The relationship between retinol-binding protein 4 levels, insulin resistance, androgen hormones and polycystic ovary syndrome.

BACKGROUND: Retinol-binding protein 4 (RPB4), a 21-kDa peptide, is a recently identified adipokine that may contribute to the pathogenesis of polycystic ovary syndrome (PCOS). The aim of this study was to explore the association between serum RBP4 levels, androgen hormones and insulin resistance (IR) in women with PCOS. METHODS: In this case-control study, 75 PCOS patients and 53 age- and body mass index (BMI)-matched control subjects referred to the Zanjan Metabolic Disease Research Center were enrolled. Serum RBP4 was measured using an enzyme-linked immunosorbent assay. BMI, waist circumference (WC), fasting levels of glucose, lipid profiles and insulin were also measured. A homeostatic model assessment of insulin resistance (HOMA-IR) value was used to determine the level of insulin resistance. RESULTS: PCOS cases had significantly higher serum RBP4 and insulin levels than control subjects (44130 ± 12760 vs. 32980 ± 9560 µg/L, p < 0.001, and 11790 ± 11480 vs. 7890 ± 4300 µU/L, p < 0.05, respectively), in univariable analysis. RBP4 showed a positive correlation with serum testosterone (r = 0.62, p < 0.0001), dehydroepiandrosterone sulfate (r = 0.45, p < 0.0001) and the waist circumference (r = 0.37, p < 0.001) of PCOS patients but not with other measured clinical and biochemical variables. However, no correlation was observed between serum RBP4 levels and HOMA-IR in all studied subjects. A final logistic regression analysis demonstrated that testosterone and dehydroepiandrosterone sulfate are independently associated with PCOS. CONCLUSION: These findings indicate that RBP4 is not independently associated with PCOS. The elevation of RBP4 levels in PCOS women might be influenced by androgen hormones. Further prospective studies are needed to clarify molecular mechanisms.

Liver X Receptor as a Possible Drug Target for Blood-Brain Barrier Integrity.

Purpose: blood-brain barrier (BBB) is made of specialized cells that are responsible for the selective passage of substances directed to the brain. The integrated BBB is essential for precise controlling of the different substances passage as well as protecting the brain from various damages. In this article, we attempted to explain the role of liver X receptor (LXR) in maintaining BBB integrity as a possible drug target. Methods: In this study, various databases, including PubMed, Google Scholar, and Scopus were searched using the following keywords: blood-brain barrier, BBB, liver X receptor, and LXR until July, 2020. Additionally, contents close to the subject of our study were surveyed. Results: LXR is a receptor the roles of which in various diseases have been investigated. LXR can affect maintaining BBB by affecting various ways such as ATP-binding cassette transporter A1 (ABCA1), matrix metalloproteinase-9 (MMP9), insulin-like growth factor 1 (IGF1), nuclear factor-kappa B (NF-κB) signaling, mitogen-activated protein kinase (MAPK), tight junction molecules, both signal transducer and activator of transcription 1 (STAT1), Wnt/ß-catenin Signaling, transforming growth factor beta (TGF-ß) signaling, and expressions of Smad 2/3 and Snail. Conclusion: LXR could possibly be used either as a target for drug delivery to brain tissue or as a target for maintaining the BBB integrity in different diseases; thereby the drug will be conducted to tissues, other than the brain. If it is verified that only LXRα is necessary for protecting BBB, some specific LXRα ligands must be found and then used in medication.

Co-Administration of Vitamin E and Atorvastatin Improves Insulin Sensitivity and Peroxisome Proliferator-Activated Receptor-γ Expression in Type 2 Diabetic Patients: A Randomized Double-Blind Clinical Trial.

