Publications by authors named "Wyka Krystyna"

47 Publications

Clinical heterogeneity among pediatric patients with autoimmune type 1 diabetes stratified by immunoglobulin deficiency.

Pediatr Diabetes 2021 Apr 10. Epub 2021 Apr 10.

Department of Pediatrics, Oncology, and Hematology, Medical University of Łódź, Łódź, Poland.

Background: Type 1 diabetes (T1D) may coexist with primary immunodeficiencies, indicating a shared genetic background.

Objective: To evaluate the prevalence and clinical characteristics of immunoglobulin deficiency (IgD) among children with T1D.

Methods: Serum samples and medical history questionnaires were obtained during routine visits from T1D patients aged 4-18 years. IgG, IgA, IgM, and IgE were measured by nephelometry and enzyme-linked immunosorbent assay (ELISA). IgG and IgM deficiency (IgGD, IgMD) were defined as IgG/IgM >2 standard deviations (SD) below age-adjusted mean. IgE deficiency was defined as IgE <2 kIU/L. IgA deficiency (IgAD) was defined as IgA >2 SD below age-adjusted mean irrespective of other immunoglobulin classes (absolute if <0.07 g/L, partial otherwise) and as selective IgAD when IgA >2 SD below age-adjusted mean with normal IgG and IgM (absolute if <0.07 g/L, partial otherwise).

Results: Among 395 patients (53.4% boys) with the median age of 11.2 (8.4-13.7) and diabetes duration 3.6 (1.1-6.0) years, 90 (22.8%) were found to have hypogammaglobulinemia. The IgGD and IgAD were the most common each in 40/395 (10.1%). Complex IgD was found in seven patients. Increased odds of infection-related hospitalization (compared to children without any IgD) was related to having any kind of IgD and IgAD; OR (95%CI) = 2.1 (1.2-3.7) and 3.7 (1.8-7.5), respectively. Furthermore, IgAD was associated with having a first-degree relative with T1D OR (95%CI) = 3.3 (1.4-7.6) and suffering from non-autoimmune comorbidities 3.3 (1.4-7.6), especially neurological disorders 3.5 (1.2-10.5).

Conclusions: IgDs frequently coexist with T1D and may be associated with several autoimmune and nonimmune related disorders suggesting their common genetic background.
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http://dx.doi.org/10.1111/pedi.13208DOI Listing
April 2021

Salivary immunoglobulin A level during steroids and chemotherapy treatment administered in remission induction phase among pediatric patients with acute lymphoblastic leukemia.

Medicine (Baltimore) 2020 Oct;99(42):e22802

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

The agents used in the treatment of acute lymphoblastic leukaemia (ALL) might affect the oral health of cancer patients.The study aims to assess the changes in the levels of immunoglobulin A (IgA) in saliva and blood, during first 22 days of intensive chemotherapy of ALL in children.Saliva and blood samples were taken from 24 patients, including 13 boys and 11 girls (age range: 4 - 17 years) on days 1, 8 and 22 of treatment. The levels of immunoglobulin A and total protein were estimated in samples at each time-point. The distribution of the quantitative variables was assessed using the Shapiro-Wilk test. Non-parametric statistics were used to compare the levels of repeated measurements and post hoc non-parametric analysis was applied for between time-point comparisons.A constant relationship was found between the levels of Ig A in blood and saliva (r = 0.28; P = .031). No change in salivary IgA level was observed in the prednisone-only prephase, but it dropped significantly on day 22 (10.7+/-4.8 vs 9.6+/-6.4 vs 5.7+/-3.9 ng/mL; P = .04), when chemotherapy was given (anthracycline, vincristine, L-asparaginase).In blood, the total protein level decreased significantly between day 1 and 22 (6.2+/-0.4 vs 5.1+/-0.3 g/dL; P = .001). Lymphocyte count (per microliter) also decreased (2.12+/-0.8 vs 0.41+/-0.1 vs 1.08+/-0.5; P = .002). Four children suffered from oral mucositis graded 1 or higher between days 8 and 22.Chemotherapy given during the treatment of childhood ALL is associated with a reduction in the level of salivary immunoglobulin A. Prevention of the drop of salivary IgA may diminish the risk of occurrence of acute mucosal complications.
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http://dx.doi.org/10.1097/MD.0000000000022802DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7571880PMC
October 2020

Radiation-Induced Hypothyroidism in Patients with Oropharyngeal Cancer Treated with IMRT: Independent and External Validation of Five Normal Tissue Complication Probability Models.

Cancers (Basel) 2020 Sep 22;12(9). Epub 2020 Sep 22.

Department of Biostatistics and Translational Medicine, Medical University of Lodz, 92-215 Lodz, Poland.

