Publications by authors named "Beata Kiec-Wilk"

105 Publications

Challenges in Transition From Childhood to Adulthood Care in Rare Metabolic Diseases: Results From the First Multi-Center European Survey.

Front Med (Lausanne) 2021 25;8:652358. Epub 2021 Feb 25.

MetabERN, Regional Coordinating Center for Rare Diseases, Udine University Hospital, Udine, Italy.

Inherited Metabolic Diseases (IMDs) are rare diseases caused by genetic defects in biochemical pathways. Earlier diagnosis and advances in treatment have improved the life expectancy of IMD patients over the last decades, with the majority of patients now surviving beyond the age of 20. This has created a new challenge: as they grow up, the care of IMD patients' needs to be transferred from metabolic pediatricians to metabolic physicians specialized in treating adults, through a process called "transition." The purpose of this study was to assess how this transition is managed in Europe: a survey was sent to all 77 centers of the European Reference Network for Hereditary Metabolic Disorders (MetabERN) to collect information and to identify unmet needs regarding the transition process. Data was collected from 63/77 (81%) healthcare providers (HCPs) from 20 EU countries. Responders were mostly metabolic pediatricians; of these, only ~40% have received appropriate training in health issues of adolescent metabolic patients. In most centers (~67%) there is no designated transition coordinator. About 50% of centers provide a written individualized transition protocol, which is standardized in just ~20% of cases. In 77% of centers, pediatricians share a medical summary, transition letter and emergency plan with the adult team and the patient. According to our responders, 11% of patients remain under pediatric care throughout their life. The main challenges identified by HCPs in managing transition are lack of time and shortage of adult metabolic physician positions, while the implementations that are most required for a successful transition include: medical staff dedicated to transition, a transition coordinator, and specific metabolic training for adult physicians. Our study shows that the transition process of IMD patients in Europe is far from standardized and in most cases is inadequate or non-existent. A transition coordinator to facilitate collaboration between the pediatric and adult healthcare teams should be central to any transition program. Standardized operating procedures, together with adequate financial resources and specific training for adult physicians focused on IMDs are the key aspects that must be improved in the rare metabolic field to establish successful transition processes in Europe.
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http://dx.doi.org/10.3389/fmed.2021.652358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7962750PMC
February 2021

Upgrading the evidence for the use of ambroxol in Gaucher disease and GBA related Parkinson: Investigator initiated registry based on real life data.

Am J Hematol 2021 05 11;96(5):545-551. Epub 2021 Mar 11.

Gaucher Unit, Shaare Zedek Medical Center, Jerusalem, Israel.

Ambroxol hydrochloride is an oral mucolytic drug available over-the-counter for many years as cough medicine. In 2009 it was identified as a pharmacological chaperone for mutant glucocerebrosidase, albeit in a several-fold higher dose. Unfortunately, there have been no pharma-driven clinical trials to establish its use. Thus, real-world observational data are needed on the safety and efficacy of ambroxol for patients with Gaucher disease (GD) and GBA-Parkinson disease (GBA-PD). Clinicians treating patients with ambroxol for GD and GBA-PD were approached to collaborate in an investigator-initiated registry. Anonymized data were collected, including demographics, GD type, GD-specific therapy (when applicable), adverse events (AEs), and, when available, efficacy data. We report the data of the first 41 patients (25 females) at a median (range) age 17 (1.5-74) from 13 centers; 11 with GD type 1(four diagnosed with PD), 27 with neuronopathic GD (nGD), and three GBA mutation carriers with PD. The median (range) treatment period and maximum dose of ambroxol were 19 (1-76) months and 435 (75-1485) mg/day, respectively. One patient with type 2 GD died of her disease. No other severe AEs were reported. Twelve patients experienced AE, including minor bowel discomfort, cough, allergic reaction, mild proteinuria, dizziness and disease progression. Clinical benefits were reported in 25 patients, including stable or improved neurological status, increased physical activity, and reduced fatigue. Until the approval of specific therapies for nGD and disease-modification for GBA-PD, these preliminary data may be encouraging to physicians and patients who consider an off-label use of ambroxol.
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http://dx.doi.org/10.1002/ajh.26131DOI Listing
May 2021

BMPR1B gene in brachydactyly type 2-A family with de novo R486W mutation and a disease phenotype.

Mol Genet Genomic Med 2021 Mar 24;9(3):e1594. Epub 2021 Jan 24.

Warsaw Genomics INC., Warszawa, Poland.

Background: Brachydactylies are a group of inherited conditions, characterized mainly by the presence of shortened fingers and toes. Based on the patients' phenotypes, brachydactylies have been subdivided into 10 subtypes. In this study, we have identified a family with two members affected by brachydactyly type A2 (BDA2). BDA2 is caused by mutations in three genes: BMPR1B, BMP2 or GDF5. So far only two studies have reported the BDA2 cases caused by mutations in the BMPR1B gene.

Methods: We employed next-generation sequencing to identify mutations in culpable genes.

