Publications by authors named "Magdalena Szopa"

33 Publications

Analysis of the Gut Mycobiome in Adult Patients with Type 1 and Type 2 Diabetes Using Next-Generation Sequencing (NGS) with Increased Sensitivity-Pilot Study.

Nutrients 2021 Mar 25;13(4). Epub 2021 Mar 25.

Department of Molecular Medical Microbiology, Chair of Microbiology, Faculty of Medicine, Jagiellonian University Medical College, 18 Czysta Street, 31-121 Krakow, Poland.

The studies on microbiome in the human digestive tract indicate that fungi could also be one of the external factors affecting development of diabetes. The aim of this study was to evaluate the quantitative and qualitative mycobiome composition in the colon of the adults with type 1 (T1D), = 26 and type 2 (T2D) diabetes, = 24 compared to the control group, = 26. The gut mycobiome was characterized in the stool samples using the analysis of the whole internal transcribed spacer (ITS) region of the fungal rDNA gene cluster by next-generation sequencing (NGS) with increased sensitivity. At the L2 (phylum) level, Basidiomycota fungi were predominant in all 3 study groups. Group T1D presented significantly lower number of Ascomycota compared to the T2D group, and at the L6 (genus) level, the T1D group presented significantly lower number of genus compared to control and T2D groups. In the T1D group, a significant positive correlation between total cholesterol and low-density lipoprotein cholesterol (LDL-C) levels and fungi of the genus and in the T2D group, a negative correlation between the total cholesterol level and genus was found. The obtained results seem to be a good foundation to extend the analysis of the relationship between individual genera and species of fungi and the parameters determining the metabolism of carbohydrates and lipids in the human body.
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http://dx.doi.org/10.3390/nu13041066DOI Listing
March 2021

Perceptions of clinical teachers acting as examiners regarding the value of Objective Structured Clinical Examinations.

Folia Med Cracov 2020 09;60(2):109-121

Department of Medical Education, Jagiellonian University Medical College, Kraków, Poland.

Objectives: OSCE (Objective Structured Clinical Examination) is a common method of assessing clinical skills used at many universities. An important and at the same time difficult aspect of good examination preparation is obtaining a properly trained and well-motivated group of assessors. To effectively recruit and maintain cooperation with assessors, it is worth to know their opinion. The aim of this study was to investigate the opinions of teacher-examiners about OSCE and to identify the factors that could shape this opinion and influence on motivation.

Methods: A cross-sectional study was conducted using a questionnaire on teachers who participated as OSCE examiners. This questionnaire consisted of 21 questions about their perceptions. Answers were rated in a five-point Likert-type scale. Chi-square or Fisher's exact test was used to analyze the data.

Results: A total of 49 (out of 52) teachers participated in this study. Nearly 90% of examiners believed that it is fair, more than 90% that it is transparent. Despite the fact that 67% of examiners believe the examination is difficult to organize and 71% believe it is stressful for students, according to 72% of respondents the OSCE has a positive effect on learning. More than 91% of examiners believed that the OSCE is an appropriate test to assess students' skills. Opinions about examination were independent of specialty, seniority, gender or taking the OSCE as students.

Conclusion: Teacher-examiners viewed the OSCE as a fair and transparent examination, adequate for assessment of skills and, despite it being difficult to organize, worth doing as it is appropriate to assess practical skills and positively influences students' motivation to learn tested skills.
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September 2020

Clinical communication course and other factors affecting patient-centered attitudes among medical students.

Folia Med Cracov 2019 ;59(2):81-92

Department of Medical Education, Jagiellonian University Medical College, Kraków, Poland.

Objectives: Patient-centered care (PCC) is associated with better relationships, resulting in a decrease in symptoms, hospitalizations and health costs. However, studies analyzing factors influencing patient-centered attitudes show ambiguous results. The purpose was to assess the impact of the Clinical Communication Course (CCC) in Jagiellonian University, Cracow and other factors on Patient-Centered Attitudes (PCA) and Attitude toward Clinical Skills Learning (CSLA).

Methods: We retrospectively compared Polish-speakers (CCC+, n = 160), English-speakers (CCCen+, n = 55) after the CCC and upperclassmen Polish-speakers without it (CCC-, n = 122). Validated questionnaires to measure PCA (Leeds Attitude Toward Concordance II and Patient-Practitioner Orientation Scale (PPOS)) and for CSLA (Communication Skills Attitude Scale with negative subscale (CSAS-N)) were used. The higher the scores, the more PCA, and negative CSLA respectively. Students completed questionnaires and answered questions regarding age, sex, motivation to study (coded as humanitarian - MotHUM, financial - MotFIN, combination - MotMIX) and considered specialization - coded as with more human contact (family medicine, psychiatry, pediatrics - SpecHUM) and others (SpecNHUM). Statistics were prepared in R.

Results: CCC+ scored higher in PPOS (2.91 vs. 2.74; p = 0.003) than CCC- and higher in CSAS-N than CCCen+ (31.22 vs. 28.32; p = 0.004). In CCC+ SpecHUM scored lower than SpecNHUM in PPOS (2.65 vs. 2.94, p = 0.012). MotFIN scored higher then MotMIX in PPOS (3.01 vs. 2.7, p = 0.036). Correlations were statistically significant.

Conclusion: CCC improved PCA in CCC+. They showed more negative CSLA than CCCen+. Among CCC+, surprisingly, SpecNHUM presented more PCA than SpecHUM as well as MotFIN compared to MotMIX.
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April 2020

The utility of MODY Probability Calculator in probands of families with early-onset autosomal dominant diabetes from Poland.

Minerva Med 2019 Dec 14;110(6):499-506. Epub 2019 Oct 14.

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

Background: Maturity-onset diabetes of the young (MODY) accounts for 1-2% of all diabetes cases. Unfortunately, circa 90% of MODY cases are misdiagnosed as type 1 or type 2 diabetes. A proper genetic diagnosis based on automatic sequencing is crucial for the use of a tailored treatment. However, this method is still expensive and, thus, patients' selection for testing should be performed precisely. In 2012, an easy-to-use tool was developed in Exeter, UK, to support genetic testing for MODY in the British population. The aim of the study was to assess the utility of MODY Probability Calculator in probands from Polish families with early-onset autosomal dominant diabetes.

Methods: We have performed a retrospective analysis of 155 probands who were qualified for genetic testing between 2006 and 2018. Probands were recruited for MODY testing based on the following criteria: 1) early age of diagnosis (≤35 years); 2) a positive, multigenerational family history of diabetes. Automatic sequencing, Sanger and, in case of initial negative results, new generation sequencing (NGS) of a set of 28 genes, were performed. MODY Probability was calculated on the website www.diabetesgenes.org.

Results: The group of probands consisted of 64 GCK-, 37 HNF1A-, and three HNF4A-MODY patients and 51 NGS-negative subjects. The median positive predictive value (PPV) was 75.5% (95% CI: 75.5-75.5%), 49.4% (95% CI: 24.4-75.5%), 45.5% (95% CI: 21.0-75.5%) and 49.4% (95% CI: 32.9-75.5%) for GCK-, HNF1A-, HNF4A-MODY and NGS-negative, respectively. The discriminative accuracy, as expressed by AUC, of PPV between MODY and NGS negative groups was 0.62 (95% CI: 0.52-0.71) with the corresponding sensitivity of 71.2% and specificity of 51.0%.