We aimed to externally validate five normal tissue complication probability (NTCP) models for radiation-induced hypothyroidism (RIHT) in a prospectively recruited cohort of 108 patients with oropharyngeal cancer (OPC). NTCP scores were calculated using original published formulas. Plasma thyrotropin (TSH) level was additionally assessed in the short-term after RT. After a median of 28 months of follow-up, thirty one (28.7%) patients developed RIHT. Thyroid mean dose and thyroid volume were significant predictors of RIHT: odds ratio equal to 1.11 (95% CI 1.03-1.19) for mean thyroid dose and 0.87 (95%CI 0.81-0.93) for thyroid volume in univariate analyses. Two of the evaluated NTCP models, published by Rønjom et al. and by Boomsma et al., had satisfactory performance with accuracies of 0.87 (95%CI 0.79-0.93) and 0.84 (95%CI: 0.76-0.91), respectively. Three remaining models, by Cella et al., Bakhshandeh et al. and Vogelius et al., performed significantly worse, overestimating the risk of RIHT in this patient cohort. A short-term TSH level change relative to baseline was not indicative of RIHT development in the follow-up (OR 0.96, 95%CI: 0.65-1.42, = 0.825). In conclusion, the models by Rønjom et al. and by Boomsma et al. demonstrated external validity and feasibility for long-term prediction of RIHT in survivors of OPC treated with Intensity-Modulated Radiation Therapy (IMRT).
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http://dx.doi.org/10.3390/cancers12092716DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563778PMC
September 2020

Fetuin-A and Interleukine-8 in Children with the Clinical Remission of Type 1 Diabetes.

Iran J Immunol 2020 Jun;17(2):144-153

Department of Pediatrics, Silesian Medical University in Katowice, Katowice, Poland.

Background: Clinical partial remission (CPR) in most patients with type 1 diabetes (T1D) is observed shortly after clinical diagnosis. Increasing body weight and impaired insulin sensitivity may play a role in the pathogenesis of CPR. Several cytokines can also participate in the development of insulin resistance.

Objective: To evaluate the relationship between birth weight, body mass index, and the concentrations of IL-8 and Fetuin-A, and the presence of clinical partial remission in children at the T1D onset.

Methods: The study group consisted of 134 children with a newly diagnosed T1D in whom the presence of CPR was evaluated in a further 2-year course of diabetes. The control group included 47 children without glucose tolerance disorders. The concentrations of IL-8 and Fetuin-A were determined by the ELISA method.

Results: CPR occurred in 75.34% of T1D patients. At T1D onset, higher values of BMI SDS in the remitters as compared to the patients without remission were observed. At the T1D onset, the concentrations of Fetuin-A (p=0.031) and IL-8 (p=0.042) were significantly higher in patients compared to those without CPR.

Conclusion: Evaluation of Fetuin-A and IL-8 levels in patients with a newly diagnosed T1D can differentiate between patients with or without CPR.
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http://dx.doi.org/10.22034/iji.2020.82797.1595DOI Listing
June 2020

HLA-A gene variation modulates residual function of the pancreatic β-cells in children with type 1 diabetes.

Pediatr Endocrinol Diabetes Metab 2020 ;26(2):73-78

Department of Pediatrics, Oncology and Hematology, Medical University of Lodz, Poland.

Aim Of The Study: The study aimed to analyze an association between the HLA-A gene variation and a risk of type 1 diabetes development and to evaluate the association of HLA class I and class II alleles with β-cell destruction.

Material And Methods: A group of 108 children with type 1 diabetes were genotyped in HLA-A, -DRB1, and -DQB1 genes using hybridization with oligonu-cleotides probes. Plasma C-peptide concentration was assessed by radioimmunoassay method.

Results: No differences in allele HLA-A distribution between type 1 diabetes patients and healthy individuals were found. Among "low C-peptide"(< 0.28 pmol/ml) individuals, the frequency of HLA-A*02 allele was 41.3%, whereas only one HLA-A*26 allele was detected in this group (0.7%). Conversely, among "high C-peptide"( 0.28 pmol/ml) probands the prevalence of A*02 allele was 19.7% (Pc = 0.008, OR = 1.4, 95% CI: 1.2-1.7) and A*26 10.5 % (Pc < 0.007, OR = 0.15, 95% CI: 0.02-0.9). Genotype analysis showed that A*02/*02 and A*02/X children were more likely to have "low" C-peptide at the onset compared to those with non-A*02/non-A*02 genotype (p = 0.008, OR = 1.6, 95% CI: 1.3-2.0 and p = 0.015, OR = 1.4, 95% CI: 1.1-1.9, respectively). A02 phenotype individuals had lower median C-peptide (0.17 pmol/ml) than non-A02 patients (0.26 pmol/ml, p = 0.008). Median C-peptide was higher in the A26-positive group comparing to A26-negative (0.40 and 0.20, respectively, p = 0.04). No association between HLA class II and C-peptide levels was observed.

