Publications by authors named "Urszula Razny"

24 Publications

  • Page 1 of 1

Association between health risk factors and dietary flavonoid intake in cohort studies.

Int J Food Sci Nutr 2021 Apr 7:1-16. Epub 2021 Apr 7.

Faculty of Health Sciences, Institute of Public Health, Department of Nutrition and Drug Research, Jagiellonian University Medical College, Krakow, Poland.

The aim of this study was to identify the health risk factors associated with flavonoid intake in cohort studies investigating the association between dietary polyphenols and the risk of cardiovascular disease (CVD). A systematic search of the PubMed and EMBASE databases was performed. Prospective studies with the background characteristics given for categories of flavonoid intake were eligible to inclusion. A bivariate meta-analysis summarising the intercepts and slopes of the linear regression and a dose-response meta-analysis of differences in means were used to analyse the relationships. The intake of total flavonoids was inversely associated with BMI, alcohol consumption, saturated fat intake, and current smoking, and positively associated with vitamin E, folate, fibre, beta-carotene intake, multivitamin supplement use, and high physical activity. The results of this study underline the importance of considering the association between dietary flavonoid consumption and CVD risk in the context of a healthy lifestyle.
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http://dx.doi.org/10.1080/09637486.2021.1908965DOI Listing
April 2021

Epigenetic Regulation of Processes Related to High Level of Fibroblast Growth Factor 21 in Obese Subjects.

Genes (Basel) 2021 Feb 21;12(2). Epub 2021 Feb 21.

Department of Clinical Biochemistry, Jagiellonian University Medical College, 15a Kopernika Street, 31-501 Krakow, Poland.

We hypothesised that epigenetics may play an important role in mediating fibroblast growth factor 21 (FGF21) resistance in obesity. We aimed to evaluate DNA methylation changes and miRNA pattern in obese subjects associated with high serum FGF21 levels. The study included 136 participants with BMI 27-45 kg/m. Fasting FGF21, glucose, insulin, GIP, lipids, adipokines, miokines and cytokines were measured and compared in high serum FGF21 ( = 68) group to low FGF21 ( = 68) group. Human DNA Methylation Microarrays were analysed in leukocytes from each group ( = 16). Expression of miRNAs was evaluated using quantitative PCR-TLDA. The study identified differentially methylated genes in pathways related to glucose transport, insulin secretion and signalling, lipid transport and cellular metabolism, response to nutrient levels, thermogenesis, browning of adipose tissue and bone mineralisation. Additionally, it detected transcription factor genes regulating FGF21 and fibroblast growth factor receptor and vascular endothelial growth factor receptor pathways regulation. Increased expression of hsa-miR-875-5p and decreased expression of hsa-miR-133a-3p, hsa-miR-185-5p and hsa-miR-200c-3p were found in the group with high serum FGF21. These changes were associated with high FGF21, VEGF and low adiponectin serum levels. Our results point to a significant role of the epigenetic regulation of genes involved in metabolic pathways related to FGF21 action.
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http://dx.doi.org/10.3390/genes12020307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7926457PMC
February 2021

DNA methylation microarrays identify epigenetically regulated lipid related genes in obese patients with hypercholesterolemia.

Mol Med 2020 10 7;26(1):93. Epub 2020 Oct 7.

Department of Clinical Biochemistry, Jagiellonian University Medical College, Kopernika 15a, 31-501, Kraków, Poland.

Background: Epigenetics can contribute to lipid disorders in obesity. The DNA methylation pattern can be the cause or consequence of high blood lipids. The aim of the study was to investigate the DNA methylation profile in peripheral leukocytes associated with elevated LDL-cholesterol level in overweight and obese individuals.

Methods: To identify the differentially methylated genes, genome-wide DNA methylation microarray analysis was performed in leukocytes of obese individuals with high LDL-cholesterol (LDL-CH, ≥ 3.4 mmol/L) versus control obese individuals with LDL-CH, < 3.4 mmol/L. Biochemical tests such as serum glucose, total cholesterol, HDL cholesterol, triglycerides, insulin, leptin, adiponectin, FGF19, FGF21, GIP and total plasma fatty acids content have been determined. Oral glucose and lipid tolerance tests were also performed. Human DNA Methylation Microarray (from Agilent Technologies) containing 27,627 probes for CpG islands was used for screening of DNA methylation status in 10 selected samples. Unpaired t-test and Mann-Whitney U-test were used for biochemical and anthropometric parameters statistics. For microarrays analysis, fold of change was calculated comparing hypercholesterolemic vs control group. The q-value threshold was calculated using moderated Student's t-test followed by Benjamini-Hochberg multiple test correction FDR.

Results: In this preliminary study we identified 190 lipid related CpG loci differentially methylated in hypercholesterolemic versus control individuals. Analysis of DNA methylation profiles revealed several loci engaged in plasma lipoprotein formation and metabolism, cholesterol efflux and reverse transport, triglycerides degradation and fatty acids transport and β-oxidation. Hypermethylation of CpG loci located in promoters of genes regulating cholesterol metabolism: PCSK9, LRP1, ABCG1, ANGPTL4, SREBF1 and NR1H2 in hypercholesterolemic patients has been found. Novel epigenetically regulated CpG sites include ABCG4, ANGPTL4, AP2A2, AP2M1, AP2S1, CLTC, FGF19, FGF1R, HDLBP, LIPA, LMF1, LRP5, LSR, NR1H2 and ZDHHC8 genes.