Results And Conclusion: In this paper, we report a case of BDA2 resulting from the presence of a heterozygous c.1456C>T, p.Arg486Trp variant in BMPR1B, which was previously associated with BDA2. The next generation sequencing analysis of the patients' family revealed that the mutation occurred de novo in the proband and was transmitted to his 26-month-old son. Although the same variant was confirmed in both patients, their phenotypes were different with more severe manifestation of the disease in the adult.
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http://dx.doi.org/10.1002/mgg3.1594DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8104157PMC
March 2021

The Gut Microbiota Profile According to Glycemic Control in Type 1 Diabetes Patients Treated with Personal Insulin Pumps.

Microorganisms 2021 Jan 12;9(1). Epub 2021 Jan 12.

Department of Metabolic Diseases, Jagiellonian University Medical College, 2 Jakubowskiego Street, 30-688 Krakow, Poland.

Recently, several studies explored associations between type 1 diabetes (T1DM) and microbiota. The aim of our study was to assess the colonic microbiota structure according to the metabolic control in T1DM patients treated with insulin pumps. We studied 89 T1DM patients (50.6% women) at the median age of 25 (IQR, 22-29) years. Pielou's evenness ( = 0.02), and Shannon's ( = 0.04) and Simpson's diversity indexes ( = 0.01), were higher in patients with glycosylated hemoglobin (HbA1c) ≥ 53 mmol/mol (7%). There were no differences in beta diversity between groups. A linear discriminant analysis effect size (LEfSe) algorithm showed that one family () was enriched in patients with HbA1c < 53 mmol/mol, whereas one family () and four species (, unclassified species of , , and ) were enriched in patients with HbA1c ≥ 53 mmol/mol. We found that at class level, the following pathways according to Kyoto Encyclopedia of Genes and Genomes were enriched in patients with HbA1c < 53 mmol/mol: bacterial motility proteins, secretion system, bacterial secretion system, ribosome biogenesis, translation proteins, and lipid biosynthesis, whereas in patients with HbA1c ≥ 53 mmol/mol, the galactose metabolism, oxidative phosphorylation, phosphotransferase system, fructose, and mannose metabolism were enriched. Observed differences in alpha diversity, metabolic pathways, and associations between bacteria and HbA1c in colonic flora need further investigation.
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http://dx.doi.org/10.3390/microorganisms9010155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7826603PMC
January 2021

Predictors of the maximal oxygen consumption in adult patients with type 1 diabetes treated with personal insulin pumps.

J Diabetes Investig 2020 Dec 30. Epub 2020 Dec 30.

Department of Metabolic Diseases, Jagiellonian University Medical College, Krakow, Poland.

Aims/introduction: Regular physical activity for adults with type 1 diabetes mellitus improves cardiorespiratory fitness (CF) and quality of life. The aim of our study was to evaluate clinical and biochemical features that might be associated with CF in a homogenous group of adults with type 1 diabetes mellitus who are all treated with a personal insulin pump (continuous subcutaneous insulin infusion).

Materials And Methods: We assessed CF in 62 patients (74.2% of whom were men) who fulfilled the eligibility criteria. To determine maximal oxygen consumption, the march-running test on the treadmill was carried out. Two hours before the test, the patients consumed a defined meal covered by a dose of rapid acting insulin analog that was reduced by 25% from their regular dose. Basal insulin infusion was reduced by 50% for an hour. Additionally, the Perceived Stress Scale-10 questionnaire was used to measure the perception of stress.

Results: There was no episode of severe hypoglycemia during or after the test. In the final model, independent predictors of maximal oxygen consumption were sex, body fat percentage, lactate at 20 min after CF test and Perceived Stress Scale-10 score. Of interest, neither short-term (continuous glucose monitoring) nor long-term (glycosylated hemoglobin) metabolic control parameters were predictors of CF.

Conclusions: In our selected homogenous group of patients with type 1 diabetes mellitus treated with personal insulin pumps, higher CF was associated with a lower percentage of body fat, male sex, higher lactate level after the CF test and the Perceived Stress Scale-10 score. The proposed protocol in our cohort proved to be safe with regard to glycemic control.
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http://dx.doi.org/10.1111/jdi.13490DOI Listing
December 2020

MiRNA Expression in Patients with Gaucher Disease Treated with Enzyme Replacement Therapy.

Life (Basel) 2020 Dec 22;11(1). Epub 2020 Dec 22.

Clinical Department of Metabolic Diseases and Diabetology, University Hospital in Krakow, 30-688 Kraków, Poland.

Aims: The aim of the work was to establish potential biomarkers or drug targets by analysing changes in miRNA concentration among patients with Gaucher disease (GD) compared to in healthy subjects.

Methods: This study was an observational, cross-sectional analysis of 30 adult participants: 10 controls and 20 adults with GD type 1. Patients with GD type 1 were treated with enzyme replacement therapy (ERT) for at least two years. The control group was composed of healthy volunteers, unrelated to the patients, adjusted with age, sex and body mass index (BMI). The miRNA alteration between these groups was examined. After obtaining preliminary results on a group of six GD patients by the high-output method (TaqMan low-density array (TLDA)), potential miRNAs were selected for confirming the results by using the qRT-PCR method. With Diane Tools, we analysed miRNAs of which differential expression is most significant and their potential role in GD pathophysiology. We also determined the essential pathways these miRNAs are involved in.