Conclusions: HLA-A alleles are not associated with disease development nevertheless strongly influence a residual pancreatic β-cell function. The results suggest a different role of HLA class I and class II in type 1 diabetes pathogenesis.
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http://dx.doi.org/10.5114/pedm.2020.95617DOI Listing
May 2021

Metabolic bone markers can be related to preserved insulin secretion in children with newly diagnosed type 1 diabetes.

Pediatr Endocrinol Diabetes Metab 2020 ;26(1):10-16

Department of Paediatrics, Diabetology, Endocrinology, and Nephrology, Medical University of Lodz, Poland.

Introduction: Type 1 diabetes (T1D) may be associated with numerous complications including bone metabolism disorders. The aim of the study was to evaluate the bone metabolism markers twice in children with a newly diagnosed T1D and after an average of seven months of its duration in relation to parameters of the clinical course of diabetes.

Material And Methods: In 100 T1D patients and 52 control subjects, the following bone turnover markers were evaluated: osteocalcin - OC, osteoprotegerin - OPG, sRANKL, and deoxypyridoline in urine - DPD and DXA examination was also performed.

Results: Lower OC concentration at T1D onset in comparison to controls (p < 0.001) and its increase during follow-up (p < 0.001) was ob-served. The OPG concentration was elevated at T1D onset as compared to the control group (p = 0.024) and decreased thereafter (p < 0.001). The s-RANKL level increased during follow-up (p < 0.001) and was lower than in controls (p < 0.001). Urine DPD con-centration also increased during follow-up in the T1D patient group (p < 0.001) and was higher in comparison to the control group (p = 0.021). BMD-TBLH was higher in the control group as compared to patients both at T1D onset (p = 0.025) and in follow-up ob-servation (p = 0.034). Moreover, OPG correlated positively with glycated haemoglobin (HbA1c) (p = 0.004) and negatively with fasting C-peptide level (p = 0.046) and BMI Z-score (p = 0.003), whereas s-RANKL correlated positively with both fasting (p < 0.001) and stimulated C-peptide levels (p < 0.001).

Conclusions: Bone metabolism disorders observed at T1D onset in children and modified after reaching the metabolic control of the disease seem to be most strongly associated with preserved insulin secretion.
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http://dx.doi.org/10.5114/pedm.2020.94391DOI Listing
March 2021

The level of extracellular superoxide dismutase in the first week of life in very and extremely low birth weight infants and the risk of developing bronchopulmonary dysplasia.

J Perinat Med 2019 Aug;47(6):671-676

Department of Neonatology, Polish Mother's Memorial Hospital - Research Institute, Lodz, Poland.

Background Antioxidant enzymes may play a significant role in the development of bronchopulmonary dysplasia (BPD). The aim of the study was to assess the relationship between the level of extracellular superoxide dismutase (SOD3) in the serum at days 1 and 7 of life and the risk of developing BPD. Methods The study comprised 103 neonates born before 32 weeks' gestation with a birth weight of ≤1500 g. Results In the investigated group, the median serum SOD3 level at day 1 of life was 4.01 ng/mL [interquartile range (IQR) 2.59-5.09 ng/mL] and at day 7 of life 3.13 ng/mL (IQR 2.49-4.34 ng/mL). A statistically significant decrease in the serum SOD3 level was found in the first week of life, P < 0.0001. No correlation was found between the serum SOD3 level at day 1 of life and gestational age R = 0.07, P = 0.4543 and birth weight R = 0.10, P = 0.3083. No statistically significant correlation was found between the dynamics of change in the SOD3 level in serum at days 1 and 7 of life and the risk of BPD development for the definition of BPD at day 28 of life, P = 0.8764 nor at 36 weeks' postmenstrual age, P = 0.6598. Conclusion The study revealed a statistically significant decrease in the serum SOD3 level in the first week of life in very and extremely low birth weight infants born before 32 weeks of gestation. In the clinical setting, no relationship was observed between the level of SOD3 in serum and the risk of developing BPD.
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http://dx.doi.org/10.1515/jpm-2018-0418DOI Listing
August 2019

Lipopolysaccharide-Binding Protein Is an Early Biomarker of Cardiac Function After Radiation Therapy for Breast Cancer.

Int J Radiat Oncol Biol Phys 2019 08 13;104(5):1074-1083. Epub 2019 Apr 13.

Department of Biostatistics and Translational Medicine, Medical University of Lodz, Poland; Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. Electronic address:

Purpose: To evaluate the prognostic potential of lipopolysaccharide-binding protein (LBP) levels after breast cancer radiation therapy (RT) for incipient cardiac dysfunction.

Methods And Materials: In this single-centered study, we prospectively enrolled female patients treated for left breast cancer. Healthy age- and sex-matched participants were recruited as controls. LBP levels, cardiac troponin T, N-terminal propeptide of the brain natriuretic peptide, fatty acid binding protein, and C-reactive protein were assessed at three timepoints-before RT, after the last RT fraction, and 1 month after the last fraction. Echocardiographic evaluation was done 3 to 3.75 years after RT.

