Endocrinology AND Hyperlipidemia [keywords]
- Bezafibrate improves insulin sensitivity and metabolic flexibility in STZ-treated diabetic mice. [JOURNAL ARTICLE]
- Diabetes 2016 Jun 9.
Bezafibrate (BEZ), a pan activator of peroxisome proliferator-activated receptors (PPARs), has been generally used to treat hyperlipidemia for decades. Clinical trials with type 2 diabetes patients indicated that BEZ also has beneficial effects on glucose metabolism, although the underlying mechanisms of these effects remain elusive. Even less is known about a potential role for BEZ in treating type 1 diabetes. Here we show that BEZ markedly improves hyperglycemia and glucose and insulin tolerance in streptozotocin (STZ)-treated mice, an insulin-deficient mouse model of type 1 diabetes. BEZ treatment of STZ mice significantly suppressed the hepatic expression of genes that are annotated in inflammatory processes, whereas the expression of PPAR and insulin target gene transcripts was increased. Furthermore, BEZ-treated mice also exhibited improved metabolic flexibility as well as an enhanced mitochondrial mass and function in the liver. Finally, we show that the number of pancreatic islets and the area of insulin positive cells tended to be higher in BEZ-treated mice. Our data suggest that BEZ may improve impaired glucose metabolism by augmenting hepatic mitochondrial performance, suppressing hepatic inflammatory pathways, and improving insulin sensitivity and metabolic flexibility. Thus, BEZ treatment might also be useful for patients with impaired glucose tolerance or diabetes.
- Evaluation of C-Reactive Protein in Patients with Chronic Obstructive Pulmonary Disease. [Journal Article]
- Open Access Maced J Med Sci 2015 Jun 15; 3(2):283-6.
Chronic Obstructive Pulmonary Disease (COPD) is associated with evidence of systemic oxidative stress, activation of circulating inflammatory cells and increased plasma level of proinflamatory cytokines which include C-reactive protein (CRP). CRP is one biomarker of extrapulmonary or systemic consequences of COPD that can be detected.The aim of this research is to determine whether the level of CRP statistically significantly correlates with the level of bronchial obstruction and the accompanying co-morbidities in patients with COPD.This study included 80 patients with exacerbation of COPD, hospitalised at the Institute for Lung Diseases and Tuberculosis in Skopje. We measured the level of CRP in the blood in all of these patients in fasting conditions. The classification of COPD patients by the severity of airflow limitation was made according to the actual version of the Global initiative for chronic Obstructive Lung Disease (GOLD). The Student's Independent Samples t-test was used for the statistic analysis of the data.In 52 (65%) of the patients with exacerbation of COPD we detected an increase of the mean value of CRP. The statistical analysis using the Student's t-test showed statistically significant differences in the mean value of CRP in patients with different level of bronchial obstruction. Hypertension, heart failure, diabetes mellitus, hyperlipidemia, coronary disease, and CVI were confirmed as co-morbidities in 45 (73.1%) of the patients, hypertension being the most frequent one (40%). The statistical analysis using the Student's t-test showed statistically significant difference of the mean value of CRP (p< 0.01) depending on the number of co-morbidities.In 52 (65%) of the patients with exacerbation of COPD, were detected an increase of the mean value of CRP. The mean values of CRP statistically significantly correlate with the level of bronchial obstruction and the number of co-morbidities in patients with COPD.
- An isoflavone cladrin prevents high-fat diet-induced bone loss and inhibits the expression of adipogenic gene regulators in 3T3-L1 adipocyte. [Journal Article]
- J Pharm Pharmacol 2016 Aug; 68(8):1051-63.