Background: Negative effects of statins on glucose metabolism have been reported. The present study aimed to investigate the effects of co-administration of vitamin E and atorvastatin on glycemic control in hyperlipidemic patients with type 2 diabetes mellitus (T2DM). Methods: A randomized double-blind clinical trial was conducted at Vali-e-Asr Teaching Hospital (Zanjan, Iran) from July 2017 to March 2018. A total of 30 T2DM female patients were allocated to two groups, namely atorvastatin with placebo (n=15) and atorvastatin with vitamin E (n=15). The patients received daily 20 mg atorvastatin and 400 IU vitamin E or placebo for 12 weeks. Anthropometric and biochemical measures were recorded pre- and post-intervention. Peroxisome proliferator-activated receptor-γ (PPAR-γ) expression was measured in peripheral blood mononuclear cells (PBMCs). Independent sample t test and paired t test were used to analyze between- and within-group variables, respectively. The analysis of covariance (ANCOVA) was used to adjust the effect of baseline variables on the outcomes. P<0.05 was considered statistically significant. Results: After baseline adjustment, there was a significant improvement in homeostatic model assessment for insulin resistance (HOMA-IR) (P=0.04) and serum insulin (P<0.001) in the atorvastatin with vitamin E group compared to the atorvastatin with the placebo group. In addition, co-administration of vitamin E with atorvastatin significantly upregulated PPAR-γ expression (OR=5.4, P=0.04) in the PBMCs of T2DM patients. Conclusion: Co-administration of vitamin E and atorvastatin reduced insulin resistance and improved PPAR-γ mRNA expression. Further studies are required to substantiate our findings. Trial registration number: IRCT 20170918036256N.

Association of Serum Zinc and Vitamin A Levels with Severity of Retinopathy in Type 2 Diabetic Patients: a Cross-Sectional Study.

Diabetic retinopathy (DR) is a common microvascular disorder which occurs in type 2 diabetes mellitus (T2DM) patients due to chronic hyperglycemia. Previous studies reported that serum zinc (Zn) and vitamin A levels were associated with certain diabetic microvascular complications. However, the relationship between Zn and vitamin A levels with the severity of DR in type 2 diabetic patients is not clear. We aimed to analyze the relationship between serum Zn and vitamin A levels with the severity of DR in T2DM. Sixty T2DM patients were selected from whom attending to the ophthalmology center of hospital from June 2017 and Feb 2018. Patients were categorized as controls, non-proliferative DR (NPDR), and proliferative DR (PDR). Anthropometric, dietary, and physical activity data were gathered. Fasting blood samples were taken to measure biochemical parameters. Serum Zn and vitamin A levels were measured via enzymatic-calorimetric and HPLC methods, respectively. Results showed that serum Zn and vitamin A levels were significantly lower in the PDR group than the controls (p = 0.03 and p = 0.008, respectively). Serum low-density lipoprotein (LDL.C) was significantly higher in the PDR than the control group (p = 0.02). Adjusting for the other variables, increase in serum Zn and vitamin A levels reduced risk of DR by 25.7% and 31.1%, respectively (p = 0.02 and p = 0.007). Higher serum LDL.C increased DR severity by 28.7%, adjusted for the variables (95% CI = 0.002, 0.02; p = 0.01). Lower serum Zn and vitamin A levels, as well as higher LDL.C in the T2DM patients, are related to DR severity.

Vitamin D status and its associations with components of metabolic syndrome in healthy children.

AIM: High prevalence of vitamin D insufficiency/deficiency has been reported in populations of different countries. The aim of this cross-sectional study was to determine the prevalence and association of vitamin D status with components of metabolic syndrome. METHODS: Lipid profile indices, anthropometric indices [body mass index and waist circumference (WC)], insulin resistance index (HOMA-IR), systolic blood pressure (SBP), diastolic blood pressure (DBP), C-reactive protein, intact parathyroid hormone (iPTH), and serum 25-hydroxyvitamin D [25(OH)D] concentration were evaluated in 297 healthy schoolchildren aged 7-11 years. Multivariate linear regression was used to determine independent predictors associated with low serum 25(OH)D concentrations. RESULTS: The mean serum 25(OH)D concentration was 14.12±8.20 ng/mL (35.3±20.5 nmol/L); 96% of children had low serum 25(OH)D levels, 31.0% were deficient, and 65.0% had insufficient levels of 25(OH)D. Vitamin D deficiency was higher in girls (χ²=13.66; p=0.00); 25(OH)D level was negatively associated with WC, HOMA-IR, SBP, DBP, and iPTH. In the multivariate model, WC, DBP, and HOMA-IR were significant independent predictor of low 25(OH)D concentrations. CONCLUSION: The prevalence of low vitamin D level in the studied healthy children was high and it is correlated with some components of metabolic syndrome. Outdoor activity for optimum sun exposure and additional studies are needed to evaluate the underlying metabolic syndrome components and hypovitaminosis D complications.

Complex formation between human kallikrein 13 and serum protease inhibitors.