Conclusions: In this highly pre-selected group of probands that were qualified for genetic testing based on clinical features, the use of MODY Probability Calculator would not substantially improve the patients' selection process for genetic testing. Further efforts to improve this tool are desirable.
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http://dx.doi.org/10.23736/S0026-4806.19.06053-1DOI Listing
December 2019

Type 2 Diabetes Mellitus and Preoperative HbA1c Level Have no Consequence on Outcomes after Laparoscopic Sleeve Gastrectomy-a Cohort Study.

Obes Surg 2019 09;29(9):2957-2962

2nd Department of General Surgery, Jagiellonian University Medical College, Kraków, Poland.

Introduction: Available clinical data on the influence of baseline HbA postoperative morbidity and readmission after laparoscopic sleeve gastrectomy is scarce. This prompted us to conduct a multicenter retrospective study evaluating the influence of chronic hyperglycemia on postoperative course among patients undergoing laparoscopic sleeve gastrectomy (SG). We aimed to investigate the influence of baseline HbA levels on postoperative outcomes in patients after SG.

Material And Methods: We conducted a multicenter retrospective cohort study of consecutive patients who underwent SG from March 2017 to March 2018 in seven referral centers for bariatric surgery. Exclusion criteria were revision surgeries, different bariatric interventions, SG combined with other procedures, and lack of necessary data. Patients were divided into three groups depending on their preoperative glycated hemoglobin level (HbA) < 5.7%, 5.7-6.4%, and ≥ 6.5%. Primary endpoints were influence of HbA on early and late postoperative morbidity, impact on prolonged length of hospital stay (LOS), and readmission rate.

Results: The HbA < 5.7% group comprised 842 (49%) patients, HbA 5.7-6.4% comprised 587 (34%), and HbA ≥ 6.5% comprised 289 (17%). Overall morbidity was 6.23%; this did not differ among groups (p = 0.571). Three patients died postoperatively. Late postoperative morbidity was comparable among groups (p = 0.312). The ratio of prolonged LOS and readmission did not differ among groups (p = 0.363 and 0.571). ROC analysis revealed that HbA > 7.3% increased OR for hospital readmission (p = 0.007).

Conclusion: Preoperative HbA does not affect postoperative morbidity and prolonged LOS after SG. Patients with HbA > 7.3% have an increased chance of hospital readmission.
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http://dx.doi.org/10.1007/s11695-019-03936-yDOI Listing
September 2019

A decision algorithm to identify patients with high probability of monogenic diabetes due to HNF1A mutations.

Endocrine 2019 04 18;64(1):75-81. Epub 2019 Feb 18.

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

Purpose: To investigate the utility of biomarkers of maturity-onset diabetes of the young (MODY), high-sensitivity C-reactive protein (hsCRP), and 1,5-anhydroglucitol (1,5-AG) in conjunction with other clinical and laboratory features to improve diagnostic accuracy and provide a diagnostic algorithm for HNF1A MODY.

Methods: We examined 77 patients with HNF1A MODY, 88 with GCK MODY mutations, 99 with type 1 diabetes, and 92 with type 2 diabetes. In addition to 1,5-AG and hsCRP, we considered body mass index (BMI), fasting glucose, and fasting serum C-peptide as potential biomarkers. Logistic regression and receiver operating characteristic curves were used in marker evaluation.

Results: Concentration of hsCRP was lowest in HNF1A MODY (0.51 mg/l) and highest in type 2 diabetes (1.33 mg/l). The level of 1,5-AG was lowest in type 1 diabetes and HNF1A MODY, 3.8 and 4.7 μg/ml, respectively, and highest (11.2 μg/ml) in GCK MODY. In the diagnostic algorithm, we first excluded patients with type 1 diabetes based on low C-peptide (C-statistic 0.98) before using high BMI and C-peptide to identify type 2 diabetes patients (C-statistic 0.92). Finally, 1,5-AG and hsCRP in conjunction yielded a C-statistic of 0.86 in discriminating HNF1A from GCK MODY. We correctly classified 92.9% of patients with type 1 diabetes, 84.8% with type 2 diabetes, 64.9% HNF1A MODY, and 52.3% GCK MODY patients.

Conclusions: Plasma 1,5-AG and serum hsCRP do not discriminate sufficiently HNF1A MODY from common diabetes types, but could be potentially useful in prioritizing Sanger sequencing of HNF1A gene.
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http://dx.doi.org/10.1007/s12020-019-01863-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6453873PMC
April 2019

Continuous Glucose Monitoring in Bariatric Patients Undergoing Laparoscopic Sleeve Gastrectomy and Laparoscopic Roux-En-Y Gastric Bypass.

Obes Surg 2019 04;29(4):1317-1326

2nd Department of General Surgery, Jagiellonian University Medical College, Kopernika 21 St., 31-501, Kraków, Poland.

Background: Few investigations have been conducted that compared blood glucose in patients with diabetes mellitus (DM2) and morbid obesity who had undergone laparoscopic sleeve gastrectomy (LSG) or gastric bypass (LRYGB). We aimed to compare the effects of these procedures using continuous glucose monitoring (CGM).

Methods: We prospectively studied patients that had qualified for LSG or LRYGB. The inclusion criteria were DM2 of ≤ 5 years, for which patients were taking oral anti-diabetic drugs, or no glucose metabolism disorder; and morbid obesity. CGM was performed between admission and the 10th postoperative day.

Results: We studied 16 patients with DM2 and 16 without. Eighteen patients underwent LSG and 14 underwent LRYGB. The median hemoglobin A1c was 5.5% (5.4-5.9%) in DM2 patients, which did not differ from control (p = 0.460). Preoperative mean daily glucose concentration was similar between DM2 and control patients (p = 0.622). For patients with DM2, LRYGB was associated with more frequent low glucose status, and these episodes lasted longer than in DM2 patients that underwent LSG (p = 0.035 and 0.049, respectively). DM2 patients that underwent LRYGB demonstrated lower glucose concentrations from third postoperative day than those that underwent LSG. Patients without DM2 did not demonstrate differences in daily mean glucose concentrations, or in incidence nor duration of hypoglycemia throughout the observation period.

Conclusion: A significantly larger reduction in interstitial glucose concentration is present from third day in patients with DM2 who undergo LRYGB vs. LSG, accompanied by a lower incidence and shorter duration of low glucose episodes.
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http://dx.doi.org/10.1007/s11695-018-03684-5DOI Listing
April 2019

Quality of life assessment in patients with HNF1A-MODY and GCK-MODY.

Endocrine 2019 05 12;64(2):246-253. Epub 2018 Nov 12.

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

Aim: The impact of maturity onset diabetes of the young (MODY) on quality of life (QoL) has never been examined. We assessed disease impact on QoL among patients with HNF1A-MODY and GCK mutation carrier status.

Methods: The study included 80 patients with HNF1A-MODY and 89 GCK gene mutation carriers. We also examined 128 type 1 diabetes (T1DM) patients for comparison. Diabetes-specific QoL was assessed using the Audit of Diabetes Dependent Quality of Life questionnaire.

Results: HNF1A-MODY and GCK-MODY groups had similar mean age (41.7 vs. 38.0 years, respectively) and BMI (24.1 vs. 24.3 kg/m), whereas T1DM patients were on average younger (34.2 years) with similar BMI (25.0 kg/m). Less than a third of GCK mutation carriers were on pharmacotherapy (n = 20, 31%), while the majority of HNF1A mutation carriers used oral drugs or insulin (n = 66, 82.5%). While current QoL was similar across the three groups (p = 0.66), two other major indices-the impact of diabetes on QoL and the average weighted impact (AWI)-differed among them (p < 0.001 for both comparisons). The impact of diabetes on patient QoL and AWI observed in both MODY groups was smaller than in T1DM. Etiological diagnosis of diabetes and a diagnosis of retinopathy were the only independent factors influencing the impact of diabetes on QoL and AWI in regression analysis. In HNF1A-MODY, all three major indices of QoL were more heavily influenced for patients on insulin in comparison to other treatment sub-groups.