This study evaluates the effect of isoflavone cladrin on high-fat diet (HFD)-induced bone loss and adipogenesis.Thirty-two 4-week-old male C57BL/6J mice were divided into four groups: a standard diet group, a HFD group and HFD group with cladrin (5 and 10 mg/kg per day orally) for 12 weeks. The effect of cladrin on bone micro-architecture, bone marrow cell lineages and hyperlipidaemia were assessed. For assessing anti-adipogenic activity of cladrin, 3T3-L1 cells were used.Cladrin attenuated HFD-induced hyperlipidaemia and bone loss by preserving bone micro-architecture and strength. Effect of cladrin was found at the level of bone marrow progenitor cells. Gene expression profile of cladrin-treated mice bone showed upregulation of osteoblast and downregulation of adipogenic transcription factors and increased OPG/RANKL ratio. Cladrin inhibited cellular lipid accumulation through downregulation of transcription factors such as PPAR-γ and C/EBP-α and modulated the expression of major adipokines involved behind obesity stimulation without eliciting cell cytotoxicity in 3T3-L1 adipocytes.We conclude that cladrin may improve obesity-induced bone loss and hyperlipidaemia in mice fed HFD and adipogenesis in 3T3-L1 cells by modifying adipokines and could offer clinical benefits as a supplement to treat obesity-induced disorders.
- Decreased baroreflex sensitivity is linked to the atherogenic index, retrograde inflammation, and oxidative stress in subclinical hypothyroidism. [JOURNAL ARTICLE]
- Endocr Res 2016 Jun 3.:1-10.
The present study investigated the link of hyperlipidemia, inflammation and oxidative stress (OS) to cardiovascular (CV) risks in subclinical hypothyroidism (SCH).We enrolled 81 subclinical hypothyroid patients and 80 healthy subjects as control. Their CV and autonomic functions were assessed by spectral analysis of heart rate variability (HRV), continuous blood pressure variability (BPV) measurement and conventional autonomic function testing. Thyroid profile, lipid profile, immunological, inflammatory and OS markers were estimated and correlated with the baro-reflex sensitivity (BRS), the marker of sympathovagal imbalance (SVI) & CV risk.Mean arterial pressure (MAP, P<0.0001), total peripheral resistance (TPR, P<0.0001), ratio of low-frequency to high-frequency power of HRV (LF-HF ratio) (P<0.0001) were significantly higher and BRS (P<0.0001) was significantly lower in SCH group than the control group. BRS significantly correlated with heart rate, MAP, LF-HF ratio, lipid risk factors, anti-thyroperoxidase antibody, thyroid-stimulating hormone, high-sensitive C-reactive protein (hsCRP), malondialdehyde (MDA) and SCH.It was concluded that SVI is associated with SCH. Though dyslipidemia, inflammation and OS contributed to decreased BRS, SCH per se contributed maximally to it. Decreased BRS could be a physiological basis of increased CV risks in patients with SCH.
- Proteinuria and lipoprotein lipase activity in Miniature Schnauzer dogs with and without hypertriglyceridemia. [Journal Article]
- Vet J 2016 Jun.:83-9.
Spontaneous hyperlipidemia in rats causes glomerular disease. Idiopathic hypertriglyceridemia (HTG) is prevalent in Miniature Schnauzers, but its relationship with proteinuria is unknown. Decreased activity of major lipid metabolism enzymes, lipoprotein lipase (LPL) and hepatic lipase (HL), may play a role in the cyclic relationship between hyperlipidemia and proteinuria. These enzymes have also not been previously investigated in Miniature Schnauzers. The aims of this study were to determine the relationship between HTG and proteinuria in Miniature Schnauzers and to measure LPL and HL activities in a subset of dogs. Fifty-seven Miniature Schnauzers were recruited (34 with and 23 without HTG). Fasting serum triglyceride concentrations and urine protein-to-creatinine ratios (UPC) were measured in all dogs, and LPL and HL activities were determined in 17 dogs (8 with and 9 without HTG). There was a strong positive correlation between triglyceride concentration and UPC (r = 0.77-0.83, P < 0.001). Proteinuria (UPC ≥ 0.5) was present in 60% of dogs with HTG and absent from all dogs without HTG (P < 0.001). Proteinuric dogs were not azotemic or hypoalbuminemic. Dogs with HTG had a 65% reduction in LPL activity relative to dogs without HTG (P < 0.001); HL activity did not differ. Proteinuria occurs with HTG in Miniature Schnauzers and could be due to lipid-induced glomerular injury. Reduced LPL activity may contribute to the severity of HTG, but further assay validation is required.
- The Contribution of GWAS Loci in Familial Dyslipidemias. [Journal Article]
- PLoS Genet 2016 May; 12(5):e1006078.