Results: We recruited 51 patients and 78 controls. Baseline LBP concentrations in the study group were significantly higher than in controls at baseline (P < .001), at 24 hours, and at 1 month after RT (P = .003 and P < .001, respectively). Other biomarkers (cardiac troponin T, N-terminal propeptide of the brain natriuretic peptide, fatty acid binding protein, and C-reactive protein) did not differ in any of the timepoints. Posttreatment LBP concentrations were significantly and positively correlated with heart- and lung-associated dose-volume histogram variables. Posttreatment and follow-up LBP levels correlated positively with the E/E' echocardiographic index reflective of the diastolic function. After adjustment for left anterior descending artery mean dose, left ventricle mean dose, mean heart dose, and type of surgery, LBP remained significantly correlated with E/E' when measured 24 hours after RT (beta = 0.41, P = .032) and 1 month after RT (beta = 0.43, P = .028).

Conclusions: Serum LBP concentrations correlate with diastolic function evaluated 3 years after the completion of RT, making LBP a potentially useful prognostic parameter.
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http://dx.doi.org/10.1016/j.ijrobp.2019.04.002DOI Listing
August 2019

Serum Level of Soluble CD226 Receptor in Healthy Individuals is Highly Variable and Associated with Age.

Iran J Immunol 2019 Mar;16(1):92-95

Department of Pediatrics, Diabetology, Endocrinology and Nephrology, Medical University of Lodz, Poland.

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http://dx.doi.org/10.22034/IJI.2019.39410DOI Listing
March 2019

Dynamic changes in specific anti-L-asparaginase antibodies generation during acute lymphoblastic leukemia treatment.

Pharmacol Rep 2019 Apr 28;71(2):311-318. Epub 2018 Nov 28.

Department of Pediatrics, Oncology, Hematology and Diabetology, Medical University of Lodz, Łódź, Poland. Electronic address:

Background: L-asparaginase (L-asp) remains one of the key components of acute lymphoblastic leukemia therapy. Immune reactions to the drug are associated with its diminished activity. The aim of the study was to determine the level of IgM, IgG and IgE-class anti-L-asp antibodies during the induction and reinduction phases of acute lymphoblastic leukemia therapy and their influence on L-asp activity.

Methods: The study group comprised 65 patients treated for acute lymphoblastic leukemia in one pediatric oncology center. L-asp antibodies were assessed using ELISA at the end of the induction and reinduction phases. L-asp activity was assessed prior to each drug administration by colorimetry.

Results: At the end of the first exposure to L-asp antibodies were detected in 35 patients (54%). In the reinduction phase of the treatment anti-L-asp antibodies were found in 38/55 patients (69%). In the induction phase patients with inadequate L-asp activity had higher IgM concentrations (median 5.88 versus 2.81 μg/mL, p = 0.03). In the reinduction phase IgG and IgM levels correlated inversely with L-asp activity. Patients with L-asp allergy had higher levels of IgG (median 61.6 versus 18.36 μg/mL, p = 0.01), whereas higher IgE levels were noted in the group of patients with inadequate drug activity (median 0.91 versus 0.64 μg/mL, p = 0.03).

Conclusions: Subsequent exposure to L-asp in the treatment of acute lymphoblastic leukemia was associated with the increase of anti-L-asp antibodies in all studied classes. However, the changes observed in specific classes of antibodies were not distinctive for L-asp hypersensitivity or inactivation, suggesting that the mechanism is more complex.
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http://dx.doi.org/10.1016/j.pharep.2018.11.002DOI Listing
April 2019

Zinc transporter 8 autoantibodies (ZnT8-ab) are associated with higher prevalence of multiple diabetes-related autoantibodies in adults with type 1 diabetes.

Diabetes Res Clin Pract 2018 Dec 19;146:313-320. Epub 2018 Nov 19.

Poznan University of Medical Sciences, Poznan, Poland.

Aim: The study aimed to assess the prevalence of zinc transporter 8 autoantibodies (ZnT8-ab), other diabetes-related autoantibodies and clinical manifestation of type 1 diabetes in adults, depending on age of the onset of disease.

Methods: 119 patients with type 1 diabetes, 66 at age <35 years (T1DM < 35) and 53 T1DM at age ≥35 years (T1DM ≥ 35). We assessed clinical features, GAD-ab, IA2-ab, ICA, ZnT8-ab and thyroid peroxidase antibodies (ATPO).

