respectively) and insulin sensitivity (mean % changes; 2, 3, and 4%, respectively) after 2months therapy when compared with baseline (all P<0.05 by paired t-test). These effects with rosuvastatin 5, 10, and 20mg were significant when compared with placebo (P=0.006 for insulin, P=0.012 for glycated hemoglobin, P=0.007 for adiponectin, and P=0.002 for insulin sensitivity by ANOVA)., Conclusions: Despite beneficial reductions in LDL cholesterol and improvement of flow-mediated dilation, rosuvastatin dose-dependently and significantly resulted in decreasing insulin sensitivity and increasing ambient glycemia by reducing adiponectin levels and increasing insulin levels in hypercholesterolemic patients., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: Experimental studies demonstrate that higher intake of omega-3 fatty acids (n-3 FA) improves insulin sensitivity, however, we reported that n-3 FA 2g therapy, most commonly used dosage did not significantly improve insulin sensitivity despite reducing triglycerides by 21% in patients. Therefore, we investigated the effects of different dosages of n-3 FA in patients with hypertriglyceridemia., Methods: This was a randomized, single-blind, placebo-controlled, parallel study. Age, sex, and body mass index were matched among groups. All patients were recommended to maintain a low fat diet. Forty-four patients (about 18 had metabolic syndrome/type 2 diabetes mellitus) in each group were given placebo, n-3 FA 1 (O1), 2 (O2), or 4 g (O4), respectively daily for 2 months., Results: n-3 FA therapy dose-dependently and significantly decreased triglycerides and triglycerides/HDL cholesterol and improved flow-mediated dilation, compared with placebo (by ANOVA). However, each n-3 FA therapy did not significantly decrease high-sensitivity C-reactive protein and fibrinogen, compared with placebo. O1 significantly increased insulin levels and decreased insulin sensitivity (determined by QUICKI) and O2 significantly decreased plasma adiponectin levels relative to baseline measurements. Of note, when compared with placebo, each n-3 FA therapy did not significantly change insulin, glucose, adiponectin, glycated hemoglobin levels and insulin sensitivity (by ANOVA). We observed similar results in a subgroup of patients with the metabolic syndrome., Conclusions: n-3 FA therapy dose-dependently and significantly decreased triglycerides and improved flow-mediated dilation. Nonetheless, n-3 FA therapy did not significantly improve acute-phase reactants and insulin sensitivity in patients with hypertriglyceridemia, regardless of dosages., (Copyright © 2014. Published by Elsevier Ireland Ltd.)

Adiponectin is a protein secreted by adipose cells that may couple regulation of insulin sensitivity with energy metabolism and serve to link obesity with insulin resistance. Obesity-related disorders characterized by insulin resistance including the metabolic syndrome, diabetes, atherosclerosis, hypertension, and coronary artery disease are associated with both decreased adiponectin levels and endothelial dysfunction. Recent studies demonstrate that adiponectin has insulin-sensitizing effects as well as antiatherogenic properties. Lifestyle modifications and some drug therapies to treat atherosclerosis, hypertension, diabetes, and coronary heart disease have important effects in increasing adiponectin levels, decreasing insulin resistance, and improving endothelial dysfunction. In this review, we discuss insights into the relationships between adiponectin levels, insulin resistance, and endothelial dysfunction that are derived from various therapeutic interventions. The effects of lifestyle modifications and cardiovascular drugs on adiponectin levels and insulin resistance suggest plausible mechanisms that may be important for understanding and treating atherosclerosis and coronary heart disease.

Background: The prevalence of obesity is gradually increasing in Japan, but in women aged in their 20 s to 50 s it has been disproportionately decreasing. However, the exact body composition of this subset of the population has not been elucidated., Methods and Results: Body composition was determined using whole-body dual energy X-ray absorptiometry and metabolic parameters in 157 Japanese female university students (21.1+/-1.9 years); 31 women had a normal body mass index (BMI), but an increased body fat mass (BFM). Only the 31 had significantly higher low-density lipoprotein-cholesterol levels (90.5 vs 99.0 mg/dl, P<0.01) and leptin concentration (7.0 vs 4.6 ng/ml, P<0.05) and lower high-density lipoprotein-cholesterol (80.4+/-15.1 vs 73.5+/-14.5 mg/dl, P<0.01) than females with normal BMI and normal BFM., Conclusions: A considerable number of young Japanese women with a normal BMI have excess BFM and relatively higher lipid and leptin levels. These findings may provide an important basis for future epidemiological surveys and studies.