Conclusions: Our results indicate that obese individuals with hypercholesterolemia present specific DNA methylation profile in genes related to lipids transport and metabolism. Detailed knowledge of epigenetic regulation of genes, important for lipid disorders in obesity, underlies the possibility to influence target genes by changing diet and lifestyle, as DNA methylation is reversible and depends on environmental factors. These findings give rise for further studies on factors that targets methylation of revealed genes.
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http://dx.doi.org/10.1186/s10020-020-00220-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7539457PMC
October 2020

Specific gene expression in type 1 diabetic patients with and without cardiac autonomic neuropathy.

Sci Rep 2020 03 27;10(1):5554. Epub 2020 Mar 27.

Department of Metabolic Diseases, University Hospital, Krakow, Poland.

We hypothesized that some molecular pathways might interact to initiate the process of nervous tissue destruction, promoting cardiac autonomic neuropathy (CAN) in the course of diabetes type 1 (T1D). The study group consisted of 60 T1D patients (58.33% women/41.67% men), on standard therapy. The control group consisted of twenty healthy volunteers recruited in accordance with age, gender and body weight. The presence of CAN was documented by the Ewing test method (ProSciCard apparatus). A microarray data analysis was performed using Gene Spring version 13. The microarray results for selected genes were confirmed by real-time PCR (qRT-PCR), using specific TaqMan Gene Expression Assays. Plasma IL-6 content was measured by an enzyme-linked immunosorbent assay (ELISA). The p < 0.05 value was considered as statistically significant. The microarray analysis, confirmed by qRTPCR, showed significant up-regulation of autophagy, quantity of mitochondria, quality regulatory genes (mTOR, GABARAPL2) apoptosis, ER-stress and inflammation (NFKB1, IL1b, IL1R1, SOD1), in T1D when compared to the control group. A significantly higher IL-6 protein level was observed in T1D patients, in comparison to the control group. We concluded that the observed changes in gene expression and activation of intracellular pathways give a coherent picture of the important role of oxidative stress in inflammation and the activation of apoptosis in the pathomechanism of DM. The significance of the inflammatory process, confirmed by the increased level of the inflammation biomarker IL-6 in the pathomechanisms of CAN was shown even in patients with properly treated T1D.
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http://dx.doi.org/10.1038/s41598-020-62498-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7101413PMC
March 2020

Enhanced GIP Secretion in Obesity Is Associated with Biochemical Alteration and miRNA Contribution to the Development of Liver Steatosis.

Nutrients 2020 Feb 13;12(2). Epub 2020 Feb 13.

Department of Clinical Biochemistry, Faculty of Medicine, Jagiellonian University Medical College, Kopernika Str. 15A, 31-501 Krakow, Poland.

Nutrient excess enhances glucose-dependent insulinotropic polypeptide (GIP) secretion, which may in turn contribute to the development of liver steatosis. We hypothesized that elevated GIP levels in obesity may affect markers of liver injury through microRNAs. The study involved 128 subjects (body mass index (BMI) 25-40). Fasting and postprandial GIP, glucose, insulin, and lipids, as well as fasting alanine aminotransferase (ALT), γ-glutamyltransferase (GGT), cytokeratin-18, fibroblast growth factor (FGF)-19, and FGF-21 were determined. TaqMan low density array was used for quantitative analysis of blood microRNAs. Fasting GIP was associated with ALT [β = 0.16 (confidence interval (CI): 0.01-0.32)], triglycerides [β = 0.21 (95% CI: 0.06-0.36], and FGF-21 [β = 0.20 (95%CI: 0.03-0.37)]; and postprandial GIP with GGT [β = 0.17 (95%CI: 0.03-0.32)]. The odds ratio for elevated fatty liver index (>73%) was 2.42 (95%CI: 1.02-5.72) for high GIP versus low GIP patients. The miRNAs profile related to a high GIP plasma level included upregulated miR-136-5p, miR-320a, miR-483-5p, miR-520d-5p, miR-520b, miR-30e-3p, and miR-571. Analysis of the interactions of these microRNAs with gene expression pathways suggests their potential contribution to the regulation of the activity of genes associated with insulin resistance, fatty acids metabolism, and adipocytokines signaling. Exaggerated fasting and postprandial secretion of GIP in obesity are associated with elevated liver damage markers as well as FGF-21 plasma levels. Differentially expressed microRNAs suggest additional, epigenetic factors contributing to the gut-liver cross-talk.
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http://dx.doi.org/10.3390/nu12020476DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7071278PMC
February 2020

Effect of insulin resistance on whole blood mRNA and microRNA expression affecting bone turnover.

Eur J Endocrinol 2019 Nov;181(5):525-537

Department of Clinical Biochemistry, Jagiellonian University Medical College, Krakow, Poland.

Objective: To evaluate the effect of insulin resistance in obesity on the expression in whole blood of mRNA and miRNA affecting bone homeostasis as well as to estimate the influence of oral glucose load (OGTT) on serum osteocalcin concentration in obese individuals with and without insulin resistance.

Design: Cross-sectional study.

Methods: Carboxylated (cOC), undercarboxylated (ucOC) and total osteocalcin were measured by ELISA in the serum of obese subjects with insulin resistance (n = 41) and obese subjects without insulin resistance (n = 41) (control group) during OGTT. Analysis of gene expression (microarray) and miRNAs (real-time PCR) was performed in venous blood (representating samples) collected before OGTT from obese with insulin resistance and controls.