Results: In T1DM < 35 lower initial serum C-peptide concentration was observed and diabetes ketoacidosis (DKA) was more common. ATPO positivity was more prevalent in T1DM ≥ 35 (35.8 vs 21.2%, p = 0.04). The prevalence of GAD-ab, IA2-ab and ZnT8-ab was similar in both groups, the titres of IA2-ab and ICA were higher in T1DM < 35 but titre of ZnT8-ab was higher in T1DM ≥ 35. The majority of T1DM < 35 patients were positive for three autoantibodies (40.9%), while T1DM ≥ 35 subjects most often presented with only one (30.2%) antibody, most commonly GAD-ab (81.2%). 45% T1DM < 35 and 34% T1DM ≥ 35 subjects were positive for ZnT8-ab. ZnT8-ab positive patients had higher titre and more frequent occurrence of multiple diabetes-related autoantibodies than ZnT8-ab negative patients.

Conclusions: Adults with T1DM < 35 and T1DM ≥ 35 differ in the severity of autoimmune response at diagnosis. ZnT8-ab positivity is related to higher titre and more frequent occurrence of multiple diabetes-related autoantibodies.
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http://dx.doi.org/10.1016/j.diabres.2018.11.007DOI Listing
December 2018

Temporal dynamics of serum let-7g expression mirror the decline of residual beta-cell function in longitudinal observation of children with type 1 diabetes.

Pediatr Diabetes 2018 12 12;19(8):1407-1415. Epub 2018 Oct 12.

Department of Biostatistics and Translational Medicine, Medical University of Lodz, Lodz, Poland.

Background/objective: In type 1 diabetes mellitus (T1DM), the introduction of insulin is typically followed by a brief remission period, with subsequent gradual decline in beta-cell function. Several studies described altered profile of circulating miRNAs (microRNAs) in T1DM patients and proposed them as biomarkers of associated pathologic processes.

Hypothesis: Serum miRNA expression profile reflects residual beta-cell function and autoimmunity in T1DM.

Subjects: The profiling group included patients with: GCK-MODY (N = 13), T1DM (N = 9), and 10 healthy controls. The longitudinal group included 34 patients with samples collected at diagnosis of T1DM and first, third, and fourth to eighth year since diagnosis.

Methods: We reanalyzed data from the profiling group for miRNAs differentially expressed between patients with T1DM, other types of diabetes and controls. Afterward, we shortlisted miRNAs on the basis of this reanalysis and literature review and quantified their expression with quantitative polymerase chain reaction. Additionally, we measured the levels of anti-islet antibodies (islet cell antibodies, glutamic acid decarboxylase antibodies, IA2 antibodies, and ZnT8A) and C-peptide concentrations across the four timepoints in the longitudinal group.

Results: miR-24 and let-7g serum expression differed significantly between GCK-MODY, controls, and HbA1c-matched T1DM patients; P < 0.05, false discovery rate < 0.05. Autoantibodies levels showed decreasing linear trend in repeated timepoints (all P < 0.0001). C-peptide concentration peaked during the first year after diagnosis, corresponding to remission phase, and declined in consecutive measurements. This dynamic was evidenced for let-7g expression levels (P = 0.0058).

Conclusions: The pattern of let-7g expression change during the course of diabetes mirrors that of C-peptide levels, hinting at this microRNA's association with the residual mass of the beta cells in patients with T1DM.
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http://dx.doi.org/10.1111/pedi.12783DOI Listing
December 2018

Coexisting psoriasis affects the clinical course of type 1 diabetes in children.

Pediatr Endocrinol Diabetes Metab 2017 ;23(3):139-145

Department of Biostatistics and Translational Medicine, Medical University of Lodz, Department of Paediatrics, Oncology, Haematology and Diabetology, Medical University of Lodz.

Introduction: Literature reports link psoriasis with insulin resistance characteristic for type 2 diabetes. However, this condition may also affect the clinical course of type 1 diabetes (T1D).

Aim: To investigate whether children with type 1 diabetes mellitus (T1D) and psoriasis have a different course of diabetes.

Methods: We evaluated patients diagnosed with T1D in the years 2002-2011 for the presence of psoriasis and matched them 1:10 with T1D-only patients by sex and duration of diabetes using propensity score. We collected T1D-onset parameters and metabolic control surrogates from six months after T1D diagnosis.

Results: We identified 14 patients with psoriasis and matched 140 controls, of whom 129 (68 boys) were eligible for the analysis. At onset T1D+psoriasis patients showed higher concentration of C-peptide than controls (median: 0.38ng/ml vs 0.15ng/ml, p=0.02). Six months later, they had non-significantly lower HbA1c (6.0 vs 6.6%, p=0.11), TC (143mg/dl vs 159mg/dl, p=0.14) HDL (54.5mg/dl vs 59mg/dl, p=0.11).

Conclusions: Patients with T1D and psoriasis present higher endogenous insulin secretion at T1D onset and a tendency for better glycemic control during the first 6 months.
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http://dx.doi.org/10.18544/PEDM-23.03.0085DOI Listing
July 2018

Markers influencing the presence of partial clinical remission in patients with newly diagnosed type 1 diabetes.