Conclusion: MODY has a smaller negative impact on QoL compared to T1DM. Mode of treatment further stratifies QoL decline for HNF1A-MODY subjects.
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http://dx.doi.org/10.1007/s12020-018-1812-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6531383PMC
May 2019

Effectiveness and safety of long-term treatment with sulfonylureas in patients with neonatal diabetes due to KCNJ11 mutations: an international cohort study.

Lancet Diabetes Endocrinol 2018 08 4;6(8):637-646. Epub 2018 Jun 4.

KG Jebsen Centre for Diabetes Research, Department of Clinical Science, University of Bergen, Bergen, Norway; Department of Paediatrics and Adolescents, Haukeland University Hospital, Bergen, Norway.

Background: KCNJ11 mutations cause permanent neonatal diabetes through pancreatic ATP-sensitive potassium channel activation. 90% of patients successfully transfer from insulin to oral sulfonylureas with excellent initial glycaemic control; however, whether this control is maintained in the long term is unclear. Sulfonylurea failure is seen in about 44% of people with type 2 diabetes after 5 years of treatment. Therefore, we did a 10-year multicentre follow-up study of a large international cohort of patients with KCNJ11 permanent neonatal diabetes to address the key questions relating to long-term efficacy and safety of sulfonylureas in these patients.

Methods: In this multicentre, international cohort study, all patients diagnosed with KCNJ11 permanent neonatal diabetes at five laboratories in Exeter (UK), Rome (Italy), Bergen (Norway), Paris (France), and Krakow (Poland), who transferred from insulin to oral sulfonylureas before Nov 30, 2006, were eligible for inclusion. Clinicians collected clinical characteristics and annual data relating to glycaemic control, sulfonylurea dose, severe hypoglycaemia, side-effects, diabetes complications, and growth. The main outcomes of interest were sulfonylurea failure, defined as permanent reintroduction of daily insulin, and metabolic control, specifically HbA and sulfonylurea dose. Neurological features associated with KCNJ11 permanent neonatal diabetes were also assessed. This study is registered with ClinicalTrials.gov, number NCT02624817.

Findings: 90 patients were identified as being eligible for inclusion and 81 were enrolled in the study and provided long-term (>5·5 years cut-off) outcome data. Median follow-up duration for the whole cohort was 10·2 years (IQR 9·3-10·8). At most recent follow-up (between Dec 1, 2012, and Oct 4, 2016), 75 (93%) of 81 participants remained on sulfonylurea therapy alone. Excellent glycaemic control was maintained for patients for whom we had paired data on HbA and sulfonylurea at all time points (ie, pre-transfer [for HbA], year 1, and most recent follow-up; n=64)-median HbA was 8·1% (IQR 7·2-9·2; 65·0 mmol/mol [55·2-77·1]) before transfer to sulfonylureas, 5·9% (5·4-6·5; 41·0 mmol/mol [35·5-47·5]; p<0·0001 vs pre-transfer) at 1 year, and 6·4% (5·9-7·3; 46·4 mmol/mol [41·0-56·3]; p<0·0001 vs year 1) at most recent follow-up (median 10·3 years [IQR 9·2-10·9]). In the same patients, median sulfonylurea dose at 1 year was 0·30 mg/kg per day (0·14-0·53) and at most recent follow-up visit was 0·23 mg/kg per day (0·12-0·41; p=0·03). No reports of severe hypoglycaemia were recorded in 809 patient-years of follow-up for the whole cohort (n=81). 11 (14%) patients reported mild, transient side-effects, but did not need to stop sulfonylurea therapy. Seven (9%) patients had microvascular complications; these patients had been taking insulin longer than those without complications (median age at transfer to sulfonylureas 20·5 years [IQR 10·5-24·0] vs 4·1 years [1·3-10·2]; p=0·0005). Initial improvement was noted following transfer to sulfonylureas in 18 (47%) of 38 patients with CNS features. After long-term therapy with sulfonylureas, CNS features were seen in 52 (64%) of 81 patients.

Interpretation: High-dose sulfonylurea therapy is an appropriate treatment for patients with KCNJ11 permanent neonatal diabetes from diagnosis. This therapy is safe and highly effective, maintaining excellent glycaemic control for at least 10 years.

Funding: Wellcome Trust, Diabetes UK, Royal Society, European Research Council, Norwegian Research Council, Kristian Gerhard Jebsen Foundation, Western Norway Regional Health Authority, Southern and Eastern Norway Regional Health Authority, Italian Ministry of Health, Aide aux Jeunes Diabetiques, Societe Francophone du Diabete, Ipsen, Slovak Research and Development Agency, and Research and Development Operational Programme funded by the European Regional Development Fund.
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http://dx.doi.org/10.1016/S2213-8587(18)30106-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6058077PMC
August 2018

Characteristics of gut microbiota in adult patients with type 1 and type 2 diabetes based on next‑generation sequencing of the 16S rRNA gene fragment.

Pol Arch Intern Med 2018 06 15;128(6):336-343. Epub 2018 Apr 15.

Introduction Scientific data indicate a possible influence of gut microbiota on the development of type 1 and type 2 diabetes mellitus (T1DM and T2DM, respectively). Sequence analysis of 16S ribosomal RNA identified several hundred bacterial species of the intestinal ecosystem, most of which cannot be cultured. Objectives We aimed to evaluate gut microbiota composition in adult patients with T1DM and T2DM and establish a link between microbiological test results and patients' clinical data. Patients and methods We examined DNA isolated from fecal samples in 3 groups: healthy volunteers (n = 23), patients with T1DM (n = 22), and patients with T2DM (n = 23). Next‑generation sequencing was performed on the MiSeq platform. Results At the phylum level, the Firmicutes bacteria prevailed (>77%) in all groups. At the taxonomic levels L2 (phylum) and L6 (genus), significant differences were demonstrated in bacterial profiles, particularly in the T2DM group. A negative correlation was observed between several genera of bacteria and the percentage of glycated hemoglobin A1c in the T2DM group, while a positive correlation was revealed between bacteria belonging to the genus Bifidobacterium and high‑density lipoprotein cholesterol levels in both T1DM and T2DM groups. Conclusions Our results provide grounds for conducting research in the field of gut microbiota in order to develop individualized therapy for patients with diabetes based on modifying the microbiota composition, as a new method for controlling glycemia. Next‑generation sequencing allows a rapid identification of the DNA of all bacteria present in the sample and their taxonomic classification.
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http://dx.doi.org/10.20452/pamw.4246DOI Listing
June 2018

Qualitative Parameters of the Colonic Flora in Patients with HNF1A-MODY Are Different from Those Observed in Type 2 Diabetes Mellitus.

J Diabetes Res 2016 11;2016:3876764. Epub 2016 Oct 11.

Department of Metabolic Diseases, Jagiellonian University Medical College, 15 Kopernika Street, 31-501 Kraków, Poland; University Hospital, 36 Kopernika Street, 31-501 Kraków, Poland.