Results: Obese subjects with insulin resistance (higher HOMA-IR and lower oral glucose insulin sensitivity index) presented significantly increased expression of WNT signalling inhibitors (DKK1, DKK2, SOST, SFRP1) and downregulation of the key factor in WNT signalling - β catenin participating in osteoblasts differentiation. Expression of miRNA involved in osteoblastogenesis was also inhibited (miR-29b, miR-181a, miR-210, miR-324-3p). During OGTT, contrary to the control group, subjects with insulin resistance presented suppression of cOC and total OC decrease after 1 and 2 h of oral glucose load.

Conclusions: Obese subjects with insulin resistance may have defects in osteoblastogenesis that was demonstrated via key signalling molecules mRNA downregulation, and increased expression of WNT antagonists as well as inhibition of expression of miRNA participating in the regulation of osteoblast differentiation. Disturbed osteoblastogenesis in insulin-resistant subjects results in the suppression of blood carboxylated and total osteocalcin decrease during OGTT.
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http://dx.doi.org/10.1530/EJE-19-0542DOI Listing
November 2019

High Fat Mixed Meal Tolerance Test Leads to Suppression of Osteocalcin Decrease in Obese Insulin Resistant Subjects Compared to Healthy Adults.

Nutrients 2018 Nov 1;10(11). Epub 2018 Nov 1.

Department of Clinical Biochemistry, Jagiellonian University Medical College, Kopernika 15a, 31-501 Krakow, Poland.

Nutrients influence bone turnover. Carboxylated osteocalcin (Gla-OC) participates in bone formation whereas its undercarboxylated form (Glu-OC) acts as a hormone in glucose metabolism. The aim of the study was to determine the responses of Gla-OC, Glu-OC, and total-OC (calculated as the sum of Gla-OC and Glu-OC) to a high fat mixed meal tolerance test (HFMTT) in non-obese (body mass index (BMI) < 30 kg/m², = 24) and obese subjects (30 < BMI < 40 kg/m², = 70) (both sexes, aged 25⁻65 years). Serum Gla-OC and Glu-OC were measured at baseline as well as at 2 and 6 h during a HFMTT by enzyme-linked immunosorbent assay (ELISA). Baseline Gla-OC, Glu-OC, and total-OC levels were lower in obese individuals compared to non-obese participants ( = 0.037, = 0.016 and = 0.005, respectively). The decrease in Gla-OC and total-OC, but not in Glu-OC, concentrations during the HFMTT was suppressed in obese, but not in non-obese controls ( < 0.05, < 0.01, = 0.08, respectively). Subjects with the highest homeostatic model assessment for insulin resistance (HOMA-IR) index values had a less pronounced decrease in total-OC compared to patients with values of HOMA-IR index in the 1st quartile ( < 0.05). Net incremental area under Gla-OC inversely correlated with adiponectin (rho = -0.35, = 0.001). Increase in insulin sensitivity and adiponectin level in obese subjects could beneficially influence postprandial bone turnover expressed by osteocalcin concentration.
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http://dx.doi.org/10.3390/nu10111611DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6267021PMC
November 2018

Relation of the protein glycation, oxidation and nitration to the osteocalcin level in obese subjects.

Acta Biochim Pol 2017 28;64(3):415-422. Epub 2017 Jul 28.

Department of Clinical Biochemistry, Jagiellonian University Medical College, Kraków, Poland.

Carboxylated osteocalcin (Gla-OC) contributes to the bone formation, whereas its undercarboxylated form (Glu-OC) takes part in the energy metabolism. In vitro studies had shown that treatment of osteoblast-like cells with advanced glycation end product-modified bovine serum resulted in reduced synthesis of collagen 1 and osteocalcin. The aim of this study was to find association between Gla-OC and markers of protein glycation, oxidation and nitration, as well as pro-inflammatory and antioxidant defense markers in obese subjects. Non-obese [(body mass index (BMI)<30 kg/m; n=34)] and obese subjects (30
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http://dx.doi.org/10.18388/abp.2017_1627DOI Listing
February 2018

Glucagon-like peptide-1 receptor agonist stimulates mitochondrial bioenergetics in human adipocytes.

Acta Biochim Pol 2017 19;64(3):423-429. Epub 2017 Aug 19.

Department of Clinical Biochemistry, Medical College, Jagiellonian University, Kraków, Poland.

Glucagon-like peptide 1 receptor agonists (GLP-1RAs) are relatively new pharmacological agents used to normalize glucose level in type 2 diabetes. Recently, GLP-1RAs have been approved for the treatment of obesity to reduce body weight in non-diabetic patients. The extra-pancre-atic effects of GLP-1RAs, as well as their molecular mechanism of action, are still poorly understood. Thus this study was aimed to verify the hypothesis that the mechanism of action of the GLP-1RAs involves mitochondria and that GLP-1RAs administration can improve mitochondrial functions. For this purpose, preadipocytes CHUBS7 were differentiated to mature adipocytes and then stimulated with GLP-1RA, exendin-4 at 100 nM for 24 h. Oxygen consumption rates, mitochondrial membrane potential, intracellular ATP (adenosine triphosphate) level, SIRT1 and SIRT3 gene expression and the histone deacetylases' activity were measured. Exendin-4 was found to uncouple mitochondrial electron transport from ATP synthesis, slightly decreasing mitochondrial membrane potential in mature adipocytes. Routine respiration and uncoupled oxy- gen consumption rates were higher in exendin-4 treated adipocytes than in the non-treated cells. The ATP level remained unchanged. Exendin-4 enhanced SIRT1 and SIRT3 genes expression. Histone deacetylases' activity in the nuclear fraction was not affected by exendin-4, although the activity of class III histone deacetylases was increased. All of the effects on mitochondrial bioenergetics induced by exendin-4 were abolished by addition of glucagon-like peptide 1 receptor antagonist. In conclusion, exendin-4 activates the sirtuin pathway and increases energy expenditure in human adipocytes. Our results suggest another mechanism that may be responsible for body weight reduction observed in patients using GLP-1RAs.
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http://dx.doi.org/10.18388/abp.2017_1634DOI Listing
February 2018