Results: 266 dysregulated miRNAs were found among 753 tested. Seventy-eight miRNAs were downregulated, and 188 were upregulated. Thirty miRNAs were significantly altered; all of them were upregulated. The analysis of pathways regulated by the selected miRNAs showed an effect on bone development, inflammation or regulation of axonal transmission in association with Parkinson's disease.

Conclusions: We revealed few miRNAs, like miR-26-5p, which are highly altered and fit the GD pathophysiological model, might be considered as novel biomarkers of disease progression but need further evaluation.
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http://dx.doi.org/10.3390/life11010002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7822051PMC
December 2020

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

Negative pressure wound therapy affects circulating plasma microRNAs in patients with diabetic foot ulceration.

Diabetes Res Clin Pract 2020 Jul 10;165:108251. Epub 2020 Jun 10.

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

Aims: Negative pressure wound therapy (NPWT) is commonly used in diabetic foot ulceration (DFU). The molecular mechanisms of NPWT action, particularly outside of the wound site, have not been described. We assessed NPWT's effect on circulating miRNA expression levels in type 2 diabetes (T2DM) patients with DFU.

Methods: We examined 34 T2DM patients treated with either NPWT (n = 24) or standard therapy (ST, n = 10). The group assignment was based on clinical criteria and local practice. Next-generation sequencing-based microRNA expression was determined on the patient's plasma collected before therapy and after 8 days.

Results: NPWT patients were similar to the ST group in terms of age, BMI, and HbA1c level; however, they differed by mean wound area (12.6 cm vs. 1.1 cm p = 0.0005). First, we analyzed the change of miRNA after NPWT or ST and observed an upregulation of let-7f-2 only in the NPWT group. Then, we analyzed the differential expression between NPWT and ST groups, looking at possible wound size effects. We found 12 differentially expressed miRNAs in pre-treatment comparison, including let-7f-2, while in post-treatment analysis we identified 28 miRNAs. The pathway enrichment analysis suggests that identified miRNAs may be involved in wound healing, particularly through angiogenesis.

Conclusion: We found initial evidence that NPWT in T2DM patients with DFU affects miRNA expression in plasma. Additionally, some differences in plasma miRNA expression may be related to wound size.
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http://dx.doi.org/10.1016/j.diabres.2020.108251DOI Listing
July 2020

Proteomic biomarkers in Gaucher disease.

J Clin Pathol 2021 Jan 14;74(1):25-29. Epub 2020 May 14.

Metabolic Diseases and Diabetology Department, Szpital Uniwersytecki w Krakowie, Kraków, małopolskie, Poland

Aims: The research work was conducted to find new biomarkers and potential drug targets in Gaucher disease type 1 (GDt1) by analysing the serum proteins.

Methods: This study was an observational, cross-sectional analysis of a group of 12 adult participants: six Gaucher disease (GD) patients and six healthy control. Fasting venous blood underwent proteomics analysis and molecular tests. Over 400 proteins were analysed, and in case of significantly different concentrations between the study and control group, we checked corresponding genes to confirm changes in their expression and consistency with protein alteration.

Results: We found 31 proteins that significantly differed in concentration between GDt1 patients and a control group. These were mostly proteins involved in the regulation of the inflammatory processes and haemostasis. The levels of proteins such as alpha-1-acid glycoprotein 2, S100-A8/A9, adenyl cyclase-associated protein 1, haptoglobin or translationally controlled tumour protein related to inflammation process were significantly higher in GD patients than in control group, whereas the levels of some proteins such as heavy constant mu and gamma 4 or complement C3/C4 complex involved in humoral response like immunoglobulins were significantly decreased in GD patients. Alteration in two proteins concentration was confirmed in RNA analysis.

Conclusions: The work revealed few new targets for further investigation which may be useful in clinical practice for diagnosis, treatment and monitoring GDt1 patients.
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http://dx.doi.org/10.1136/jclinpath-2020-206580DOI Listing
January 2021

Case report of endoprosthesis -Y implantation in severe respiratory failure in the MPSII patient; comparison with literature data.

BMC Pulm Med 2020 Apr 20;20(1):99. Epub 2020 Apr 20.

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

Background: The tracheobronchomalacia is a life-threatening complication of mucopolysaccharidosis (MPS) without known effective, optimal treatment. The severe expiratory collapse of the trachea and bronchi is one of causes of the high rate of deaths in the course of airway impairment in MPSII patients.

Case Presentation: Due to the adynamic tracheobronchomalacia despite of enzymatic treatment (ERT) in our MPSII patient, a life-saving tracheal bifurcated type-Y endoprosthesis (a self-expanding, metal stent for the prosthesis of tracheal and bronchial stenosis) was implanted. In the followed months, the breathing efficiency improved, but then gradual worsening, progression of bronchi occlusion at the stent border resulted in patient's death.