J Pediatr Endocrinol Metab 2017 Oct;30(11):1147-1153

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Background: The aim of the study was to compare the selected markers in children with and without partial clinical remission (CR) of newly diagnosed type 1 diabetes (T1D).

Methods: The study group consisted of 186 patients (F/M; 87/99) at onset of T1D and 24 months of follow-up. Partial CR was defined as insulin requirement <0.5 IU/kg and glycated hemoglobin (HbA1c) <7%.

Results: Partial CR was observed in 115/186 (61.83%) of patients. At diagnosis body mass index standard deviation (BMI SDS) was higher among remitters than in non-remitters (p=0.0051) and remitters were younger (p=0.0029). In the follow-up a higher triglyceride concentration in non-remitters compared to remitters (p=0.0455) and a lower high density lipoprotein (HDL) cholesterol level (p=0.0119) were noticed.

Conclusions: Younger age and higher BMI at diagnosis of T1D can predispose to partial CR in children. In patients with CR of T1D after 2 years of follow-up a lipid profile improvement is observed.
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http://dx.doi.org/10.1515/jpem-2017-0100DOI Listing
October 2017

Factors affecting long-term efficacy of T regulatory cell-based therapy in type 1 diabetes.

J Transl Med 2016 12 1;14(1):332. Epub 2016 Dec 1.

Department of Clinical Immunology and Transplantology, Medical University of Gdańsk, Debinki 7, 80-210, Gdańsk, Poland.

Background: Recent studies suggest that immunotherapy using T regulatory cells (Tregs) prolongs remission in type 1 diabetes (T1DM). Here, we report factors that possibly affect the efficacy of this treatment.

Methods: The metabolic and immune background of 12 children with recently diagnosed T1DM, as well as that of untreated subjects, during a 2-year follow-up is presented. Patients were treated with up to 30 × 10/kg b.w. of autologous expanded CD3CD4CD25CD127 Tregs.

Results: The disease progressed and all patients were insulin-dependent 2 years after inclusion. The β-cell function measured by c-peptide levels and the use of insulin were the best preserved in patients treated with two doses of Tregs (3/6 in remission), less so after one dose (1/6 in remission) and the worst in untreated controls (no remissions). Increased levels of Tregs could be seen in peripheral blood after their adoptive transfer together with the shift from naïve CD62LCD45RA to memory CD62LCD45RA Tregs. Increasing serum levels of proinflammatory cytokines were found: IL6 increased in all subjects, while IL1 and TNFα increased only in untreated group. Therapeutic Tregs were dependent on IL2, and their survival could be improved by other lymphocytes.

Conclusions: The disease progression was associated with changing proportions of naïve and memory Tregs and slowly increasing proinflammatory activity, which was only partially controlled by the administered Tregs. The therapeutic cells were highly dependent on IL2. We conclude that the therapy should be administered at the earliest to protect the highest possible mass of islets and also to utilize the preserved content of Tregs in the earlier phases of T1DM. Trial registration http://www.controlled-trials.com/ISRCTN06128462 ; registered retrospectively.
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http://dx.doi.org/10.1186/s12967-016-1090-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5131539PMC
December 2016

Lipopolysaccharide-binding protein is efficient in biodosimetry during radiotherapy of lung cancer.

Biomed Rep 2016 Oct 8;5(4):450-454. Epub 2016 Aug 8.

Department of Radiotherapy, Medical University of Łódź, 93-509 Łódź, Poland.

The aim of the present study was to determine if the serum levels of early markers of inflammation, such as interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), C-reactive protein (CRP), and lipopolysaccharide-binding protein (LBP) were correlated with the radiation dose received by the pulmonary and mediastinal structures of patients with non-small cell lung cancer (NSCLC). This pilot study included 26 patients with NSCLC who received total radiation doses ranging from 54 to 74 Gy (2.0 Gy/fraction). Cytokines were measured at baseline by enzyme-linked immunosorbant assay, and following administration of total doses of 20 and 40 Gy. A control group of 26 participants was sampled for comparisons with patient baseline cytokine levels. Only data from the 40-Gy cytokine blood levels of patients with NSCLC were identified to be correlated with histograms of the parameters of each patient's radiotherapy protocol. The IL-6, TNF-α and CRP median baseline levels of the patients with NSCLC were significantly higher than those of the controls (all P≤0.01). No differences were observed between the LBP levels of the patients and controls [median, 36.34 (25-75%; 31.35-39.27) vs. 36.92 (30.20-44.05) µg/ml, respectively; P=0.42]. No significant differences in the levels of the four cytokines between baseline, and at 20 and 40 Gy were observed [IL-6 (P=0.19); TNF-α (P=0.68); CRP (P=0.44) and LBP (P=0.29)]. LBP was significantly and positively correlated with the mean radiation dose to the lung (r=0.409; P=0.038), and showed a positive correlation with the percentage of lung volume exposed to at least 20 Gy of the planned radiation dose (=0.3536; P=0.0764). CRP levels were positively correlated with the mean radiation dose to the esophagus (=0.404; P=0.041); however, IL-6, TNF-α and CRP were not significantly associated with other lung dosimetry parameters. Thus, LBP levels were correlated with radiation exposure of pulmonary tissues, and LBP may be a marker that warrants further investigation on radiotoxicity in NSCLC patients.
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http://dx.doi.org/10.3892/br.2016.739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5038356PMC
October 2016

[Humoral response markers in GCK MODY].