Carboxylated and undercarboxylated osteocalcin in metabolic complications of human obesity and prediabetes.

Diabetes Metab Res Rev 2017 03 7;33(3). Epub 2016 Nov 7.

Department of Clinical Biochemistry, Jagiellonian University Medical College, Krakow, Poland.

Background: Carboxylated osteocalcin (Gla-OC) participates in bone remodeling, whereas the undercarboxylated form (Glu-OC) takes part in energy metabolism. This study was undertaken to compare the blood levels of Glu-OC and Gla-OC in nonobese, healthy obese, and prediabetic volunteers and correlate it with the metabolic markers of insulin resistance and early markers of inflammation.

Methods: Nonobese (body mass index [BMI] <30 kg/m ; n = 34) and obese subjects (30
Results: Gla-OC in obese patients was significantly lower compared to nonobese ones (11.36 ± 0.39 vs 12.69 ± 0.90 ng/mL, P = .048) and weakly correlated with hsCRP (r = -0.18, P = .042), visfatin concentration (r = -0.19, P = .033), and BMI (r = -0.17, P = .047). Glu-OC was negatively associated with fasting insulin levels (r = -0.18, P = .049) and reduced in prediabetic individuals compared with healthy obese volunteers (3.04 ± 0.28 vs 4.48 ± 0.57, P = .025).

Conclusions: Decreased blood concentration of Glu-OC may be a selective early symptom of insulin resistance in obesity, whereas the decreased level of Gla-OC seems to be associated with the appearance of early markers of low grade inflammation accompanying obesity.
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http://dx.doi.org/10.1002/dmrr.2862DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6681168PMC
March 2017

Omega-3 fatty acid supplementation influences the whole blood transcriptome in women with obesity, associated with pro-resolving lipid mediator production.

Biochim Biophys Acta 2016 11 12;1861(11):1746-1755. Epub 2016 Aug 12.

Department of Clinical Biochemistry, Collegium Medicum, Jagiellonian University, Krakow, Poland.

The n-3 polyunsaturated fatty acids (PUFAs) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) may reduce low-grade inflammation associated with obesity. The relationship between therapeutic response to n-3 PUFAs and modification of the transcriptome in obesity or metabolic syndrome remains to be explored. Blood samples were obtained from women with obesity before and after three-months supplementation with a moderate dose of n-3 PUFAs (1.8g EPA+DHA per day) or from controls. n-3 PUFAs (GC) and plasma concentrations of lipoxins, resolvins, protectin X (GC-MS/MS) and inflammatory markers (ELISA) were measured. Whole blood transcriptome was assayed using microarray. Women supplemented with n-3 PUFAs for 3months had significantly higher levels of EPA and DHA in plasma phosphatidylcholine. n-3 PUFA supplementation, in contrast to placebo, significantly decreased the concentrations of several inflammatory markers (SELE, MCP-1, sVCAM-1, sPECAM-1, and hsCRP), fasting triglycerides and insulin and increased the concentrations of pro-resolving DHA derivatives in plasma. The microarray data demonstrated effects of n-3 PUFAs on PPAR-α, NRF2 and NF-κB target genes. N-3 PUFAs increased DHA-derived pro-resolving mediators in women with obesity. Elevated resolvins and up-regulation of the resolvin receptor occurred in parallel with activation of PPAR-α target genes related to lipid metabolism and of NRF2 up-regulated antioxidant enzymes.
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http://dx.doi.org/10.1016/j.bbalip.2016.08.005DOI Listing
November 2016

Dicarbonyl stress in clinical obesity.

Glycoconj J 2016 08 24;33(4):581-9. Epub 2016 Jun 24.

Clinical Sciences Research Laboratories, Warwick Medical School, University of Warwick, University Hospital, Coventry, CV2 2DX, UK.