Familial combined hyperlipidemia (FCH) is a complex and common familial dyslipidemia characterized by elevated total cholesterol and/or triglyceride levels with over five-fold risk of coronary heart disease. The genetic architecture and contribution of rare Mendelian and common variants to FCH susceptibility is unknown. In 53 Finnish FCH families, we genotyped and imputed nine million variants in 715 family members with DNA available. We studied the enrichment of variants previously implicated with monogenic dyslipidemias and/or lipid levels in the general population by comparing allele frequencies between the FCH families and population samples. We also constructed weighted polygenic scores using 212 lipid-associated SNPs and estimated the relative contributions of Mendelian variants and polygenic scores to the risk of FCH in the families. We identified, across the whole allele frequency spectrum, an enrichment of variants known to elevate, and a deficiency of variants known to lower LDL-C and/or TG levels among both probands and affected FCH individuals. The score based on TG associated SNPs was particularly high among affected individuals compared to non-affected family members. Out of 234 affected FCH individuals across the families, seven (3%) carried Mendelian variants and 83 (35%) showed high accumulation of either known LDL-C or TG elevating variants by having either polygenic score over the 90th percentile in the population. The positive predictive value of high score was much higher for affected FCH individuals than for similar sporadic cases in the population. FCH is highly polygenic, supporting the hypothesis that variants across the whole allele frequency spectrum contribute to this complex familial trait. Polygenic SNP panels improve identification of individuals affected with FCH, but their clinical utility remains to be defined.
- Increased thioredoxin levels are related to insulin resistance in familial combined hyperlipidaemia. [Journal Article]
- Eur J Clin Invest 2016 Jul; 46(7):636-42.
Thioredoxins (TRX) are major cellular protein disulphide reductases that are critical for redox regulation. Oxidative stress and inflammation play promoting roles in the genesis and progression of atherosclerosis, but until now scarce data are available considering the influence of TRX activity in familial combined hyperlipidaemia (FCH). Since FCH is associated with high risk of cardiovascular disease, the objective of the present study was to assess oxidative stress status in FCH patients, and evaluate the influence of insulin resistance (IR).A cohort of 35 control subjects and 35 non-related FCH patients were included, all of them nondiabetic, normotensive and nonsmokers. We measured lipid profile, glucose and insulin levels in plasma, and markers of oxidative stress and inflammation such as oxidized glutathione (GSSG), reduced glutathione (GSH) and TRX.Familial combined hyperlipidaemia subjects showed significantly higher levels of GSSG, GSSG/GSH ratio and TRX than controls. In addition, FCH individuals with IR showed the worst profile of oxidative stress status compared to controls and FCH patients without IR (P < 0·01). TRX levels correlated with higher insulin resistance.Familial combined hyperlipidaemia patients showed increased TRX levels. TRX was positively correlated with IR. These data could partially explain the increased risk of cardiovascular events in primary dyslipidemic patients.
- Type 2 Diabetes Mellitus Trajectories and Associated Risks. [JOURNAL ARTICLE]
- Big Data 2016 Mar 1; 4(1):25-30.
Disease progression models, statistical models that assess a patient's risk of diabetes progression, are popular tools in clinical practice for prevention and management of chronic conditions. Most, if not all, models currently in use are based on gold standard clinical trial data. The relatively small sample size available from clinical trial limits these models only considering the patient's state at the time of the assessment and ignoring the trajectory, the sequence of events, that led up to the state. Recent advances in the adoption of electronic health record (EHR) systems and the large sample size they contain have paved the way to build disease progression models that can take trajectories into account, leading to increasingly accurate and personalized assessment. To address these problems, we present a novel method to observe trajectories directly. We demonstrate the effectiveness of the proposed method by studying type 2 diabetes mellitus (T2DM) trajectories. Specifically, using EHR data for a large population-based cohort, we identified a typical trajectory that most people follow, which is a sequence of diseases from hyperlipidemia (HLD) to hypertension (HTN), impaired fasting glucose (IFG), and T2DM. In addition, we also show that patients who follow different trajectories can face significantly increased or decreased risk.
- Low-Density Lipoprotein Receptor-Dependent and Low-Density Lipoprotein Receptor-Independent Mechanisms of Cyclosporin A-Induced Dyslipidemia. [Journal Article]
- Arterioscler Thromb Vasc Biol 2016 Jul; 36(7):1338-49.