Conclusion: The Y-stent implantation appears to be a short-term, life-saving solution without satisfactory long-term effects due to the progress of peripheral bronchomalacia and increased tissue proliferation and granulation, that arises during the illness' course.
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http://dx.doi.org/10.1186/s12890-020-1143-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7171830PMC
April 2020

Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation.

J Inherit Metab Dis 2020 07 21;43(4):671-693. Epub 2020 Apr 21.

Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic.

Mannose phosphate isomerase-congenital disorder of glycosylation (MPI-CDG) deficiency is a rare subtype of congenital disorders of protein N-glycosylation. It is characterised by deficiency of MPI caused by pathogenic variants in MPI gene. The manifestation of MPI-CDG is different from other CDGs as the patients suffer dominantly from gastrointestinal and hepatic involvement whereas they usually do not present intellectual disability or neurological impairment. It is also one of the few treatable subtypes of CDGs with proven effect of oral mannose. This article covers a complex review of the literature and recommendations for the management of MPI-CDG with an emphasis on the clinical aspect of the disease. A team of international experts elaborated summaries and recommendations for diagnostics, differential diagnosis, management, and treatment of each system/organ involvement based on evidence-based data and experts' opinions. Those guidelines also reveal more questions about MPI-CDG which need to be further studied.
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http://dx.doi.org/10.1002/jimd.12241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7574589PMC
July 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

Efficacy and safety of long-term insulin pump treatment in patients with type 1 diabetes aged over 50 years.

Endocr J 2020 Mar 4;67(3):367-371. Epub 2020 Mar 4.

Department of Metabolic Diseases, Jagiellonian University Medical College, Kraków, Poland.

Continuous subcutaneous insulin infusion (CSII) therapy using insulin pumps has become widely used in the treatment of type 1 diabetes mellitus (T1DM). This retrospective study aimed to assess the efficacy and safety of long-term insulin pump treatment in patients with T1DM aged ≥50 years. The study included patients aged ≥50 years, who had a diagnosis of T1DM based on clinical criteria and/or presence of autoantibodies characteristic of autoimmune diabetes, and had received ≥5 years of recent and uninterrupted treatment with a personal insulin pump. We analyzed records on HbA1c levels across the entire observation period. The cohort comprised 17 patients, of whom 6 (35%) were men and 11 (65%) were women. The mean duration of observation was 6.6 years, during which patients had a mean of 8.4 HbA1c measurements. Mean HbA1c level over the entire observation period was 6.7% (range, 5.3-7.4%). Overall, 11 patients (65%) had mean HbA1c levels at the ADA-recommended target of <7% and 5 patients (29%) had mean HbA1c <6.5%. Mean HbA1c level was significantly lower at the end of the observation period than at the start (6.52% versus 6.91%; difference, -0.39%; p < 0.01), indicating an improvement in glycaemic control over time. On average, patients experienced one level 1 hypoglycaemia episode every 2.4 days. This retrospective analysis of at least 5 years of follow-up of selected patients with T1DM aged ≥50 years at the start of observation, showed that CSII is a safe and effective treatment option in this age group.
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http://dx.doi.org/10.1507/endocrj.EJ19-0188DOI Listing
March 2020

Dual-action ambroxol in treatment of chronic pain in Gaucher Disease.

Eur J Pain 2020 05 9;24(5):992-996. Epub 2020 Mar 9.

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

A significant number of patients with Gaucher disease (GD) suffer from chronic or acute pain that reduces their quality of life. A mutation in lysosomal enzyme β-glucosidase (GCase) leads to an accumulation of glucocerebroside in the macrophage-lineage cells, causing the development of clinical symptoms. Novel studies have revealed that ambroxol (trans-4-(2-amino-3,5-dibromobenzylamino)-cyclohexanol), the well-known mucolytic drug, acts as a chaperone for the mutant, misfolded enzyme. In addition, as has recently been shown, ambroxol is a Na 1.8 channel blocker in Aβ, Aδ and unmyelinated C fibres, and therefore reduces the transmission of sensory stimuli from the primary afferent neurons to the dorsal spinal cord. In this way, it can act analgetically. Thus, in addition to broncholytic properties, ambroxol combines two other important functions: it enhances enzyme replacement therapy (ERT) and pain management in patients with GD. We present a 38-year-old female patient with type 3 GD who had reported permanent bone pain in the lumbar-sacral part of the spine for over a year without any pathology evidenced in the undertaken, recommended diagnostic tests. The pain was partly controlled with standard analgesics, that is, paracetamol and tramadol. Ambroxol was introduced at a dose of 150mg/d without a noticeable effect. However, when the dose was increased up to 450mg/d, the intensity of pain diminished and subsided within the following months. Two of three attempts to reduce the dose of ambroxol resulted in a pain relapse within a week, which subsided after resetting the previous, higher dose. This observation of the effects of ambroxol in a GD patient is worth considering for other GD patients with chronic pain.
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http://dx.doi.org/10.1002/ejp.1538DOI Listing
May 2020

[Cardiovascular autonomic neuropathy in the course of diabetes - the review of actual knowledge.]