The glyoxalase system in the cytoplasm of cells provides the primary defence against glycation by methylglyoxal catalysing its metabolism to D-lactate. Methylglyoxal is the precursor of the major quantitative advanced glycation endproducts in physiological systems - arginine-derived hydroimidazolones and deoxyguanosine-derived imidazopurinones. Glyoxalase 1 of the glyoxalase system was linked to anthropometric measurements of obesity in human subjects and to body weight in strains of mice. Recent conference reports described increased weight gain on high fat diet-fed mouse with lifelong deficiency of glyoxalase 1 deficiency, compared to wild-type controls, and decreased weight gain in glyoxalase 1-overexpressing transgenic mice, suggesting a functional role of glyoxalase 1 and dicarbonyl stress in obesity. Increased methylglyoxal, dicarbonyl stress, in white adipose tissue and liver may be a mediator of obesity and insulin resistance and thereby a risk factor for development of type 2 diabetes and non-alcoholic fatty liver disease. Increased methylglyoxal formation from glyceroneogenesis on adipose tissue and liver and decreased glyoxalase 1 activity in obesity likely drives dicarbonyl stress in white adipose tissue increasing the dicarbonyl proteome and related dysfunction. The clinical significance will likely emerge from on-going clinical evaluation of inducers of glyoxalase 1 expression in overweight and obese subjects. Increased transcapillary escape rate of albumin and increased total body interstitial fluid volume in obesity likely makes levels of glycation of plasma protein unreliable indicators of glycation status in obesity as there is a shift of albumin dwell time from plasma to interstitial fluid, which decreases overall glycation for a given glycemic exposure.
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http://dx.doi.org/10.1007/s10719-016-9692-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4975769PMC
August 2016

Hypoglycemic episodes are associated with inflammatory status in patients with type 1 diabetes mellitus.

Atherosclerosis 2016 08 3;251:334-338. Epub 2016 May 3.

Department of Metabolic Diseases, Jagiellonian University Medical College, Krakow, Poland; University Hospital, Krakow, Poland. Electronic address:

Backgroud: Glycemic control may be associated with inflammatory status in type 1 diabetes (T1DM). We examined the association between glucose control parameters and circulating inflammation markers in T1DM.

Methods: The study included 101 T1DM patients treated with personal insulin pumps (T1DM duration 15.2 + 7.3 years). The analysed glycemic parameters included HbA1c, mean glucose level, standard deviation and number of hypoglycemic episodes (glucose <55 mg/dL) from the last 7 days. Blood was collected for testing inflammatory markers (IL-6, VCAM, ICAM, E-selectin).

Results: The T1DM cohort had good glycemic control (HbA1c 7.1 ± 0.8%, mean daily glucose 141.5 ± 27.1 mg/dL and the mean number of hypoglycemic episodes was 5.6 ± 4.0/week). In a forward stepwise multiple linear regression analysis the number of hypoglycemic episodes predicted the levels of the investigated markers (sICAM p = 0.0019, sVCAM p = 0.021, sE-selectin p = 0.048, and IL-6 p = 0.049). None of the other glycemic parameters was shown to be an independent predictor.

Conclusions: For the first time, we report an association between the number of mild hypoglycemic episodes, recorded in a real life setting, and the level of inflammatory markers in T1DM patients with good glycemic control.
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http://dx.doi.org/10.1016/j.atherosclerosis.2016.05.002DOI Listing
August 2016

Effect of caloric restriction with or without n-3 polyunsaturated fatty acids on insulin sensitivity in obese subjects: A randomized placebo controlled trial.

BBA Clin 2015 Dec 22;4:7-13. Epub 2015 May 22.

Department of Clinical Biochemistry, Jagiellonian University Medical College, 31-501 Krakow, Poland.

Background: Caloric restriction and n-3 polyunsaturated fatty acid (PUFA) supplementation protect from some of the metabolic complications. The aim of this study was to assess the influence of a low calorie diet with or without n-3 PUFA supplementation on glucose dependent insulinotropic polypeptide (GIP) output and insulin sensitivity markers in obese subjects.

Methods: Obese, non-diabetic subjects (BMI 30-40 kg/m(2)) and aged 25-65 yr. were put on low calorie diet (1200-1500 kcal/day) supplemented with either 1.8 g/day n-3 PUFA (DHA/EPA, 5:1) (n = 24) or placebo capsules (n = 24) for three months in a randomized placebo controlled trial. Insulin resistance markers and GIP levels were analysed from samples obtained at fasting and during an oral glucose tolerance test (OGTT).

Results: Caloric restriction with n-3 PUFA led to a decrease of insulin resistance index (HOMA-IR) and a significant reduction of insulin output as well as decreased GIP secretion during the OGTT. These effects were not seen with caloric restriction alone. Changes in GIP output were inversely associated with changes in red blood cell EPA content whereas fasting GIP level positively correlated with HOMA-IR index. Blood triglyceride level was lowered by caloric restriction with a greater effect when n-3 PUFA were included and correlated positively with fasting GIP level.

Conclusions: Three months of caloric restriction with DHA + EPA supplementation exerts beneficial effects on insulin resistance, GIP and triglycerides.

General Significance: Combining caloric restriction and n-3 PUFA improves insulin sensitivity, which may be related to a decrease of GIP levels.
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http://dx.doi.org/10.1016/j.bbacli.2015.05.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4737910PMC
December 2015

Influence of dietary fatty acids on differentiation of human stromal vascular fraction preadipocytes.

Biochim Biophys Acta 2015 Sep 9;1851(9):1146-55. Epub 2015 May 9.

Department of Clinical Biochemistry Collegium Medicum, Jagiellonian University, Cracow, Poland.