Objective: Coronary remodeling based on collagen abnormalities in diabetes might be associated with potential interactions between the matrix metalloproteinase (MMP) system, which regulates extracellular matrix turnover, and the fibrinolytic system, which is involved in the fibrin degradation process. We characterized the profiles of the MMP and fibrinolytic systems in insulin-resistant diabetic rat hearts., Methods and Results: By immunohistochemistry and in situ hybridization, transforming growth factor-beta1 (TGF-beta1) expression increased in coronary vessels, the perivascular area, and cardiomyocytes in diabetic rat hearts. Increased expression of plasminogen activator inhibitor-1 (PAI-1) in coronary vessels and the perivascular area was evident in diabetic hearts. In contrast, diabetic hearts exhibited reduced activity and expression of MMP-2 and decreased expression of membrane type-1 MMP (MT1-MMP). Both intravascular and extravascular collagen type I and III immunoreactivity and fibrin deposition were seen in diabetic coronary vessels. These alterations were reversed to nondiabetic levels by the angiotensin II type 1 receptor blocker candesartan, which prevented the development of perivascular fibrosis observed after Masson's trichrome staining., Conclusions: In addition to upregulation of PAI-1, downregulation of MMP-2 and MT1-MMP might play a crucial role in coronary matrix remodeling in insulin-resistant diabetes. These molecules appear to be regulated by angiotensin II via stimulation of TGF-beta1.

With the use of Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a model of human non-insulin-dependent diabetes mellitus (NIDDM), we assessed whether ANG II is involved in coronary capillary angiogenesis at the insulin-resistant stage of NIDDM (20 wk of age). In OLETF rats, ANG II labeling and angiotensin type 1 (AT(1)) receptor expression in coronary vessels were increased more than in nondiabetic controls. A marked increase in vascular expression of vascular endothelial growth factor (VEGF) at both mRNA and protein levels was found in OLETF rats. The increased expression level of VEGF was associated with accumulation of hypoxia-inducible factor-1alpha (HIF-1alpha) activated by increased advanced glycation end products (AGEs). Morphometric analysis showed a significantly increased total coronary capillary density, which was a result of arterialization of the venular capillary portion in OLETF rats. Treatment of OLETF rats with candesartan, an AT(1) receptor blocker, inhibited vascular expressions of VEGF, HIF-1alpha, and AGEs, and ameliorated the morphometric changes. These results suggest a key role of ANG II in the pathogenesis of the coronary capillary remodeling in this NIDDM model.

Pemafibrate, a novel selective peroxisome proliferator-activated receptor modulator, has beneficial effects on lipid metabolism. However, its effects on glucose metabolism in individuals with type 2 diabetes (T2DM) remain to be fully clarified. This was a subanalysis of the PARM-T2D study, a multicenter prospective observational study on the use of pemafibrate versus conventional therapy for 52 weeks in subjects with T2DM complicated with hypertriglyceridemia. The subanalysis included participants who did not change their treatment for diabetes and did not receive insulin or insulin secretagogues during the study period. Changes in glucose metabolism markers, including homeostatic model assessment (HOMA2) scores and disposition index, were assessed. A total of 279 participants (141 in the pemafibrate group; 138 in the control group) met the criteria for the subanalysis. There were no significant changes in HbA1c during the 52-week study period in both groups. However, the pemafibrate group showed significant improvements versus the control group for insulin resistance assessed by HOMA2-R (−0.15 versus 0.08; estimated treatment difference −0.23 (95% confidence interval −0.44, −0.02); p = 0.03) and maintenance of β-cell function assessed by disposition index (0.015 versus −0.023; estimated treatment difference 0.037 (95% confidence interval 0.005, 0.069); p = 0.02). Correlation analyses showed that improvements in HOMA2-R and disposition index were significantly associated with improvements in lipid abnormalities and γ-glutamyl transpeptidase. In conclusion, pemafibrate reduced insulin resistance and maintained β-cell function in subjects with T2DM and hypertriglyceridemia, presumably by improving lipid profiles and lipid-related hepatocyte stress. [ABSTRACT FROM AUTHOR]