Postepy Biochem 2019 Dec 30;65(4):306-312. Epub 2019 Dec 30.

Szpital Uniwersytecki w Krakowie, Katedra Chorób Metabolicznych, Collegium Medicum Uniwersytetu Jagiellońskiego.

Diabetic neuropathy, including autonomic cardiovascular neuropathy, is the most common chronic complication of diabetes. It causes serious health and social consequences, leading to a significant reduction of life expectancy in DM patients. Its development is initially asymptomatic and therefore often underestimated, and only the early detection of diabetic neuropathy gives a real chance to stop its progression and prevent irreversible damage to the nerves. The optimal glycemic control is the most important factor preventing the development of neuropathy, inhibiting its occurrence and progression. In the advanced stage, however, only symptomatic treatment remains. The article provides an overview of current knowledge about etiopathogenesis, therapy, symptoms and the latest clinical trials on NSN and DM.
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http://dx.doi.org/10.18388/pb.2019_287DOI Listing
December 2019

NPWT in diabetic foot wounds-a systematic review and meta-analysis of observational studies.

Endocrine 2020 04 9;68(1):44-55. Epub 2020 Jan 9.

Department of Metabolic Diseases, Jagiellonian University Medical College, Krakow, Poland.

Purpose: Negative-pressure wound therapy (NPWT) is an adjunct modality in diabetic foot ulcerations (DFUs). Randomized controlled trials (RCTs) have shown its advantage over standard approaches; however, data from observational studies remain scarce.We performed a systematic review of observational non-RCTs evaluating NPWT efficacy and safety in patients with DFU.

Methods: Electronic databases were searched for observational studies involving NPWT. The results of single-arm studies were presented as percentages of patients with the outcome of interest. A meta-analysis of comparative studies provided point estimates of outcomes. Continuous outcomes were reported as either weighted or standardized mean differences and dichotomous data as relative risks (RR).

Results: The search identified 16 relevant observational studies, 12 single-arm, and 4 comparative, reporting on a total of 18,449 patients with DFU, of whom 1882 were managed with NPWT. In the NPWT-treated patients, ulcers were larger (average size range 6.6-27.9 cm), as compared with controls (≤3 cm). The pooled results showed healing and major amputation in 51% and 5% of NPWT patients, respectively. The meta-analysis of comparative studies revealed lower risk of major amputation [RR = 0.23 (0.07; 0.80)] in NPWT-treated patients. The pooled results for healing rate and risk of any amputation were inconclusive due to large between-study heterogeneity. Overall, 6 deaths out of 158 patients were reported, none of them related to NPWT. Serious adverse events occurred in 6% of patients on NPWT.

Conclusions: This systematic review of observational studies provided supportive evidence that NWPT is an efficient and safe adjunct treatment in the management of DFUs.
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http://dx.doi.org/10.1007/s12020-019-02164-9DOI Listing
April 2020

Epigenetic mechanism in search for the pathomechanism of diabetic neuropathy development in diabetes mellitus type 1 (T1DM).

Endocrine 2020 04 4;68(1):235-240. Epub 2020 Jan 4.

University Hospital in Krakow, Kraków, Poland.

Objective: The aim of this study was to check the hypothesis concerning the crucial role of DNA methylation (one of the epigenetic mechanisms) within selected genes related to the destruction and regeneration of neural cells and its input in the pathogenesis of diabetic neuropathy, using a model of the DNA in peripheral blood cells.

Methods: A cross-sectional, case-control study was conducted, consisting of 24 adult Type 1 Diabetes Melitus (T1DM) patients with autonomic neuropathy (CAN), 25 T1DM patients without neuropathy and 25 matched, healthy adults acting as a control (Ctrl). The Ewing's tests, using the ProSciCard apparatus (Mewicon CATEEM-Tec GmbH), was employed to assess the severity of the patients' symptoms of autonomic neuropathy. For DNA methylation analysis, DNA material of each sample DNA after bisulfite conversion was used for the hybridization of BeadChips (Infinium Methylation EPIC Kit, Illumina), and imaged on the Illumina HiScan. The changes in the expression of selected genes were examined using real-time PCR. Probes were labeled using fluorescein amidite, FAM (Thermo Fisher Scientific). Amplification was performed using the continuous fluorescence detection 7900 HT Fast Real-Time PCR system (Thermo Fisher Scientific). The expression ratio of the target mRNA was normalized to the level of 18s RNA and compared with the control. Statistical analysis was performed using Statistica version 13.1. The statistically significant results were recognized, with a value of p < 0.05.

Results: Clinical analysis of the investigated groups revealed a significantly higher percentage of personal insulin pump users in the group without neuropathy. The glucose metabolic control, based on the HbA1c level analysis, was also significantly better in T1DM patients without CAN. The Bumphunter method for DNA methylation analysis showed statistically significant regions related to the genes involved in nerve regeneration ninjurin 2 (NINJ2) and functionality (BR serine/threonine kinase 2 BRSK2, claudin 4 CLDN4). When compared with T1DM patients without neuropathy, T1DM patients with neuropathy showed significantly increased methylation in the first NINJ2 axon, and a lower level of DNA methylation in the region of the first intron of BRSK2, as well as the CLDN4 5'UTR regions. The qRT-PCR results confirmed the decreased expression of NINJ2 and CLDN4 genes in patients with T1DM with CAN.