Mediators such as cytokines, eicosanoids, nitric oxide and growth factors may regulate adipogenesis as well as inflammation. It is well documented that production of some form of eicosanoids activates lipid synthesis during adipogenesis but also contributes to the formation of factors maintaining low-level systemic inflammation. Developing nutrients for reduction of adipogenesis and inflammation can enhance preventive efficacy of daily diet. This study examined the effects of free fatty acid influence on changes in lipid biosynthesis and corresponding gene expression during differentiation of human subcutaneous adipose tissue stromal vascular fraction (SVF) cells. Proadipogenic conditions promoted SVF cell differentiation and lipid droplet (LD) formation up to 15 days. This correlated with gene expression of adipocyte differentiation markers as well as inflammatory cytokines and their receptors. Addition of free fatty acids to differentiation medium increased their incorporation during the first period of differentiation (48 h). Presence of eicosanoid acid (EPA) during the initial period of differentiation by elevation of Perilipin 3 protein (TIP47), may be responsible for smaller LD formation. Presence of arachidonic acid (AA) tends to deposit lipids in large form of LDs. Prolongation of differentiation up to 15 days decreased AA or EPA in cellular lipids. PUFA through up-regulation of both phospholipase 2 and enzymes related to eicosanoid production influenced type and quantity of eicosanoids which regulated the extent of SVF cell differentiation. Formation of small LDs and reduction of pro-inflammatory mediators in adipose tissue are the consequence of eicosanoid production with anti-inflammatory potential from EPA.
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http://dx.doi.org/10.1016/j.bbalip.2015.05.002DOI Listing
September 2015

Impact of antiretroviral therapy on selected metabolic disorders - pilot study.

Adv Clin Exp Med 2014 Jul-Aug;23(4):539-49

Department of Clinical Biochemistry, Jagiellonian University, Collegium Medicum, Kraków, Poland.

Background: Taking into consideration the aging of HIV infected individuals, changes in the metabolism aggravated by the antiretroviral therapy significantly impact their health. Mechanisms responsible for lipodystrophy, dyslipidemia and insulin resistance (IR) occurrence have not been completely understood. Only recently, the free fatty acids (FFAs) metabolic turnover has become considered to be the independent risk factor for cardiovascular complications.

Material And Methods: We designed the follow-up study in which patients were recruited before the introduction of ARV therapy and then observed up to 1 year. The impact of ARV therapy on the development of metabolic complications, inflammation markers and changes in adipokines secretion was investigated. The fasting and postprandial responses of FFAs, triglycerides (TG), glucose, insulin and glucose-dependent insulinotropic peptide (GIP) were measured. Changes in body composition were followed by impedance and a CT scan of adipose tissue volume of the abdomen and thighs.

Results: Significant impact of ARV therapy on metabolic disturbances was reported. Not only fasting, but also postprandial levels of FFAs and TG were found to increase during the follow up.

Conclusions: The increased concentration of FFAs is suggested to be the triggering event in the development of hypertriglyceridemia and insulin resistance during ARV therapy. Changes in postprandial FFAs and TG during the follow up indicate the increasing risk of cardiovascular diseases. We conclude that modern ARV therapy during the period of 12 months does not induce changes in the fat distribution, although increased limb fat correlated with higher plasma leptin level, which may be the marker of increased risk of metabolic driven cardiovascular complications.
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http://dx.doi.org/10.17219/acem/37218DOI Listing
November 2014

Metabolic complications and selected cytokines in HIV-infected individuals.

Pol Arch Med Wewn 2014 13;124(1-2):27-35. Epub 2013 Dec 13.

Introduction: Human immunodeficiency virus (HIV)-infected individuals are at a higher risk of developing metabolic disturbances. The pathogenesis of these complications is complex and not fully explored.

Objectives: The aim of the study was to investigate the effect of HIV infection and antiretroviral (ARV) therapy on the development of metabolic changes and adipocytokine concentrations. The analysis of the differences in the investigated parameters among lipodystrophic and nonlipodystrophic patients was also performed.

Patients And Methods: A total of 42 HIV‑infected patients on ARV therapy (HIV[+]ARV[+]), 13 HIV‑infected ARV naive patients (HIV[+]ARV[-]), and 20 healthy controls were included in the study. A lipid profile, fasting free fatty acids (FFAs), glucose, insulin, and insulin resistance (homeostasis model assessment of insulin resistance--HOMA‑IR) were tested. Serum concentrations of tumor necrosis factor α (TNF‑α), interleukin 6 (IL‑6), adiponectin, leptin, and fatty acid-binding protein 4 (FABP4) were determined.

Results: Increased FFA levels were observed in HIV(+)ARV(-) patients. HIV(+)ARV(+) patients had significantly higher triglycerides and insulin level compared with controls. HOMA‑IR showed a tendency to be higher in HIV(+)ARV(+) patients compared with the other study groups. The ARV therapy longer than 2 years resulted in more pronounced metabolic abnormalities. HIV infection itself had a significant effect on inflammation expressed by elevated TNF‑α and IL‑6 levels. We did not observe differences in adiponectin and FABP4 concentrations among the study groups, while the leptin concentration was significantly lower in HIV‑infected lipodystrophic than in nonlipodystrophic patients.

Conclusions: HIV infection induces lipid disorders, especially associated with fatty acid turnover augmented by ARV therapy. Compared with FABP4, leptin is a better biological marker of metabolic complications in HIV‑infected patients.
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November 2015

Mitochondrial function and apoptosis of peripheral mononuclear cells (PBMCs) in the HIV infected patients.

Curr HIV Res 2013 Jun;11(4):263-70

Chair of Gastroenterology, Hepatology and Infectious Diseases, Department of Infectious Diseases Jagiellonian University, Collegium Medicum, Sniadeckich 5, 31-531 Kraków, Poland.