. Type 2 diabetes mellitus (T2DM) is determined by genetic and environmental factors. There have been many studies on the relationship between the composition of the gastrointestinal bacterial flora, T2DM, and obesity. There are no data, however, on the gut microbiome structure in monogenic forms of the disease including Maturity Onset Diabetes of the Young (MODY). . The aim of the investigation was to compare the qualitative parameters of the colonic flora in patients with HNF1AMODY and T2DM and healthy individuals. 16S sequencing of bacterial DNA isolated from the collected fecal samples using the MiSeq platform was performed. . There were significant between-group differences in the bacterial profile. At the phylum level, the amount of Proteobacteria was higher ( = 0.0006) and the amount of Bacteroidetes was lower ( = 0.0005) in T2DM group in comparison to the control group. In HNF1A-MODY group, the frequency of Bacteroidetes was lower than in the control group ( = 0.0143). At the order level, Turicibacterales was more abundant in HNF1A-MODY group than in T2DM group. . It appears that there are differences in the gut microbiome composition between patients with HNF1A-MODY and type 2 diabetes. Further investigation on this matter should be conducted.
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http://dx.doi.org/10.1155/2016/3876764DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5078663PMC
June 2017

Differential regulation of serum microRNA expression by HNF1β and HNF1α transcription factors.

Diabetologia 2016 07 8;59(7):1463-1473. Epub 2016 Apr 8.

Department of Paediatrics, Oncology, Haematology and Diabetology, Medical University of Lodz, Lodz, Poland.

Aims/hypothesis: We aimed to identify microRNAs (miRNAs) under transcriptional control of the HNF1β transcription factor, and investigate whether its effect manifests in serum.

Methods: The Polish cohort (N = 60) consisted of 11 patients with HNF1B-MODY, 17 with HNF1A-MODY, 13 with GCK-MODY, an HbA1c-matched type 1 diabetic group (n = 9) and ten healthy controls. Replication was performed in 61 clinically-matched British patients mirroring the groups in the Polish cohort. The Polish cohort underwent miRNA serum level profiling with quantitative real-time PCR (qPCR) arrays to identify differentially expressed miRNAs. Validation was performed using qPCR. To determine whether serum content reflects alterations at a cellular level, we quantified miRNA levels in a human hepatocyte cell line (HepG2) with small interfering RNA knockdowns of HNF1α or HNF1β.

Results: Significant differences (adjusted p < 0.05) were noted for 11 miRNAs. Five of them differed between HNF1A-MODY and HNF1B-MODY, and, amongst those, four (miR-24, miR-27b, miR-223 and miR-199a) showed HNF1B-MODY-specific expression levels in the replication group. In all four cases the miRNA expression level was lower in HNF1B-MODY than in all other tested groups. Areas under the receiver operating characteristic curves ranged from 0.79 to 0.86, with sensitivity and specificity reaching 91.7% (miR-24) and 82.1% (miR-199a), respectively. The cellular expression pattern of miRNA was consistent with serum levels, as all were significantly higher in HNF1α- than in HNF1β-deficient HepG2 cells.

Conclusions/interpretation: We have shown that expression of specific miRNAs depends on HNF1β function. The impact of HNF1β deficiency was evidenced at serum level, making HNF1β-dependent miRNAs potentially applicable in the diagnosis of HNF1B-MODY.
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http://dx.doi.org/10.1007/s00125-016-3945-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4901123PMC
July 2016

Assessment of Newly Proposed Clinical Criteria to Identify HNF1A MODY in Patients with an Initial Diagnosis of Type 1 or Type 2 Diabetes Mellitus.

Adv Med 2016 28;2016:4243784. Epub 2016 Jan 28.

Department of Metabolic Diseases, Jagiellonian University Medical College, Jagiellonian University, 15 Kopernika Street, 31-501 Krakow, Poland.

The most common form of maturity-onset diabetes of the young (MODY) is caused by mutations in the hepatocyte nuclear factor 1A (HNF1A) gene. However, most HNF1A mutation-carriers are initially misdiagnosed with type 1 (T1DM) or type 2 (T2DM) diabetes mellitus; hence, they often receive nonoptimal treatment. The aim of our study was to test newly proposed clinical criteria for the identification of HNF1A MODY in patients with a diagnosis of T1DM or T2DM. To achieve this, the following criteria to preselect patients for screening were used: for T1DM: TDIR (total daily insulin requirement) > 0.3 IU of insulin/kg and the percentage of basal insulin > 30% of TDIR; for T2DM: sulphonylurea- (SU-) based oral treatment (monotherapy or combined with Metformin) > 15 years and BMI < 30 kg/m(2). We reviewed the clinical data of 140 patients with T1DM and 524 clinically diagnosed with T2DM. On the basis of these criteria, we found a HNF1A mutation in 1 out of 2 individuals with a diagnosis of T1DM and 1 out of 11 selected individuals with a diagnosis of T2DM. We believe that the simplicity of the proposed criteria might prove useful in clinical practice, as an alternative to more time-consuming classical diagnostic techniques.
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http://dx.doi.org/10.1155/2016/4243784DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4749764PMC
March 2016

A family with the Arg103Pro mutation in the NEUROD1 gene detected by next-generation sequencing - Clinical characteristics of mutation carriers.

Eur J Med Genet 2016 Feb 8;59(2):75-9. Epub 2016 Jan 8.

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

Unlabelled: Until now only a few families with early onset autosomal diabetes due to the NEUROD1 gene mutations have been identified. Moreover, only some of them meet strict MODY (maturity-onset diabetes of the young) criteria. Next-generation sequencing (NGS) provides an opportunity to detect more pathogenic mutations in this gene. Here, we evaluated the segregation of the Arg103Pro mutation in the NEUROD1 gene in a pedigree in which it was detected, and described the clinical characteristics of the mutation carriers.

Methods: We included 156 diabetic probands of MODY families, among them 52 patients earlier tested for GCK-MODY and/or HNF1A-MODY by Sanger sequencing with negative results. Genetic testing was performed by targeted NGS sequencing using a panel of 28 monogenic diabetes genes.

Results: As detected by NGS, one patient had the missense Arg103Pro (CGC/CCC) mutation in the gene NEUROD1 changing the amino-acid structure of the DNA binding domain of this transcription factor. We confirmed this sequence difference by Sanger sequencing. This family had previously been tested with negative results for HNF1A gene mutations. 17 additional members of this family were invited for further testing. We confirmed the presence of the mutation in 11 subjects. Seven adult mutation carriers (all but one) from three generations had been already diagnosed with diabetes. There were 3 individuals with the Arg103Pro mutation diagnosed before the age of 30 years in the family. The range of age of the four unaffected mutation carriers (3 minors and 1 adult) was 3-48 years. Interestingly, one mutation carrier had a history of transient neonatal hypoglycemia, of which the clinical course resembled episodes typical for HNF4A-MODY.

Conclusions: We report a family with autosomal dominant diabetes related to a new NEUROD1 mutation, one of very few meeting MODY criteria. The use of the NGS method will facilitate identification of more families with rare forms of MODY.
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http://dx.doi.org/10.1016/j.ejmg.2016.01.002DOI Listing
February 2016

Genetic testing for monogenic diabetes using targeted next-generation sequencing in patients with maturity-onset diabetes of the young.

Pol Arch Med Wewn 2015 9;125(11):845-51. Epub 2015 Nov 9.

Introduction: Molecular diagnosis of monogenic diabetes mellitus is important for individualized patient care. Next-generation sequencing (NGS) enables a simultaneous analysis of multiple genes in a single test.