Abstract: Hypercholesterolemia and dyslipidemia are independent risk factors for cardiovascular disease and death. Statins are the drugs of choice to decrease plasma cholesterol and have other beneficial actions beyond lipid-lowering leading to substantial improvements in cardiovascular morbidity and mortality. However, evaluation of the effects of statins to reduce overall morbidity and mortality must integrate metabolic consequences of statin therapy with its lipid-lowering effect. Indeed, reduction in LDL-cholesterol to target level achieved by statins does not completely eliminate risk of cardiovascular disease and may elevate metabolic risk factors that contribute to dysregulation of metabolic homeostasis. This may lead to increased incidence of diabetes and its cardiovascular complications that are explained, in part, by reciprocal relationships between insulin resistance and endothelial dysfunction. Genetic factors may determine 40–60% of total cholesterol levels and 70% of the efficacy of statin treatments. Metabolic and cardiovascular phenotypes that are either genetically determined or environmentally acquired are also important determinants of responses to specific statins. Moreover, differences between biological outcomes of specific statins or increasing dosages of statins result in differential metabolic actions due to off-target or unknown mechanism that have important implications for the use of statins to reduce overall morbidity and mortality. In this review, we discuss differential cardiovascular and metabolic pleiotropic actions of specific statins that interact in a context-dependent manner with patient phenotypes and genotypes. These important considerations may influence progression of atherosclerosis, risk of diabetes, and modulation of insulin resistance that help determine overall morbidity and mortality in patients undergoing statin therapy. [Copyright &y& Elsevier]

Abstract: Reciprocal relationships between endothelial dysfunction and insulin resistance suggest that therapies improving endothelial dysfunction will simultaneously improve insulin sensitivity and other metabolic parameters. However, previous studies with some statins either did not alter insulin sensitivity or promoted insulin resistance despite significant improvements in endothelial dysfunction and decreases in circulating pro-inflammatory markers. This may be due to pleiotropic or off-target effects of some statins to cause insulin resistance by diverse mechanisms unrelated to endothelial dysfunction. Indeed, there is evidence of other differential metabolic actions of distinct statins including effects on hydroxymethylglutaryl-CoA reductase inhibition, isoprotenoid synthesis, calcium release, glucose transport, insulin secretion, and/or insulin resistance. Pravastatin increases expression of adiponectin mRNA, enhances adiponectin secretion, increases plasma levels of adiponectin, and enhances insulin sensitivity in mice and humans. Clinical studies including large scale randomized controlled trials demonstrate potential differences between individual statins, with pravastatin promoting risk reduction for new onset of diabetes. Conversely, other statins including atorvastatin, rosuvastatin, and simvastatin all promote significant increase in this risk. Given the frequent concordance of metabolic diseases including diabetes, obesity, and metabolic syndrome with cardiovascular diseases associated with hyperlipidemia, it is important to understand the potential metabolic risks and benefits of therapies with distinct statins. In this review, we discuss these differential effects of statins on metabolic homeostasis and insulin sensitivity. [Copyright &y& Elsevier]

We investigated whether benidipine, a long-acting calcium channel blocker (CCB), can normalize cardiac expression profiles of the endothelin (ET)-1 system in insulin-resistant diabetes. Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a model of human Type 2 diabetes, were treated for 12 wk with vehicle or benidipine (3 mg·kg-1day-1). OLETF rats exhibited a significant increase in ET-1 in plasma and left ventricular (LV) tissues compared with nondiabetic controls. Expression of prepro-ET-, ET-converting enzyme, and ETA and ETB receptors in LV tissues was also significantly higher in OLETF rats. The two MAPKs, iNK and p38MAPK both of which are activated by ET-1, were more abundantly expressed in OLETF rat LV tissues. All these alterations were reversed to nondiabetic levels when OLETF rats were treated with the subdepressor dose of benidipine. Furthermore, benidipine therapy resulted in hindering cardiomyocyte hypertrophy and cardiac perivascular fibrosis in OLETF rats. The beneficial actions of benidipine at the subdepressor dose on cardiac remodeling in insulin-resistant diabetes may involve normalization of the upregulated ET-1 system. [ABSTRACT FROM AUTHOR]