BACKGROUND: The kallikrein family is a group of 15 serine protease genes clustered on chromosome 19q13.4. Human kallikrein gene 13 (KLK13) is a member of this family and encodes for a trypsin-like, secreted serine protease (hK13). Given that other kallikreins are sequestered by serum protease inhibitors, we hypothesized that hK13 may also interact with similar inhibitors. Our objective was to identify serum protease inhibitors that interact with human hK13. METHODS: Recombinant hK13 produced in yeast was added to male and female sera and various biological fluids and the spiked samples were analyzed with an hK13 ELISA assay. Enzymatically active hK13 was 125I-labeled and used in in vitro reactions with candidate protease inhibitors and serum samples. The mixtures were then subjected to gel filtration and SDS-PAGE analysis. Candidate inhibitors were also tested in enzymatic assays of hK13 activity. RESULTS: The recovery of recombinant hK13 from male and female sera, measured by three versions of the hK13-ELISA, ranged from 5% to 10%. The same recovery was obtained when serum samples from males and females were spiked with hK13 from amniotic fluid and seminal plasma. However, when hK13 was added to other biological fluids, such as amniotic fluid and breast milk, recovery ranged from 70% to 98%. In vitro analysis indicated that enzymatically active 125I-labeled hK13 forms SDS-stable complexes with alpha2-antiplasmin, alpha2-macroglobulin and alpha1-antichymotrypsin. When added to serum, active hK13 formed stable complexes with molecular masses corresponding to hK13 and the inhibitors mentioned above. CONCLUSIONS: hK13 interacts and forms complexes with serum protease inhibitors, including alpha2-macroglobulin, alpha1-antichymotrypsin and alpha2-antiplasmin.

Comparative Proteomics Study of Streptozotocin-induced Diabetic Nephropathy in Rats Kidneys Transfected with Adenovirus-mediated Fibromodulin Gene.

BACKGROUND: Transforming Growth Factor-beta (TGF-ß) activation appears to be crucial for tissue injury in Diabetic Nephropathy (DN). Fibromodulin, the small leucine-rich proteoglycan, has been proposed to be the potent TGF-ß modulator. In this study, the therapeutic effects of fibromodulin in the kidneys of streptozotocin (STZ)-induced diabetic rats were investigated. METHODS: Diabetic rats received intraperitoneal (IP) injections of recombinant adenovirus expression vectors (RAd5) containing fibromodulin (RAd-FMOD) and were killed after 10 weeks. Proteins were isolated from the rat kidney and separated using two-dimensional gel electrophoresis. The differentially expressed proteins were analyzed using Matrix-assisted laser desorption/ ionization time-of-flight mass spectrometry (MALDI-TOF-MS). RESULTS: Ten spots were identified using MALDI-TOF-MS. The identified proteins were primarily responsible for cell metabolism, cytoskeleton formation, and oxidative stress. RAd-FMOD treatment markedly attenuated the albuminuria in diabetic rats. CONCLUSION: Taken together, these results provide a valuable clue in exploring the mechanism underlying the therapeutic effects of fibromodulin in diabetic nephropathy suggesting that it can be a potential agent in the treatment of this disease.

Defining a cutoff point for vitamin D deficiency based on insulin resistance in children.

BACKGROUND: Vitamin D deficiency is a common worldwide problem. Low levels of serum 25-hydroxy vitamin D [25(OH)D], as a marker of vitamin D deficiency, have been linked to a wide field of health problems, including metabolic diseases such as insulin resistance, type 1 and type 2 DM. There is no universal definition for cutoff value of vitamin D deficiency and it seems that it varies in different populations. OBJECTIVE: Most previous studies have used a start rise of PTH as a criteria to detect threshold of serum 25(OH)D, However, the aim of this study was to determine a cutoff point of serum 25(OH)D for vitamin D deficiency based on HOMA-IR. MATERIALS AND METHODS: Two hundred and ninety seven healthy children (aged 7-11 years) were enrolled. Serum 25(OH)D and PTH were measured and HOMA-IR was calculated. The ROC curve was utilized to obtain a cutoff of vitamin D deficiency based on HOMA-IR. RESULTS: 25(OH)D concentrations were inversely correlated with HOMA-IR levels (Spearman's r=-0.14, p=0.016). Serum 25(OH)D cutoff point was 11.6ng/mL (29nmol/L) in relation with HOMA-IR >2.1. By using this cutoff value, the prevalence of vitamin D deficiency was 43.4% in this study population of healthy children. CONCLUSION: We found that serum 25(OH)D levels are inversely associated with insulin resistance. These results suggest that in MetS patients it may benefit to determine cutoff value of 25(OH)D levels based on HOMA-IR.