Pediatr Endocrinol Diabetes Metab 2016 ;22(3)

Department of Pediatrics, Endocrinology and Diabetes, Medical University of Silesia.

Background: The prevalence of antibodies to pancreatic islets in monogenic diabetes remains unknown and the incidence estimation is difficult as the occurrence of autoantibodies in patient is one of the well-known exclusion criteria for further genetic diagnostics. They has been found not only among patients with type 1 diabetes, but also in other types of diabetes: Type 2 diabetes, Latent Autoimmune Diabetes in Adults (LADA) (16) and monogenic diabetes (MD).

Aim: Immunological characteristic of GCK MODY patients.

Methods: The study group included families of 27 adolescent patients with GCK MODY (39 parents and 19 siblings) monitored in the Department of Pediatrics, Endocrinology and Diabetes and in the Diabetes Clinic of John Paul II Upper Silesian Child Health Centre in Katowice in the years 2007-2012. All patients and family members with GCK MODY underwent a blood sample drawing for immunological (classic humoral response markers: ICA, GAD, IA-2, IAA) and biochemical diagnostics. Pediatric, diabetes and family medical history was collected from the subjects and parents.

Results: Immunological diagnostics was performed in all patients except 1 (96.3%). Immunological diagnostics included 17 (89.5%) parents and 7 (87.5%) siblings with diagnosed GCK MODY. 8 (30.8%) adolescent patients with GCK MODY, 3 subjects (17.64%) among parents (with GCK MODY), as well as 2 subjects (28.57%) among siblings (with GCK MODY) showed a positive antibodies screen.

Conclusion: The results of our study in children with GCK MODY and their family members suggest that the occurrence of classic antibodies directed against pancreatic islets antigens is fairly common in patients with GCK MODY. Despite various observations and many legitimate discussions, it is difficult to clarify the pathogenesis of the occurrence of autoantibodies in monogenic diabetes.
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http://dx.doi.org/10.18544/PEDM-22.03.0056DOI Listing
March 2018

The Pro12Ala PPARg2 gene polymorphism involves residual C-peptide secretionand BMI in type 1 diabetes.

Pediatr Endocrinol Diabetes Metab 2015 ;20(3):88-94

Department of Pediatrics, Oncology, Hematology and Diabetology, Medical University of Lodz, Poland.

Introduction And Aim: Since insulin resistance is genetically determined and observed in type 1 diabetes, the study was designed to elucidate an involvement of Ala 12 Pro PPARg2 gene polymorphism in residual C-peptide secretion and BMI variation in children with type 1 diabetes.

Material And Methods: In 103 patients with type 1 diabetes genetic analysis of PPARg2 polymorphism, C-peptide measurements and evaluation of BMI and clinical parameters were performed. Control group consisted of 109 healthy subjects.

Results: In diabetic patients, only three individuals exhibited Ala 12 Ala genotype (2.9%) and 29 patients were heterozygous Ala 12 Pro (28.2%). Interestingly, Ala12+ variants were associated with higher C-peptide levels in 6 th , 12 th and 24 th months after the onset than Pro 12 Pro genotype (0.39±0.24 pmol/mL vs. 0.22±0.14 pmol/mL, P=0.007 and 0.19±0.09 vs. 0.11±0.07, P=0.01 and 0.13±0.09 vs. 0.07±0.05, P=0.021, respectively). Similarly, C-peptide was also significantly increased in patients with history of type 2 diabetes in the first-degree relatives. The observation was even more evident when Ala12+ variants were taken together with family history of type 2 diabetes. Besides, in 24 th and 36 th months after the onset, Ala12+ variants revealed to be associated with higher BMI normalized by age and sex as compared to Pro 12 Pro (0.557±0.84 vs. -0.119±0.73, P=0.001 and 0.589±0.919 vs. 0.066±0.630, P=0.016, respectively).

Conclusions: Thus, it is likely that PPARg2 gene polymorphism and/or the genetically determined insulin resistance may be associated with residual C-peptide secretion and involve excessive BMI in type 1 diabetes.
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http://dx.doi.org/10.18544/PEDM-20.03.0007DOI Listing
September 2017

Atypical phenotypic features among carriers of a novel Q248X nonsense mutation in the HNF1B gene.