Cyclosporin A (CsA) is an immunosuppressant commonly used to prevent organ rejection but is associated with hyperlipidemia and an increased risk of cardiovascular disease. Although studies suggest that CsA-induced hyperlipidemia is mediated by inhibition of low-density lipoprotein receptor (LDLr)-mediated lipoprotein clearance, the data supporting this are inconclusive. We therefore sought to investigate the role of the LDLr in CsA-induced hyperlipidemia by using Ldlr-knockout mice (Ldlr(-/-)).Ldlr(-/-) and wild-type (wt) C57Bl/6 mice were treated with 20 mg/kg per d CsA for 4 weeks. On a chow diet, CsA caused marked dyslipidemia in Ldlr(-/-) but not in wt mice. Hyperlipidemia was characterized by a prominent increase in plasma very low-density lipoprotein and intermediate-density lipoprotein/LDL with unchanged plasma high-density lipoprotein levels, thus mimicking the dyslipidemic profile observed in humans. Analysis of specific lipid species by liquid chromatography-tandem mass spectrometry suggested a predominant effect of CsA on increased very low-density lipoprotein-IDL/LDL lipoprotein number rather than composition. Mechanistic studies indicated that CsA did not alter hepatic lipoprotein production but did inhibit plasma clearance and hepatic uptake of [(14)C]cholesteryl oleate and glycerol tri[(3)H]oleate-double-labeled very low-density lipoprotein-like particles. Further studies showed that CsA inhibited plasma lipoprotein lipase activity and increased levels of apolipoprotein C-III and proprotein convertase subtilisin/kexin type 9.We demonstrate that CsA does not cause hyperlipidemia via direct effects on the LDLr. Rather, LDLr deficiency plays an important permissive role for CsA-induced hyperlipidemia, which is associated with abnormal lipoprotein clearance, decreased lipoprotein lipase activity, and increased levels of apolipoprotein C-III and proprotein convertase subtilisin/kexin type 9. Enhancing LDLr and lipoprotein lipase activity and decreasing apolipoprotein C-III and proprotein convertase subtilisin/kexin type 9 levels may therefore provide attractive treatment targets for patients with hyperlipidemia receiving CsA.
- Effect of two polymorphisms of the resistin gene (rs10401670 and rs1862513) on resistin levels and biochemical parameters in morbidly obese patients 1 year after a biliopancreatic diversion surgery. [JOURNAL ARTICLE]
- Clin Nutr 2016 Apr 13.
Two single nucleotide polymorphisms (SNPs) of the resistin gene RETN have been described: rs10401670 and rs1862513. The objective of this study was to investigate the effect of these SNPs on changes in serum resistin levels, biochemical parameters and weight after biliopancreatic diversion surgery in morbidly obese patients without diabetes mellitus.A sample of 155 patients with morbid obesity without diabetes mellitus was enrolled. Anthropometric and biochemical evaluations were realized at the basal visit and at 12 months. The percentage of subjects with hypertension and hyperlipidemia was also reported.Initial percentage excess weight loss, body mass index, weight, waist circumference, fat mass, blood pressure, low-density lipoprotein cholesterol, total cholesterol, triglycerides levels, insulin and the homeostasis model assessment for insulin sensitivity (HOMA-IR) improve after 12 months. No differences in these improvements were detected between the two genotypes (wild vs mutant group) in each SNP analysis. Resistin levels only changed after surgery in wild genotypes of both SNPs (rs1862513 and rs10401670). The improvement in insulin levels was lower in the mutant group of rs1862513 (-3.4 ± 0.4 UI/dl vs -2.3 ± 0.2 UI/dl; P < 0.05) and rs1040167 (-3.3 ± 0.2 UI/dl vs -1.9 ± 0.3 UI/dl; P < 0.05). The decrease of HOMA-IR was lower in mutant group of rs1862513 (-1.4 ± 0.1 units vs -0.9 ± 0.3 units; P < 0.05) and rs10401670 (-1.2 ± 0.2 units vs -0.9 ± 0.3 units; P < 0.05).The main result of this study was that the mutant genotype of two SNPs of the RETN gene (rs1862513 and rs10401670) was associated with a lack of change in resistin secondary to biliopancreatic diversion. The improvement in insulin levels and HOMA-IR was also lower in these patients.