Conclusions: The different DNA methylation profiles, correlating with the expression of genes related to nervous tissue development and regeneration in patients with T1DM with autonomic neuropathy provide evidence for the role of epigenetic mechanisms promoting the development of CAN, a chronic complication of T1DM.
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http://dx.doi.org/10.1007/s12020-019-02172-9DOI Listing
April 2020

Effects of Negative Pressure Wound Therapy on Levels of Angiopoetin-2 and Other Selected Circulating Signaling Molecules in Patients with Diabetic Foot Ulcer.

J Diabetes Res 2019 28;2019:1756798. Epub 2019 Oct 28.

Department of Metabolic Diseases, Jagiellonian University Medical College, Krakow, Poland.

Background And Aims: Diabetic foot ulcers (DFUs) are linked to amputations and premature deaths. Negative pressure wound therapy (NPWT) has been used for DFUs. The mechanism of NPWT's action may be associated with its influence on circulating molecules. We assessed NPWT's effect on the plasma levels of angiopoietin-2 (Ang2), a key regulator of angiogenesis, and its microvesicular receptors (Tie2) as well as the microvesicles (MVs) themselves in DFU patients.

Materials And Methods: We included 69 patients with type 2 diabetes mellitus (T2DM) and neuropathic, noninfected DFUs-49 were treated with NPWT and 20 were treated with standard therapy (ST). Assigning patients to the NPWT group was not random but based on DFU characteristics, especially wound area. Ang2 was measured by ELISA in the entire group, while in a subgroup of 19 individuals on NPWT and 10 on ST, flow cytometry was used to measure Tie2+ and the corresponding isotype control (Iso+) and annexin V (AnnV+) as well as total MVs. Measurements were performed at the beginning and after 8 ± 1 days of therapy.

Results: Treatment groups were similar for basic characteristics but differed by their median DFU areas (10.3 (4.2-18.9) vs. 1.3 (0.9-3.4) cm, = 0.0001). At day 0, no difference was observed in Ang2 levels, total MVs, MV Tie+, and MV AnnV+ between the groups. Ang2 decreased after 8 days in the NPWT group, unlike in the ST group (3.54 (2.40-5.40) vs. 3.32 (2.33-4.61), = 0.02, and 3.19 ± 1.11 vs. 3.19 ± 1.29 ng/mL, = 0.98, respectively). No other parameters were identified that may have been influenced by the NPWT treatment.

Conclusion: NPWT in T2DM patients with neuropathic, noninfected DFU seems to lead to reduction of the Ang2 level. Influencing the level of Ang2 may constitute one of NPWT-related mechanisms to accelerate wound healing.
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http://dx.doi.org/10.1155/2019/1756798DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6855047PMC
April 2020

Assessment of selected food intake frequency in patients with type 1 diabetes treated with personal insulin pumps

Rocz Panstw Zakl Hig 2019 ;70(3):259-265

Department of Metabolic Diseases, University Hospital, Krakow, Poland

Background: It has been established that in Type 1 Diabetes Mellitus (T1DM), regardless of the insulin therapy model used, diet and proper eating habits are still important in the treatment of the disease. The dietary intervention in these patients is aimed at maintaining proper body weight, obtaining target fasting and post meal blood glucose levels, optimizing lipid profiles.

Objective: The aim of the study was to assess dietary habits in a homogeneous group of adults with T1DM treated with personal insulin pumps.

Material And Methods: The study included 141 adult patients (57% women) with type 1 diabetes treated with personal insulin pumps. The surveyed population was characterized by an average age of 25.8 ± 6.2 years, an average duration of diabetes 13.9 ± 6.9 years, and treatment with a personal pump for 8.2 ± 4.1 years and mean BMI 23.0 ± 2.8 g/m2. All were dwellers of south-eastern Poland. The validated KomPAN questionnaire was used to assess the frequency of consumption of individual food products.

Results: The mean percentage of HbA1c in the study group was 7.3% [56 mmol/mol]. The mean total cholesterol level was 4.4 mmol/l, HDL - 1.7 mmol/l, LDL - 2.3 mmol/l and triglycerides - 0.8 mmol/l. In the multivariate regression model, no correlation was found between dietary quality parameters and metabolic compensation measured with HbA1c or lipidogram and the place of residence (village, small town, big city). However, there were differences in the quality of the diet depending on the sex. Women were characterized by higher index of a healthy diet (pHDI-10) (26.3 vs 21.4, p=0.005) and lower index of unhealthy diet (nHDI-14) (13.3 vs 18.6, p <0.001) than men.

Conclusions: The results of this study clearly suggest, that despite good metabolic control, patients require more education on the choice of healthy product groups.
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http://dx.doi.org/10.32394/rpzh.2019.0076DOI Listing
February 2020

Is treatment of type 1 diabetes mellitus (insulin therapy, metabolic control) optimal for preventing cardiovascular autonomic neuropathy?