Objectives: We aimed to assess the feasibility of using NGS for detecting mutations in a set of known monogenic diabetes gene mutations in a cohort of Polish patients with maturity-onset diabetes of the young (MODY) with earlier negative Sanger sequencing results for HNF1A-MODY or GCK-MODY.

Patients And Methods: We selected a panel of 28 chromosomal genes in which mutations have been reported to cause monogenic diabetes. The MiSeq platform was used for NGS. An exon-capture assay was designed to include coding regions and splice sites. A total of 54 patients with existing negative Sanger sequencing screening results for HNF1A or GCK gene mutations were selected for the study.

Results: NGS results were generated for all 54 patients and 9 positive controls with previously identified HNF1A or GCK gene mutation. All selected positive controls were confirmed by NGS. Among 28 genes, mutations were detected in 16. The type of the analyzed genetic changes was described in the NGS study as high (n = 3) or moderate (n = 76). Among the detected mutations, there were 4 known GCK gene mutations that had been previously missed in Sanger sequencing. So far, Sanger sequencing allowed us to confirm 21 gene mutations detected by NGS, and segregation with diabetes in 14 pedigrees.

Conclusions: Our pilot study using NGS for monogenic diabetes screening in the MODY cohort confirmed that it improves the detection of diabetes-related sequence differences. The screening with NGS should also include diabetic patients for whom Sanger-based screening for particular subtypes of MODY provided negative results.
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http://dx.doi.org/10.20452/pamw.3164DOI Listing
July 2016

Comparison of Glomerular Filtration Rate Estimation from Serum Creatinine and Cystatin C in HNF1A-MODY and Other Types of Diabetes.

J Diabetes Res 2015 10;2015:183094. Epub 2015 Aug 10.

Department of Metabolic Diseases, Jagiellonian University Medical College, 15 Kopernika Street, 31-501 Krakow, Poland ; University Hospital, Krakow, Poland.

Introduction: We previously showed that in HNF1A-MODY the cystatin C-based glomerular filtration rate (GFR) estimate is higher than the creatinine-based estimate. Currently, we aimed to replicate this finding and verify its clinical significance.

Methods: The study included 72 patients with HNF1A-MODY, 72 with GCK-MODY, 53 with type 1 diabetes (T1DM), 70 with type 2 diabetes (T2DM), and 65 controls. Serum creatinine and cystatin C levels were measured. GFR was calculated from creatinine and cystatin C using the CKD-EPI creatinine equation (eGRF-cr) and CKD-EPI cystatin C equation (eGFR-cys), respectively.

Results: Cystatin C levels were lower (p < 0.001) in the control (0.70 ± 0.13 mg/L), HNF1A (0.75 ± 0.21), and GCK (0.72 ± 0.16 mg/L) groups in comparison to those with either T1DM (0.87 ± 0.15 mg/L) or T2DM (0.9 ± 0.23 mg/L). Moreover, eGFR-cys was higher than eGRF-cr in HNF1A-MODY, GCK-MODY, and the controls (p = 0.004; p = 0.003; p < 0.0001). This corresponded to 8.9 mL/min/1.73 m2, 9.7 mL/min/1.73 m2, and 16.9 mL/min/1.73 m2 of difference. Additionally, T1DM patients had higher eGFR-cr than eGFR-cys (11.6 mL/min/1.73 m(2); p = 0.0004); no difference occurred in T2DM (p = 0.91).

Conclusions: We confirmed that eGFR-cys values in HNF1A-MODY patients are higher compared to eGFR-cr. Some other differences were also described in diabetic groups. However, none of them appears to be clinically relevant.
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http://dx.doi.org/10.1155/2015/183094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4546972PMC
July 2016

Are late-night eating habits and sleep duration associated with glycemic control in adult type 1 diabetes patients treated with insulin pumps?

J Diabetes Investig 2015 Jul 14;6(4):460-4. Epub 2015 Jan 14.

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

Aims/introduction: Little is known about the impact of sleep duration and late-night snacking on glycemic control in patients with type 1 diabetes using insulin pumps. The aim of the present study was to examine whether late-night eating habits and short sleep duration are associated with glycemic control in continuous subcutaneous insulin infusion-treated type 1 diabetic patients.

Materials And Methods: We included 148 consecutive adult type 1 diabetic subjects using an insulin pump (100 women and 48 men). Participants completed a questionnaire regarding sleep duration (classified as short if ≤6 h) and late-night snacking. Other sources of information included medical records and data from blood glucose meters. Glycemic control was assessed by glycated hemoglobin (HbA1c) levels and mean self-monitoring of blood glucose (SMBG) readings.

Results: The mean age of patients was 26 years, mean type 1 diabetes duration was 13.4 years and mean HbA1c level was 7.2%. In a univariate regression analysis, sleep duration was a predictor of both HbA1c (β = 0.51, P = 0.01) and SMBG levels (β = 11.4, P = 0.02). Additionally, an association was found between frequent late-night snacking and higher SMBG readings (often snacking β = 18.1, P = 0.05), but not with increased HbA1c levels. In the multivariate linear regression, independent predictors for HbA1c and SMBG were sleep duration and patient age. In a univariate logistic regression, sleep duration and frequency of late-night snacking were not predictors of whether HbA1c target levels were achieved.

Conclusions: Short sleep duration, but not late-night snacking, seems to be associated with poorer glycemic control in type 1 diabetic patients treated with continuous subcutaneous insulin infusion.
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http://dx.doi.org/10.1111/jdi.12320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4511306PMC
July 2015

Circulating ghrelin level is higher in HNF1A-MODY and GCK-MODY than in polygenic forms of diabetes mellitus.

Endocrine 2015 Dec 19;50(3):643-9. Epub 2015 May 19.

Department of Metabolic Diseases, Jagiellonian University Medical College, 15 Kopernika Street, 31-501, Krakow, Poland.

Ghrelin is a hormone that regulates appetite. It is likely to be involved in the pathophysiology of varying forms of diabetes. In animal studies, the ghrelin expression was regulated by the hepatocyte nuclear factor 1 alpha (HNF1A). Mutations of the HNF1A gene cause maturity onset diabetes of the young (MODY). We aimed to assess the circulating ghrelin levels in HNF1A-MODY and in other types of diabetes and to evaluate its association with HNF1A mutation status. Our cohort included 46 diabetic HNF1A gene mutation carriers, 55 type 2 diabetes (T2DM) subjects, 42 type 1 diabetes (T1DM) patients, and 31 glucokinase (GCK) gene mutation carriers with diabetes as well as 51 healthy controls. Plasma ghrelin concentration was measured using the immunoenzymatic assay with polyclonal antibody against the C-terminal fragment of its acylated and desacylated forms. Ghrelin concentrations were 0.75 ± 0.32, 0.70 ± 0.21, 0.50 ± 0.20, and 0.40 ± 0.16 ng/ml in patients with HNF1A-MODY, GCK-MODY, T1DM, and T2DM, respectively. The ghrelin levels were higher in HNF1A-MODY and GCK-MODY than in T1DM and T2DM (p < 0.001 for all comparisons) but lower than in non-diabetic controls (1.02 ± 0.29 ng/ml, p < 0.001 for both comparisons). In the multivariate linear model, the differences between both MODY groups and common diabetes types remained significant. Analysis by a HNF1A mutation type indicated that ghrelin concentration is similar in patients with different types of sequence differences. Plasma ghrelin level is higher in HNF1A-MODY and GCK-MODY than in the common polygenic forms of diabetes.
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http://dx.doi.org/10.1007/s12020-015-0627-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4662709PMC
December 2015

Intima-media thickness and endothelial dysfunction in GCK and HNF1A-MODY patients.