Background Effects of omega-3 fatty acids (n − 3 FA) combined with fenofibrate are not yet investigated, compared with fenofibrate. Methods This was a randomized, single-blind, placebo-controlled, parallel study. Age, sex, and body mass index were matched among groups. All patients were recommended to maintain a low fat diet. Fifty patients with hypertriglyceridemia in each group were given placebo, n − 3 FA 2 g + fenofibrate 160 mg (combination), or fenofibrate 160 mg, respectively daily for 2 months. Results Placebo, combination, and fenofibrate significantly decreased triglycerides by 7%, 41% and 30%, respectively and triglycerides/HDL cholesterol ratio by 11%, 45% and 32%, respectively relative to baseline measurements (all P < 0.05 by paired t -test). When compared with placebo and fenofibrate, these with combination were significant ( P < 0.001 by ANOVA). When compared with placebo, both combination and fenofibrate significantly decreased apolipoprotein B and non-HDL cholesterol and improved flow-mediated dilation and reduced CRP and fibrinogen (all P < 0.05 by ANOVA), however, there were no significant differences between combination and fenofibrate. When compared with placebo, both combination and fenofibrate significantly reduced insulin and glucose (both P < 0.05 by ANOVA), and improved insulin sensitivity ( P = 0.005 by ANOVA). However, there were no significant differences between combination and fenofibrate. Conclusions When compared with fenofibrate, combination significantly decreased triglycerides and triglycerides/HDL cholesterol ratio. Otherwise, combination and fenofibrate significantly reduced apolipoprotein B and non-HDL cholesterol and improved flow-mediated dilation and reduced CRP and fibrinogen to a similar extent. Also, combination and fenofibrate significantly improved insulin sensitivity to a similar extent by reducing insulin and glucose in patients with hypertriglyceridemia. [ABSTRACT FROM AUTHOR]

Background Ezetimibe demonstrates decreasing visceral fat and improving insulin sensitivity (IS) in animals and humans. We first reported that simvastatin dose-dependently worsens insulin sensitivity. Whether ezetimibe may compensate untoward effects of simvastatin, depending on dosages of simvastatin has not been investigated in patients with hypercholesterolemia, compared with simvastatin alone. Methods This was a randomized, single-blind, placebo-controlled, parallel study. Fifty-one in each group were given placebo, ezetimibe 10 mg combined with simvastatin 10 mg (Vyto10), ezetimibe 10 mg combined with simvastatin 20 mg (Vyto20), or simvastatin 20 mg alone (Simva20) daily for 2 months. Results Placebo, Vyto10, Vyto20, and Simva20 improved flow-mediated dilation relative to baseline measurements. Placebo therapy did not significantly change insulin and IS and adiponectin levels and visceral fat area (VFA) and VFA/subcutaneous fat area (SFA) relative to baseline measurements. Vyto10 therapy significantly decreased CRP and insulin levels and increased adiponectin levels and IS, and reduced VFA, VFA/SFA, and blood pressure. Vyto20 therapy did not significantly change insulin levels and IS and adiponectin levels but significantly reduced CRP levels and VFA, VFA/SFA, and blood pressure. Simva20 therapy significantly decreased adiponectin levels and IS but did not significantly change VFA, VFA/SFA, and blood pressure. Of note, these different effects of each therapy were significant by ANOVA. Conclusions Vyto10, Vyto20, and Simva20 showed significant reduction of LDL cholesterol levels and improvement of flow-mediated dilation in patients with hypercholesterolemia. However, Vyto10, Vyto20, and Simva20 showed significantly differential metabolic effects, depending on dosages of simvastatin. [ABSTRACT FROM AUTHOR]