Endokrynol Pol 2019 7;70(4):323-329. Epub 2019 Mar 7.

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

Introduction: Long-term poor metabolic control promotes the occurrence of microvascular complications, such as cardiovascular autonomic neuropathy (CAN) and atherogenic hyperlipidaemia, which translates into increased mortality in patients with type 1 diabetes mellitus (T1DM). The aim of the study was to assess the prevalence of CAN in patients with T1DM in relation to treatment method (continuous subcutaneous insulin infusion, CSII, versus multiple daily injections using pens, MDI) and metabolic control.

Material And Methods: The study group comprised 93 adults (60 women, 33 men), mean age 31 years, with T1DM being treated at a local clinical centre from 2011 to 2015. The presence of CAN, the results of laboratory tests, and anthropometric data were analysed. The subjects were divided into two groups according to treatment method (CSII, MDI).

Results: The median duration of diabetes was 16 years. 61% of the subjects used MDI and 39% used CSII. 41% of the subjects presented with CAN (confirmed with the Ewing test using ProSciCard apparatus), with a significantly lower prevalence in the group of patients treated with CSII (15.4% vs. 60.4%; p < 0.001). The mean HbA1c level in the CSII-treated group was noticeably lower (7.44 ± 1.67% vs.8.55 ± 1.1%, p < 0.001), and these patients also had lower triglyceride levels (0.71 vs. 1.32 mmol/L, p < 0.001). Regardless of the treatment method, 72% of all patients under 40 years of age achieved their therapeutic target of LDL cholesterol level < 2.6 mmol/L, whereas only 13% of all those over 40 years old achieved an LDL cholesterol level < 1.8 mmol/L.

Conclusions: The presented results draw attention to the high prevalence of CAN among T1DM patients. The study reveals the need for more intensive monitoring and treatment of hyperlipidaemia, despite good glycaemic control, especially in those over the age of 40 years.
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http://dx.doi.org/10.5603/EP.a2019.0011DOI Listing
February 2020

Negative pressure wound therapy use in diabetic foot syndrome-from mechanisms of action to clinical practice.

Eur J Clin Invest 2019 Apr 29;49(4):e13067. Epub 2019 Jan 29.

Department of Metabolic Diseases, Jagiellonian University Medical College, Krakow, Poland.

Background: Diabetes and its complications constitute a rising medical challenge. Special attention should be given to diabetic foot syndrome (DFS) due to its high rate of associated amputation and mortality. Negative pressure wound therapy (NPWT) is a frequently used supportive modality in a diabetic foot with ulcerations (DFUs).

Design: Here, we reviewed the current knowledge concerning the tissue and molecular mechanisms of NPWT action with an emphasis on diabetes research followed by a summary of clinical DFU studies and practice guidelines.

Results: Negative pressure wound therapy action results in two types of tissue deformations-macrodeformation, such as wound contraction, and microdeformation occurring at microscopic level. Both of them stimulate a wound healing cascade including tissue granulation promotion, vessel proliferation, neoangiogenesis, epithelialization and excess extracellular fluid removal. On the molecular level, NPWT results in an alteration towards more pro-angiogenic and anti-inflammatory conditions. It increases expression of several key growth factors, including vascular endothelial growth factor and fibroblast growth factor 2, while expression of inflammatory cytokinesis reduced. The NPWT application also alters the presence and function of matrix metalloproteinases. Clinical studies in DFU patients showed a superiority of NPWT over standard therapy in terms of efficacy outcomes, primarily wound healing and amputation rate, without a rise in adverse events. International guidelines point to NPWT as an important adjuvant therapy in DFU whose use is expected to increase.

Conclusions: This current knowledge improves our understanding of NPWT action and its tailoring for application in diabetic patients. It may inform the development of new treatments for DFU.
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http://dx.doi.org/10.1111/eci.13067DOI Listing
April 2019

Case report of dysregulation of primary bile acid synthesis in a family with X-linked adrenoleukodystrophy.

Medicine (Baltimore) 2018 Dec;97(49):e13353

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

Rationale: X-linked adrenoleukodystrophy (X-ALD) is a rare disorder caused by mutations in the ABCD1 gene, coding for peroxisomal membrane transporter adrenoleukodystrophy (ALD) protein. The disease is characterized by accumulation of very long chain fatty acids (VLCFAs) in tissues. Adult adrenomyeloneuropathy (AMN) and the cerebral inflammatory form of ALD are the main phenotypes presenting various symptoms.

Patient Concerns: We report a case of 37-year-old patient with diagnosis of X-ALD, confirmed based on elevated VLCFA concentrations and genetic testing of ABCD1 gene. The complete clinical picture in the patient indicates AMN phenotype with cerebral involvement.

Diagnoses: The reduced synthesis of unconjugated cholic and chenodeoxycholic acids, and the reduction to 28% to 29% of peroxisomal beta-oxidation of behenic acid and normal peroxisomal metabolism of pristanic and palmitic acid were observed in the X-ALD patient. Sanger sequencing of major genes involved in primary bile acid (BA) synthesis failed to identify pathogenic mutations of the investigated set of genes.