Eur J Endocrinol 2015 Mar 10;172(3):277-83. Epub 2014 Dec 10.

Department of Metabolic DiseasesJagiellonian University Medical College, 15 Kopernika Street, Krakow 31-501, PolandUniversity HospitalKrakow, PolandTranslational Medicine LaboratoryDepartment of Internal MedicineDepartment of Clinical BiochemistryJagiellonian University Medical College, Krakow, PolandDepartment of PediatricsOncology, Hematology and Diabetology, Medical University of Lodz, Lodz, Poland Department of Metabolic DiseasesJagiellonian University Medical College, 15 Kopernika Street, Krakow 31-501, PolandUniversity HospitalKrakow, PolandTranslational Medicine LaboratoryDepartment of Internal MedicineDepartment of Clinical BiochemistryJagiellonian University Medical College, Krakow, PolandDepartment of PediatricsOncology, Hematology and Diabetology, Medical University of Lodz, Lodz, Poland

Objective: Mutations in the glucokinase (GCK) gene, along with hepatocyte nuclear factor 1A (HNF1A) gene mutations, are the most frequent cause of maturity-onset diabetes of the young (MODY). GCK-MODY patients are typically characterized by a moderate fasting hyperglycemia; however, little is known about atherosclerosis and intermediate-related phenotypes in these subjects.

Design: To examine carotid artery intima-media thickness (IMT) and endothelial function assessed by brachial artery flow-mediated dilatation (FMD) in GCK gene mutations carriers and HNF1A-MODY.

Methods: A total of 64 subjects with GCK gene mutations, and 52 HNF1A gene mutation carriers as well as 53 nondiabetic controls were examined. IMT and FMD were assessed by ultrasonography. Appropriate statistical tests were performed to assess differences between the groups, and multivariate linear regression was done for the association with IMT and FMD.

Results: The clinical characteristics of all groups were similar with the mean age at examination of 35.1, 41.1, and 39.5 years for GCK, HNF1A and the control group respectively. The highest mean IMT value was in the HNF1A-MODY group: 7.0±1.4 mm, whereas it reached 6.3±1.4 mm in GCK mutation carriers and 6.3±1.3 mm in controls (P=0.008). After adjustment for possible clinical and biochemical cofounders, IMT remained higher in HNF1A-MODY patients as compared with GCK-MODY patients (P=0.02) and controls (P=0.0003). FMD was significantly lower in HNF1A (9.9±4.6%) and GCK-MODY (11.1±4.6%) patients in comparison with controls (13.9±4.7%; P=0.0001). After adjustment, FMD remained lower in HNF1A-MODY (P=0.0005) and GCK-MODY patients (P=0.01) as compared with controls.

Conclusions: Both examined MODY groups demonstrated evidence of endothelial dysfunction. In addition, HNF1-MODY patients seem to be more prone to an early atherosclerotic phenotype.
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http://dx.doi.org/10.1530/EJE-14-0713DOI Listing
March 2015

Quantitative evaluation of fungi of the genus Candida in the feces of adult patients with type 1 and 2 diabetes - a pilot study.

Gut Pathog 2014 15;6(1):43. Epub 2014 Oct 15.

Department of Microbiology, Jagiellonian University Medical College, 18 Czysta St, 31-121 Krakow, Poland.

Background: Gastrointestinal tract microbiota, particularly bacterial microflora, seem to have a different qualitative and quantitative composition in both type 1 (T1DM) and type 2 diabetes (T2DM) mellitus cases as compared to non-diabetic individuals. So far, there are no data from diabetes research concerning the prevalence of fungi, particularly the most common genus, i.e. Candida, which are important components of human colon microflora. We aimed to examine whether there are quantitative changes of Candida fungi in the feces of patients with T1DM and T2DM as compared to healthy controls.

Findings: Overall, we included 44 diabetic patients (27 patients with T1DM and 17 with T2DM) as well as 17 healthy, non-diabetic controls. Feces and blood samples were collected from all study individuals. DNA was isolated from fecal samples and quantitative real time PCR (qPCR) was applied in order to determine the number of fungal cells. Statistical association with selected clinical and biochemical features was examined. There was a difference in the amount of Candida in the feces among the three examined groups (p = 0.007). Candida spp. populations in T1DM and T2DM subjects were larger as compared to controls (p = 0.017 and p = 0.037, respectively). However, no difference was found between T1DM and T2DM. No association was identified between the quantity of fungi and examined patients' characteristics, except for negative correlation with blood lipid parameters in T2DM group.

Conclusions: Candida fungi appear to be more prevalent in the feces of patients with T1DM and T2DM. Their amount seems to be associated with serum lipids in T2DM patients. This initial finding requires further confirmation.
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http://dx.doi.org/10.1186/s13099-014-0043-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4201707PMC
October 2014

Less but better: cardioprotective lipid profile of patients with GCK-MODY despite lower HDL cholesterol level.

Acta Diabetol 2014 Aug 19;51(4):625-32. Epub 2014 Feb 19.

Department of Pediatrics, Oncology, Hematology and Diabetology, Medical University of Lodz, 36/50 Sporna Str., 91-738, Lodz, Poland.

Patients with diabetes caused by single-gene mutations generally exhibit an altered course of diabetes. Those with mutations of the glucokinase gene (GCK-MODY) show good metabolic control and low risk of cardiovascular complications despite paradoxically lowered high-density lipoprotein (HDL) cholesterol levels. In order to investigate the matter, we analyzed the composition of low-density lipoprotein (LDL) and HDL subpopulations in such individuals. The LipoPrint(©) system (Quantimetrix, USA) based on non-denaturing, linear polyacrylamide gel electrophoresis was used to separate and measure LDL and HDL subclasses in fresh-frozen serum samples from patients with mutations of glucokinase or HNF1A, type 1 diabetes (T1DM) and healthy controls. Fresh serum samples from a total of 37 monogenic diabetes patients (21 from GCK-MODY and 16 from HNF1A-MODY), 22 T1DM patients and 15 healthy individuals were measured in this study. Concentrations of the small, highly atherogenic LDL subpopulation were similar among the compared groups. Large HDL percentage was significantly higher in GCK-MODY than in control (p = 0.0003), T1DM (p = 0.0006) and HNF1A-MODY groups (p = 0.0246). Patients with GCK-MODY were characterized by significantly lower intermediate HDL levels than controls (p = 0.0003) and T1DM (p = 0.0005). Small, potentially atherogenic HDL content differed significantly with the GCK-MODY group showing concentrations of that subfraction from control (p = 0.0096), T1DM (p = 0.0193) and HNF1A-MODY (p = 0.0057) groups. Within-group heterogeneity suggested the existence of potential gene-gene or gene-environment interactions. GCK-MODY is characterized by a strongly protective profile of HDL cholesterol subpopulations. A degree of heterogeneity within the groups suggests the existence of interactions with other genetic or clinical factors.
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http://dx.doi.org/10.1007/s00592-014-0567-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4127439PMC
August 2014

Medical care of pregnant women with type 1 diabetes: current guidelines and clinical practice.

Pol Arch Med Wewn 2013 23;123(1-2):59-65. Epub 2013 Jan 23.