Abstract: Background: Rosuvastatin and pravastatin have differential hydrophilicity and potency to inhibit hydroxymethylglutaryl-CoA reductase that may be relevant to changes in adiponectin levels, insulin resistance, and the rate of new onset diabetes in large clinical studies. Therefore, we hypothesized that rosuvastatin and pravastatin may have differential metabolic effects in hypercholesterolemic patients. Methods: This was a randomized, single-blind, placebo-controlled, parallel study. Age, gender, and body mass index were matched. Fifty-four patients were given placebo, rosuvastatin 10mg, or pravastatin 40mg, respectively once daily for 2months. Results: When compared with pravastatin therapy, rosuvastatin therapy significantly reduced total, LDL cholesterol, and apolipoprotein B levels (P <0.05 by post-hoc comparison), but comparably improved flow-mediated dilation after 2months. Interestingly, rosuvastatin therapy significantly increased fasting insulin (mean % changes; 28%, P =0.005). and HbA1c (1%, P =0.038) while decreasing plasma adiponectin levels (9%, P =0.010) and insulin sensitivity (assessed by QUICKI; 2%, P =0.007) when compared with baseline. By contrast, pravastatin therapy significantly decreased fasting insulin (8%, P =0.042), and HbA1c levels (1%, P =0.019) while increasing plasma adiponectin levels (36%, P =0.006) and insulin sensitivity (3%, P =0.005) when compared with baseline. Moreover, these differential effects were evident when outcomes of rosuvastatin and pravastatin therapy were directly compared (P =0.002 for insulin levels by ANOVA on Ranks, P =0.003 for adiponectin, P =0.003 for QUICKI, and P =0.010 for HbA1c by ANOVA). Conclusions: While significantly reducing lipoprotein profiles, rosuvastatin therapy had unwanted metabolic effects in hypercholesterolemic patients when compared with pravastatin therapy, that may be clinically relevant in patients prone to metabolic diseases. [Copyright &y& Elsevier]

Abstract: Background: Omega-3 fatty acids and fenofibrate are both used to treat patients with hypertriglyceridemia. However, a head-to-head comparison of the lipoprotein and metabolic effects of these two medicines has not been published. Methods: This was a randomized, single-blind, placebo-controlled, parallel study. Age, sex, and body mass index were matched among groups. All patients were recommended to maintain a low fat diet. Fifty patients in each group were given placebo, omega-3 fatty acids 2g (most commonly used dosage in Korean patients), or fenofibrate 160mg, respectively daily for 2 months. Results: Omega-3 fatty acids therapy decreased triglycerides by 21% and triglycerides/HDL cholesterol and improved flow-mediated dilation (P <0.01), however, did not significantly change insulin, plasma adiponectin levels, and insulin sensitivity (determined by QUICKI) relative to baseline measurements. Fenofibrate therapy decreased total cholesterol, triglycerides by 29%, and triglycerides/HDL-cholesterol (all P <0.01) and improved flow-mediated dilation when compared with baseline. When compared with placebo and omega-3 fatty acids, fenofibrate therapy decreased non-HDL cholesterol (P <0.001) and triglycerides/HDL cholesterol (P =0.016) while increasing HDL cholesterol (P <0.001) and apolipoprotein AI (P =0.001). Of note, when compared with omega-3 fatty acids, fenofibrate therapy decreased fasting insulin (P =0.023) and increased plasma adiponectin (P =0.002) and insulin sensitivity (P =0.015). Conclusions: Omega-3 fatty acids and fenofibrate therapy promoted similar changes in triglycerides and endothelium-dependent dilation. However, fenofibrate therapy had substantially better effects on lipoprotein and metabolic profiles in patients with hypertriglyceridemia. [Copyright &y& Elsevier]

Abstract: Background: We investigated effects of fenofibrate therapy on endothelial dysfunction and adipocytokine profiles. Methods: A randomized, single-blind, placebo-controlled, cross-over study was conducted in 53 patients with primary hypertriglyceridemia. We administered placebo or fenofibrate 160mg daily for 8 weeks. Results: When compared with placebo, fenofibrate therapy substantially lowered plasma levels of TNF-α by 6±3% (P =0.014) and hsCRP from 1.10 to 0.90mg/l (P =0.004). When compared with placebo, fenofibrate therapy increased plasma levels of adiponectin by 17±4% (P =0.001), insulin sensitivity by 4±1% (as assessed by QUICKI, P =0.009), and decreased plasma levels of leptin and resistin by 4±7% (P =0.022) and 10±3% (P =0.001), respectively. There were correlations between percent changes in QUICKI and percent changes in adiponectin levels (r =0.279, P =0.043) or leptin (r =−0.280, P =0.042). Conclusions: Fenofibrate therapy significantly reduced pro-inflammatory biomarkers and improved adipocytokines levels and insulin sensitivity in hypertriglyceridemic patients. [ABSTRACT FROM AUTHOR]