Interventions: Plasma concentrations of BAs, VLCFAs, and beta-oxidation of C22:0, C16:0, and pristanic acid were studied in primary skin fibroblasts of the patient. In addition, we performed sequencing of the ABCD1, ABCD3, CYP7A1, CYP7B1, CYP27A1, HSD3B7, AKR1D1, and SLC27A5 genes in the X-ALD family.

Outcomes: In the Polish family affected with AMN a dysregulation of the primary BA synthesis pathway was found.

Lessons: We have demonstrated the coincidence of the adult form of X-ALD with abnormalities in BA synthesis. We suggest that decreased synthesis of BAs may be an additional dysfunction as a consequence of the ABCD1 c.659T>C, p.(Leu220Pro) mutation and may be further evidence that disturbed cholesterol metabolism is important in the pathology of ALD.
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http://dx.doi.org/10.1097/MD.0000000000013353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6310492PMC
December 2018

Basal Insulin Dose in Adults with Type 1 Diabetes Mellitus on Insulin Pumps in Real-Life Clinical Practice: A Single-Center Experience.

Adv Med 2018 5;2018:1473160. Epub 2018 Jun 5.

Department of Metabolic Diseases, Jagiellonian University Medical College, Kraków, Poland.

Introduction: Basal insulin (BI) infusion in pump therapy of type 1 diabetes (T1DM) mimics physiological secretion during the night and between meals. The recommended percentage of the total BI to daily insulin dose (termed the %BI) ranges between 30 and 50%. We analyzed whether this recommendation was followed in adults with T1DM from a university center, and whether BI doses were linked with glycemic control.

Materials And Methods: We included 260 consecutive patients with T1DM (159 women and 101 men) treated with continuous subcutaneous insulin infusion at the Department of Metabolic Diseases, Krakow, Poland. Data were downloaded from patients' pumps and collected from medical records. We analyzed the settings of BI and the association of %BI with HbA1c level. Linear regression was performed.

Results: The mean age of T1DM individuals was 26.6 ± 8.2 years, BMI was 23.1 ± 3.0 kg/m, T1DM duration was 13.3 ± 6.4 years, and HbA1c level was 7.4%. There were 69.6% (=181) of T1DM patients with %BI in the recommended range. The T1DM duration and HbA1c level of patients with a %BI <30% (=23) was 9.5 years and 6.4%, respectively; for a %BI of 30-50%, it was 13.2 years and 7.4%; and for a %BI >50% (=56), it was 15.8 years and 7.8% ( < 0.001 for both three-group comparisons). Multiple regression identified %BI among independent predictors of the HbA1c level.

Conclusion: In this real-life analysis, the recommendations concerning %BI dosing were not followed by almost one-third of adult T1DM patients. Low %BI was associated with better glycemic control; however, this requires further confirmation.
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http://dx.doi.org/10.1155/2018/1473160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6008663PMC
June 2018

APOE genotype influences insulin resistance, apolipoprotein CII and CIII according to plasma fatty acid profile in the Metabolic Syndrome.

Sci Rep 2017 07 24;7(1):6274. Epub 2017 Jul 24.

Hugh Sinclair Unit of Human Nutrition and Institute for Cardiovascular and Metabolic Research, University of Reading, Whiteknights, Reading, RG6 6AP, UK.

Metabolic markers associated with the Metabolic Syndrome (MetS) may be affected by interactions between the APOE genotype and plasma fatty acids (FA). In this study, we explored FA-gene interactions between the missense APOE polymorphisms and FA status on metabolic markers in MetS. Plasma FA, blood pressure, insulin sensitivity and lipid concentrations were determined at baseline and following a 12-week randomized, controlled, parallel, dietary FA intervention in 442 adults with MetS (LIPGENE study). FA-APOE gene interactions at baseline and following change in plasma FA were assessed using adjusted general linear models. At baseline E4 carriers had higher plasma concentrations of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (apo B) compared with E2 carriers; and higher TC, LDL-C and apo B compared with E3/E3. Whilst elevated plasma n-3 polyunsaturated FA (PUFA) was associated with a beneficially lower concentration of apo CIII in E2 carriers, a high proportion of plasma C16:0 was associated with insulin resistance in E4 carriers. Following FA intervention, a reduction in plasma long-chain n-3 PUFA was associated with a reduction in apo CII concentration in E2 carriers. Our novel data suggest that individuals with MetS may benefit from personalized dietary interventions based on APOE genotype.
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http://dx.doi.org/10.1038/s41598-017-05802-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5524844PMC
July 2017

The additive effect on the antiepileptic treatment of ambroxol in type 3 Gaucher patient. The early observation.

Blood Cells Mol Dis 2018 02 11;68:192-193. Epub 2016 Dec 11.

Department of Metabolic Diseases University Hospital, Krakow, Poland. Electronic address:

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http://dx.doi.org/10.1016/j.bcmd.2016.12.001DOI 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