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

The prevalence of all types of diabetes mellitus is increasing worldwide. Diabetes is a common metabolic complication of pregnancy. For many years, pregnancy complicated by type 1 diabetes was associated with a particularly poor prognosis, and while this has changed dramatically over the last 2 decades, a lot has yet to be done. The continuous relationship between the maternal glucose level and the prevalence of pregnancy complications is well‑documented. The list of outcomes includes congenital malformations, stillbirths, neonatal mortality, macrosomia, hypoglycemia, and many others. Several new therapeutic and monitoring tools have become available over the recent years, for example, short- and long‑acting insulin analogs, personal pumps, and continuous glucose monitoring systems. Interestingly, pregnancy planning and preconception education proved to be particularly effective in improving glycemic control in type 1 diabetic women and achieving therapeutic goals recommended by clinical guidelines. This resulted in the reduction of some maternal and neonatal pregnancy outcomes reported from various populations, but despite this remarkable progress the prevalence of the most common complication, neonatal macrosomia, is still substantially higher than in the newborns of mothers without diabetes. The likely causes of this phenomenon are short episodes of hyperglycemia, particularly postprandial ones, liberal diet, maternal obesity, and substantial weight gain during pregnancy - these potential reasons should be addressed in clinical practice. In the future, new therapeutic devices, such as close‑loop insulin pumps, may help further improve the prognosis in pregnant women with type 1 diabetes.
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http://dx.doi.org/10.20452/pamw.1595DOI Listing
January 2014

Impact of the FTO gene variation on fat oxidation and its potential influence on body weight in women with polycystic ovary syndrome.

Clin Endocrinol (Oxf) 2012 Jul;77(1):120-5

Department of Endocrinology, Diabetology and Internal Medicine, Medical University of Białystok, Białystok, Poland.

Context: Polycystic ovary syndrome (PCOS) is a heterogeneous disorder where insulin resistance might be involved in the development of endocrine and metabolic abnormalities. It has recently been shown that the FTO gene modifies weight, fat mass and insulin sensitivity in women with PCOS, where its role might be larger than in other phenotypes.

Objective: The aim of this study was to estimate the effect of a variation of the FTO gene on carbohydrate and lipid oxidation in PCOS women.

Patients: The study group consisted of 65 women with PCOS and 28 healthy, normally menstruating women.

Measurements: Clinical examination, anthropometric measurements, euglycaemic hyperinsulinaemic clamp and measurements of serum sex hormones were performed. Carbohydrate and lipid oxidation were evaluated with indirect calorimetry in the baseline state and during last 30 min of the clamp. The FTO rs9939609 polymorphism was genotyped using the restriction fragment length polymorphism method.

Results: There were no differences in carbohydrate and lipid oxidation between PCOS and control women. In the PCOS group, TT homozygotes had higher baseline fat oxidation in comparison with carriers of the A allele (P = 0·018), which was not found in the control group. We did not observe the effect of the FTO gene variation on insulin-stimulated lipid oxidation and neither on the baseline nor on the insulin-stimulated carbohydrate oxidation.

Conclusion: Our data show that this FTO gene variation might influence the baseline lipid oxidation in PCOS patients. This might potentially be one of the mechanisms explaining the impact of the FTO gene on body weight in PCOS.
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http://dx.doi.org/10.1111/j.1365-2265.2012.04379.xDOI Listing
July 2012

Lipoprotein composition in HNF1A-MODY: differentiating between HNF1A-MODY and type 2 diabetes.

Clin Chim Acta 2012 May 14;413(9-10):927-32. Epub 2012 Feb 14.

NIHR Clinical Research Facility, Peninsula College or Medicine and Dentistry, University of Exeter, Exeter, UK.

Introduction: The young-onset diabetes seen in HNF1A-MODY is often misdiagnosed as Type 2 diabetes. Type 2 diabetes, unlike HNF1A-MODY, is associated with insulin resistance and a characteristic dyslipidaemia. We aimed to compare the lipid profiles in HNF1A-MODY, Type 2 diabetes and control subjects and to determine if lipids can be used to aid the differential diagnosis of diabetes sub-type.

Methods: 1) 14 subjects in each group (HNF1A-MODY, Type 2 diabetes and controls) were matched for gender and BMI. Fasting lipid profiles and HDL lipid constituents were compared in the 3 groups. 2) HDL-cholesterol was assessed in a further 267 patients with HNF1A-MODY and 297 patients with a diagnosis of Type 2 diabetes to determine its discriminative value.

Results: 1) In HNF1A-MODY subjects, plasma-triglycerides were lower (1.36 vs. 1.93 mmol/l, p = 0.07) and plasma-HDL-cholesterol was higher than in subjects with Type 2 diabetes (1.47 vs. 1.15 mmol/l, p = 0.0008), but was similar to controls. Furthermore, in the isolated HDL; HDL-phospholipid and HDL-cholesterol ester content were higher in HNF1A-MODY, than in Type 2 diabetes (1.59 vs. 1.33 mmol/L, p = 0.04 and 1.10 vs. 0.83 mmol/L, p = 0.019, respectively), but were similar to controls (1.59 vs. 1.45 mmol/L, p = 0.35 and 1.10 vs. 1.21 mmol/L, p = 0.19, respectively). 2) A plasma-HDL-cholesterol > 1.12 mmol/L was 75% sensitive and 64% specific (ROC AUC = 0.76) at discriminating HNF1A-MODY from Type 2 diabetes.

Conclusion: The plasma-lipid profiles of HNF1A-MODY and the lipid constituents of HDL are similar to non-diabetic controls. However, HDL-cholesterol was higher in HNF1A-MODY than in Type 2 diabetes and could be used as a biomarker to aid in the identification of patients with HNF1A-MODY.
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http://dx.doi.org/10.1016/j.cca.2012.02.005DOI Listing
May 2012

Cystatin C is not a good candidate biomarker for HNF1A-MODY.

Acta Diabetol 2013 Oct 19;50(5):815-20. Epub 2012 Feb 19.

Department of Metabolic Diseases, Jagiellonian University Medical College, 15 Kopernika Street, 31-501, Krakow, Poland.

Cystatin C is a marker of glomerular filtration rate (GFR). Its level is influenced, among the others, by CRP whose concentration is decreased in HNF1A-MODY. We hypothesized that cystatin C level might be altered in HNF1A-MODY. We aimed to evaluate cystatin C in HNF1A-MODY both as a diagnostic marker and as a method of assessing GFR. We initially examined 51 HNF1A-MODY patients, 56 subjects with type 1 diabetes (T1DM), 39 with type 2 diabetes (T2DM) and 43 non-diabetic individuals (ND) from Poland. Subjects from two UK centres were used as replication panels: including 215 HNF1A-MODY, 203 T2DM, 39 HNF4A-MODY, 170 GCK-MODY, 17 HNF1B-MODY and 58 T1DM patients. The data were analysed with additive models, adjusting for gender, age, BMI and estimated GFR (creatinine). In the Polish subjects, adjusted cystatin C level in HNF1A-MODY was lower compared with T1DM, T2DM and ND (p < 0.05). Additionally, cystatin C-based GFR was higher than that calculated from creatinine level (p < 0.0001) in HNF1A-MODY, while the two GFR estimates were similar or cystatin C-based lower in the other groups. In the UK subjects, there were no differences in cystatin C between HNF1A-MODY and the other diabetic subgroups, except HNF1B-MODY. In UK HNF1A-MODY, cystatin C-based GFR estimate was higher than the creatinine-based one (p < 0.0001). Concluding, we could not confirm our hypothesis (supported by the Polish results) that cystatin C level is altered by HNF1A mutations; thus, it cannot be used as a biomarker for HNF1A-MODY. In HNF1A-MODY, the cystatin C-based GFR estimate is higher than the creatinine-based one.
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http://dx.doi.org/10.1007/s00592-012-0378-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3898131PMC
October 2013

No association between polymorphisms in the INSIG1 gene and the risk of type 2 diabetes and related traits.