HIV infection results in the development of immunodeficiency mainly due to the apoptosis of infected and by stander CD4 cells. The aim of the study was to follow the mitochondrial dependent pathway of apoptosis, one of the suggested mechanisms of above process. The inner mitochondrial membrane potential (MMP), Adenosine-5'-triphosphate (ATP) generation, apoptosis and necrosis markers of peripheral mononuclear cells (PBMCs) were compared in HIV infected patients and HIV negative control group. The correlation of blood viral load, TNFα concentration, CD4 cells count and duration of ARV therapy was considered. Additionally, group of HIV infected ARV-naive patients was involved for the follow-up study and the effects of one year of ARV therapy on measured parameters were studied. PBMCs of HIV infected individuals (especially without ARV therapy) demonstrated lower MMP and ATP generation and higher percentage of apoptotic/necrotic PBMCs. Correlation between blood TNFα level and mitochondrial dysfunction was observed. The first months of ARV therapy resulted in most significant restoration of mitochondrial function and living PBMCs count. HIV infection and ARV therapy have significant impact on mitochondrial function and apoptosis of PBMCs. They are driven by abnormal mitochondrial function apoptosis of immune cells which seems to be the key element leading to immunosuppression, thus an early intervention in this process by therapy can be beneficial for symptomatology of HIV infected patients.
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http://dx.doi.org/10.2174/1570162x113116660055DOI Listing
June 2013

Increased nitric oxide availability attenuates high fat diet metabolic alterations and gene expression associated with insulin resistance.

Cardiovasc Diabetol 2011 Jul 22;10:68. Epub 2011 Jul 22.

Department of Clinical Biochemistry, Jagiellonian University Medical College, Kopernika 15a Street, 31-501 Cracow, Poland.

Background: High fat diet impairs nitric oxide (NO) bioavailability, and induces insulin resistance. The link between NO availability and the metabolic adaptation to a high fat diet is not well characterized. The purpose of this study was to investigate the effect of high fat diet on metabolism in mice with decreased (eNOS-/-) and increased (DDAH overexpressed) NO bioavailability.

Methods: eNOS-/- (n = 16), DDAH (n = 24), and WT (n = 19) mice were fed a high fat diet (HFD) for 13 weeks. Body weight, biochemical parameters, adipokines and insulin were monitored. The matrigel in vivo model with CD31 immunostaining was used to assess angiogenesis. Gene expression in adipose tissues was analyzed by microarray and Real Time PCR. Comparisons of the mean values were made using the unpaired Student t test and p < 0.05 were considered statistically significant.

Results: eNOS-/- mice gained less weight than control WT and DDAH mice. In DDAH mice, a greater increase in serum adiponectin and a lesser increment in glucose level was observed. Fasting insulin and cholesterol levels remained unchanged. The angiogenic response was increased in DDAH mice. In adipose tissue of DDAH mice, genes characteristic of differentiated adipocytes were down-regulated, whereas in eNOS-/- mice, genes associated with adipogenesis, fatty acid and triglyceride synthesis were upregulated.

Conclusions: Our results indicate that increased NO availability attenuates some HFD induced alterations in metabolism and gene expression associated with insulin resistance.
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http://dx.doi.org/10.1186/1475-2840-10-68DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3212914PMC
July 2011

Modulatory effect of high saturated fat diet-induced metabolic disturbances on angiogenic response in hepatocyte RXRα knockout mice.

Pharmacol Rep 2010 Nov-Dec;62(6):1078-89

Department of Clinical Biochemistry, Medical College, Jagiellonian University, Kopernika 15a, PL 31-501 Kraków, Poland.

Metabolic syndrome and diabetes lead to pathological angiogenesis and angiopathy. Metabolic disturbances occur as an effect of genetic and environmental interaction. Hyperleptinemia accompanies obesity and leptin is a potent proangiogenic factor. The aim of the study was to investigate the effect of high fat diet-induced alterations in gene expression and angiogenic response in the hRXRα ko mice lacking of hyperglycemia. hRXRα ko and control mice were fed either standard or high saturated fat (HF) diet for 7 weeks. Body weight and biochemical parameters (glucose, triglycerides, cholesterol), insulin and adipokines (leptin, adiponectin) were monitored. At sixth week of feeding, mice were subcutaneously injected for 6 days with matrigel containing bFGF. Then, matrigel plugs were used for immunohistochemical staining of cells with CD31 antibody and gene expression assessment (by microarray confirmed for some genes with quantitative real time PCR). For description of angiogenesis CD31 positive structures were counted in the matrigel sections. HF diet feeding of the hRXRα ko mice resulted in increased serum cholesterol and leptin level and in tendency to decrease angiogenesis (number of vessels with lumen). The microarray studies revealed that HF diet down-regulated genes related to angiogenesis (Nos3, Kdr) and up-regulated genes connected with apoptosis (activators of caspase 3, proapoptotic genes Bcl2) and proinflammatory pathway (NfκB pathway, Tnfα). Summing up, HF diet feeding of hRXRα ko mice resulted in dyslipidemia and hyperleptinemia as well as impaired angiogenic response, and cell apoptosis. These results argue for independent participation of dyslipidemia and hyperleptinemia in pathology of angiogenic response associating metabolic syndrome.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3908669PMC
http://dx.doi.org/10.1016/s1734-1140(10)70370-4DOI Listing
August 2011

Angiogenesis in Balb/c mice under beta-carotene supplementation in diet.