A report of high triglyceride level in cord blood of Iranian newborns.

BACKGROUND: Since cord blood triglyceride level have been reported very different in recent articles, the purpose of this study is determination of triglyceride level in cord blood of Iranian newborns and compare it with other reports. METHODS: In this study, cord blood of 174 healthy term newborn infants (97 girls, 77 boys) born from healthy mothers have been used. Triglyceride level has been measured by calorie metric method Statistical analysis was performed by independent t test, Mann-Whitney regression test and Spearman correlation coefficient method using SPSS 16 .0 software (SPSS, USA). RESULTS: The mean of cord blood triglyceride was 1.37 ± 4.81 mg /dl and there was no statistical difference between two sexes. There was not exist linear relationship between triglyceride and weight, height, head circumference, body mass index and sex of the babies. In 8.6% of our new born infants, triglyceride levels were more than 95th percentile of triglyceride level reported in Iranian population. In 33.9% of our cases, triglyceride levels were more than 95(th) percentile of triglyceride level reported in the Nelson text book of Pediatrics. In this study, the 95th percentile of triglyceride level in cord blood was 132.5 mg /dl. CONCLUSION: The mean and 95(th) percentiles of triglyceride levels in cord blood of our newborn infants were higher than other reports. We recommend that larger studies should be conducted in this area to establish preventive ways for increasing epidemic of the metabolic syndrome.

Multiple correlations between cord blood leptin concentration and indices of neonatal growth.

BACKGROUND AND AIMS: The discovery of a role for leptin in controlling fetal and neonatal growth suggests a fetal origin of some adult chronic diseases and has stimulated research into the mechanisms of action of leptin early in life. The aim of this study was to determine umbilical cord blood leptin levels and to evaluate their association with newborn growth indices. METHODS: Two hundred healthy newborns (89 males, 110 females, and one of undetermined gender; gestational ages ranging from 34-43 weeks) and their healthy mothers were enrolled in this study conducted at Moovsavi Hospital in Zanjan, Iran. The body size index of each newborn was determined in terms of birth weight, birth length, head circumference, body mass index (BMI) and ponderal index. Umbilical cord blood leptin levels were measured by ELISA. RESULTS: Umbilical cord leptin concentration was found to positively correlate with birth weight (r=0.322; p<0.0001), neonatal BMI (r=0.247; p<0.0001), ponderal index (r=0.206; p=0.04), and gestational age (r=0.221; p=0.002). There was no significant correlation between cord leptin and birth length or umbilical glucose concentration. Umbilical cord leptin concentrations (15.20+/-12.3 vs. 12.08+/-11.7; p=0.01) were significantly greater in female as compared to male newborns, respectively. Linear regression analysis indicated that umbilical cord leptin levels correlated with birth weight, umbilical triglyceride concentration, neonatal gender, and method of delivery. CONCLUSIONS: Our findings confirm the association of leptin concentrations with weight gain in fetal and newborn infants.

Correlation of anthropometric indices with common cardiovascular risk factors in an urban adult population of Iran: data from Zanjan Healthy Heart Study.

The purpose of this study was to determine the anthropometric index that best predicts common cardiovascular risk factors. A total of 2768 individuals (1310 men and 1458 women) aged 21-75 years with full relevant data from the Zanjan Healthy Heart Study (a prospective study in Zanjan and Abhar, two main cities of Zanjan Province, Iran) were recruited. Common cardiovascular risk factors (TG, TC, HDL-c, LDL-c, fast blood sugar, blood pressure), anthropometric indices (BMI, WC, WHR, WHtR) were measured using standard process, and their correlated classification was evaluated by partial correlation and Receiver Operator Characteristic (ROC) curve analysis. Area under curve (AUC) of WHtR was the largest for most (6 of 7) of the common cardiovascular risk factors in both men and women; followed by WC (4 of the 7 including ties) in men, while AUCs of three anthropometric indices (WC, BMI, WHR) were the same with the largest for 1 of 7 risk factors in women. These results show that the high prevalence of lipid profiles, as cardiovascular risk factors, need special attention, intervention and appropriate treatment. Consistence with other reports, WHtR is a better discriminator of cardiovascular risk factors compared with the other three indices (BMI, WC, and WHR). We determined its optimal cut-off point of 0.5 for both genders. However, due to differences in reported cut-off values across different ethnic groups, future research and longitudinal data is needed before reaching an internationally accepted simple and appropriate measure that could be effectively used in the clinical and epidemiological fields.