Am J Clin Nutr 2010 Jul 5;92(1):252-7. Epub 2010 May 5.

Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.

Background: The insulin-induced gene 1 (INSIG1) encodes a protein that blocks proteolytic activation of sterol regulatory element binding proteins, which are transcription factors that activate genes that regulate cholesterol, fatty acid, and glucose metabolism.

Objective: We tested for associations between 6 INSIG1 tag single nucleotide polymorphisms (SNPs) (and captured all common variations in INSIG1) and the risk of type 2 diabetes (T2D), obesity, and related traits in 10,567 adults and 1155 adolescents from 5 population-based studies, a T2D case-control study, and a T2D case-series.

Design: We genotyped tag SNPs and tested them for associations with the risk of T2D or obesity and with body mass index, waist circumference, systolic and diastolic blood pressure, and concentrations of fasting glucose, 2-h oral-glucose-tolerance test glucose, cholesterol, and triglyceride, with the assumption of an additive effect of the minor allele. Dominant effects were tested for the less-frequent SNPs (minor allele frequency <5%). Summary statistics of each study underwent meta-analysis.

Results: Meta-analyses, which included 1655 T2D cases and 2911 control subjects, showed no association between any of the INSIG1 SNPs and T2D (P > 0.08). Furthermore, none of the SNPs showed an association with obesity in 1666 obese and 5737 nonobese individuals (P > 0.17). In agreement, none of the associations between the SNPs and any of the metabolic traits showed convincing associations in the 7562 adults from 4 population-based studies. Although a few nominally significant associations emerged, none of the associations survived multiple-testing correction. We observed no convincing associations with any of the studied traits in 1155 adolescents.

Conclusion: Although our study was sufficiently powered to identify small effects, the results suggest that common variation in INSIG1 is unlikely to have a major effect on T2D and obesity risk and related traits in white Europeans.
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http://dx.doi.org/10.3945/ajcn.2010.29422DOI Listing
July 2010

Dipeptidyl peptidase-IV inhibitors are efficient adjunct therapy in HNF1A maturity-onset diabetes of the young patients--report of two cases.

Diabetes Technol Ther 2010 Apr;12(4):313-6

Department of Metabolic Diseases, Jagiellonian University Medical College, 15 Kopernika Street, Krakow, Poland.

Background: In HNF1A maturity-onset diabetes of the young (MODY), sulfonylurea (SU) is the first-line treatment. Over time, such therapy fails, and additional treatment is required. Dipeptidyl peptidase IV (DPP-IV) inhibitors are new agents that lower blood glucose by prolonging the activity of circulating incretins.

Methods: We applied DPP-IV inhibitors in two HNF1A MODY patients whose earlier therapeutic regimen included SU.

Results: Case 1, a 39-year-old woman, a carrier of the ArgR171X HNF1A mutation, with a 7-year history of diabetes was on 160 mg of gliclazide and 2,000 mg of metformin. Her initial hemoglobin A1c (HbA1c) level was 7.2%, while the mean glucose level on the CGMS((R)) (Medtronic, Northridge, CA) record was 162 mg/dL. Sitagliptine, in a dose of 100 mg/day, was added to the previous treatment. Case 2, a 62-year-old woman, a carrier of the IVS7nt-6G>A mutation, with a 41-year history of diabetes was treated with 240 mg/day gliclazide and 6 IU of insulin/day. Her initial HbA1c was 8.8%, and average glycemia reached 172 mg/dL. In her case, we started the combined therapy with 50 mg of vildagliptine twice daily. Patients were reexamined after 3 months, and HbA1c fell to 6.3% in both subjects. Similarly, significant improvement in glycemic control on CGMS was observed as the average glycemia decreased to 114 mg/dL and 134 mg/dL in Case 1 and Case 2, respectively. No episodes of hypoglycemia or other side effects were recorded. As intravenous glucose tolerance tests (IVGTTs) were performed before and after DPP-IV implementation, we were able to assess their impact on insulin secretion under fasting conditions. We saw a substantial rise in insulin level increment during IVGTT (by 9.8 and13.4 mIU/L in Case 1 and Case 2, respectively).

Conclusions: DPP-IV inhibitors may be an effective tool of combined therapy in HNF1A MODY, and they seem to improve beta-cell function under fasting conditions.
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http://dx.doi.org/10.1089/dia.2009.0159DOI Listing
April 2010

LMNA gene mutation search in Polish patients: new features of the heterozygous Arg482Gln mutation phenotype.

Endocrine 2009 Dec 27;36(3):518-23. Epub 2009 Oct 27.

Department of Metabolic Diseases, Jagiellonian University, Medical College, 15 Kopernika Street, 31-501 Krakow, Poland.

Mutations of the LMNA gene have been shown to cause an autosomal dominant form of insulin resistance with familial partial lipodystrophy (PLD), frequently accompanied by diabetes. LMNA mutations are considered to be a rare cause of monogenic diabetes; however, they are probably sometimes misdiagnosed as type 2 diabetes (T2DM). We examined whether skin fold thickness measurements may be an effective screening procedure to select individuals with T2DM for molecular testing of the LMNA gene. We also aimed to search for mutations in diabetic patients with evident clinical features of lipodystrophy. Skin fold measurements were performed in 249 not pre-selected T2DM patients. The sum of two trunk skin fold measurements divided by the sum of two peripheral was obtained. Men with a skin fold ratio above 2.5 and women above 1.5 were selected for further molecular analysis of the LMNA gene by direct sequencing. We also examined eight patients presenting typical clinical features of lipodystrophy. We selected 16 patients with T2DM on the basis of skin fold measurements. LMNA gene sequencing in this group revealed no mutation that could be attributable to diabetic phenotype. However, in the group of subjects with apparent lipodystrophic phenotype, we identified one Arg482Gln mutation. This female, diagnosed with diabetes at the age of 51 years, was characterized by insulin resistance but, unlike previously reported LMNA Arg48Gln mutation carriers, she was not overweight. The patient also presented with chronic kidney disease and pulmonary fibrosis that could potentially be a part of the phenotype related to the identified LMNA mutation. We did not find the evidence that screening based on skin fold measurements alone could be an efficient approach to select T2DM patients for molecular testing of the LMNA gene; the presence of features typical for laminopathy seems to be required for such testing. A clinical picture related to the LMNA Arg482Gln mutation may be more diversified than it was previously considered and include low BMI and pulmonary fibrosis.
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http://dx.doi.org/10.1007/s12020-009-9265-0DOI Listing
December 2009

[Variants of adiponectin gene as risk factors for the metabolic syndrome].

Przegl Lek 2009 ;66(5):257-62

Zakład Biochemii Klinicznej, Collegium Medicum, Uniwersytet Jagielloński, Kraków.

Adiponectin, a protein secreted by adipose tissue but present at low levels in obesity, is now widely recognized as a key determinant of insulin sensitivity and of protection against obesity-associated metabolic syndrome. The adiponectin gene is very polymorphic and several of its variants contribute to adiponectin level, function and are associated with metabolic syndrome phenotypes. The results differ ethnically. The association of identified variants with obesity and its consequences, type 2 diabetes and cardiovascular disease is reviewed. This data may enable patients at greater risk of the adverse effects of obesity to be identified and, as such, benefit from more targeted therapy and prevention.
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October 2009