Genes Nutr 2010 Mar 28;5(1):9-16. Epub 2009 Nov 28.

Angiogenesis is a process of new blood vessel formation from pre-existing ones. The most important steps in angiogenesis include detachment, proliferation, migration, homing and differentiation of vascular wall cells, which are mainly endothelial cells and their progenitors. The study focused on the effect of beta-carotene (BC) supplementation (12,000 mg/kg) in the diet on angiogenesis in Balb/c mice. Female Balb/c mice were fed for 5 weeks with two different diets: with BC or without BC supplementation. After 4 weeks of feeding, Balb/c mice were injected subcutaneously with two matrigel plugs with or without basic fibroblast growth factor (bFGF). Six days later, the animals were killed, and the matrigel plugs were used for immunohistochemical staining with CD31 antibody and for gene expression analysis. Microarray and Real-Time PCR data showed down-regulation of genes involved in proliferation and up-regulation of genes encoding inhibitors of apoptosis, proteins regulating cell adhesion, matrix-degrading enzymes and proteins involved in the VEGF pathway. The results of this study demonstrated that BC proangiogenic activity (with or without bFGF) in vivo seemed to be more significantly associated with cells' protection from apoptosis and their stimulation of chemotaxis/homing than cell proliferation.
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http://dx.doi.org/10.1007/s12263-009-0160-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2820200PMC
March 2010

Angiogenesis in the New Zealand obese mouse model fed with high fat diet.

Lipids Health Dis 2009 Apr 6;8:13. Epub 2009 Apr 6.

Department of Clinical Biochemistry, Collegium Medicum, Jagiellonian University, Cracow, Poland.

Background: Obesity and its complications lead to vascular injury, atherosclerosis, diabetes and pathological angiogenesis. One of the models to study the obesity and its entanglements is the New Zealand Obese mice model. Aim of this study was to check the effect of high fat diet on changes in biochemical parameters as well as on process of angiogenesis in NZO mice.

Methods: NZO mice were fed with standard (ST) or high fat (HF) diet for seven weeks. Body weight and serum biochemical parameters were monitored. The PECAM1 positive vessel-like structures immunostaining, as well as the gene expression of the matrigel penetrating cells by microarray (confirmed by real-time PCR method) were analyzed.

Results: Mice fed with HF diet developed obesity. Number of newly created vessels with lumen was correlated with hyperglycemia and animal weight gain. The number of PECAM1 positive cells in matrigel tended to increase during HF diet. Microarray results revealed changes in gene expression (activation of the oxidative stress and insulin resistance, inhibition of apoptosis and cell differentiation), however without markers of endothelial cell network maturation.

Conclusion: Observed changes in the NZO mice on HF diet argue for the hyperglycemia related activation of angiogenesis, leading to the formation of pathological, immature network.
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http://dx.doi.org/10.1186/1476-511X-8-13DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2674043PMC
April 2009

Hepatocyte RXR alpha deletion in mice leads to inhibition of angiogenesis.

Genes Nutr 2009 Mar 18;4(1):69-72. Epub 2009 Feb 18.

Department of Clinical Biochemistry, Jagiellonian University Medical College, Kopernika 15a Street, 31-501, Cracow, Poland,

To investigate the effect of RXRalpha deficiency in liver on angiogenesis, hepatocyte RXRalpha-deficient and control wild-type mice were fed either standard or high-fat diet (HF) for 7 weeks. In the 6th week of feeding, Matrigel model of in vivo angiogenesis was applied. Matrigel plug infiltrating cells were then used for visualization of vessels (CD31 staining) as well as for gene expression analysis. HF diet appeared to decrease angiogenesis in hRXRalpha-deficient mice. Genes related to angiogenesis (Nos3, Kdr) were down-regulated, whereas genes connected with adipogenesis (Cebpb, Srebf1), apoptosis (Gzmb, Bcl2) and proinflammatory pathway (NfkappaB, Tnfalpha) were up-regulated by HF diet in hRXRalpha-deficient mice in the microarray study. Our results suggest that impaired fatty acid metabolism in liver (hRXRalpha-deficient mice) leads to impaired angiogenesis due to lipotoxicity and promotion of adipogenesis.
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http://dx.doi.org/10.1007/s12263-009-0111-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2654051PMC
March 2009

Impaired leptin activity in New Zealand Obese mice: model of angiogenesis.

Genes Nutr 2008 Dec 26;3(3-4):177-80. Epub 2008 Nov 26.

Department of Clinical Biochemistry, Jagiellonian University Medical College, Kopernika 15a, 31-501, Cracow, Poland,

Leptin is prompt to drive angiogenesis, effecting proper vascularisation. Tissue remodeling (including adipose organ) is associated with the angiogenic response. The aim of this study was to investigate the effect of hyperleptinemia on angiogenesis in subcutaneous (s.c.) in vivo matrigel model in mice on a high fat (HF) diet. HF promoted adipose tissue accumulation and biochemical changes resembling metabolic syndrome. However, the impact of this dietary treatment on angiogenesis, measured in s.c. matrigel model was not significant. Changes in leptin concentration were not accompanied by significant angiogenic response. This lack of leptin activity and impaired signal transduction at the molecular level suggests malfunction of the leptin receptor in NZO mice.
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http://dx.doi.org/10.1007/s12263-008-0103-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2593019PMC
December 2008