Endokrynol Pol 2015 ;66(1):15-21

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

Introduction: Hepatocyte transforming factor 1B-maturity onset diabetes mellitus of the young (HNF1B-MODY) is an autosomal dominant type of monogenic diabetes caused by a mutation in the gene encoding hepatocyte nuclear factor 1beta (HNF-1beta). The aim of this study was to determine if a HNF1B gene mutation was responsible for a dominantly inherited form of diabetes mellitus among the members of a three-generation Polish family.

Material And Methods: The index subject was a 13-year-old boy with metabolic syndrome, spina bifida occulta, posterior urethral valves, congenital ureteropelvic junction obstruction, and a family history of diabetes of autosomal dominant trait of inheritance. We performed clinical and laboratory examinations of his family and sequenced the HNF1B gene.

Results: A novel Q248X mutation (nucleotide C to T transition at position 742 of the exon 3 of HNF1B gene, resulting in stop codon formation) was identified. Phenotypes of family members sharing this mutation are highly variable, and include previously known abnormalities of the urinary system and pancreas, diabetes mellitus of variable onset and severity, hyperinsulinaemia, insulin resistance, metabolic syndrome, elevated aminotransferases, hyperbilirubinemia, hyperamylasemia, short stature and cataracts. To the best of our knowledge, spina bifida occulta, pectus carinatum, and splenomegaly have not been previously reported.

Conclusions: Our results broaden the spectrum of HNF1B gene mutations and HNF1B-MODY-related phenotypes.
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http://dx.doi.org/10.5603/EP.2015.0004DOI Listing
January 2017

Chromosome 18q deletion syndrome with autoimmune diabetes mellitus: putative genomic loci for autoimmunity and immunodeficiency.

Pediatr Diabetes 2016 Mar 18;17(2):153-9. Epub 2014 Nov 18.

Department of Pediatrics, Oncology, Hematology and Diabetology, Medical University of Lodz, Lodz, Poland.

A girl with 18q deletion syndrome was diagnosed with autoimmune diabetes mellitus and Hashimoto's thyroiditis at the age of 3 yr. In addition, the girl suffered from recurrent infections due to immunoglobulin A and IgG4 deficiency. She was also found to have CD3+CD4+FoxP3+, CD3+CD4+FoxP3+CD25+, and CD3+CD4+CD25+CD127 regulatory T cells deficiency. The exceptional coincidence of the two autoimmune disorders occurring at an early age, and associated with immune deficiency, implies that genes located on deleted 19.4 Mbp region at 18q21.32-q23 (chr18:58,660,699-78,012,870) might play a role in the pathogenesis of autoimmunity leading to β cell destruction and diabetes.
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http://dx.doi.org/10.1111/pedi.12235DOI Listing
March 2016

Chemokine receptor CXCR3 ligands in bronchoalveolar lavage fluid: associations with radiological pattern, clinical course, and prognosis in sarcoidosis.

Pol Arch Med Wewn 2014 23;124(7-8):395-402. Epub 2014 May 23.

Introduction:  Sustained inflammation in sarcoidosis may lead to lung fibrosis. The activity of numerous chemokines responsible for proliferation and activity of T lymphocytes may play a crucial role in this process and may have predictive value. These include cytokines induced by interferon γ, such as CXCL9, 10, and 11-ligands of chemokine receptor CXCR3.

Objectives:  The aim of the study was to estimate the role of CXCR3 ligands in the pathogenesis of sarcoidosis and the predictive value of their concentrations in bronchoalveolar lavage (BAL) fluid. 

Patients And Methods:  CXCL9, 10, and 11 concentrations in BAL fluid were measured by an enzyme‑linked immunosorbent assay in patients with sarcoidosis (n = 59) and controls (n = 34). A total of 46 patients were followed up for 24 months to compare the results between the subgroups with complete remission and with chronic disease.

Results:  Protein-standardized CXCL11 concentrations in BAL fluid from patients with stage II sarcoidosis were higher than in those with stage I (median [interquarile range], 0.95 [0.26-2.39] vs. 0.32 [0.13-0.74] pg/μg protein, P = 0.02). CXCL10 levels in BAL fluid from patients without Löfgren syndrome were higher compared with those the syndrome (0.69 [0.51-1.05] vs. 0.40 [0.27-0.70] pg/μg protein, P = 0.05). None of these markers predicted the chronic course of the disease. CXCL10 levels in BAL fluid correlated with serum angiotensin‑converting enzyme, and CXCL11 levels with parenchymal lesions on high‑resolution computed tomography. Only nonstandardized CXC11 concentrations in BAL fluid were higher in sarcoidosis.

Conclusions:  Our results support the hypothesis that cytokines CXCL9, 10, and 11 may be involved in the pathogenesis of chronic sarcoidosis. However, the lack of notable differences between the sarcoidosis and control groups, as well as the lack of associations with the chronic course suggest that they should not be considered as potential prognostic markers.  
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http://dx.doi.org/10.20452/pamw.2349DOI Listing
October 2016

Are zinc transporter type 8 antibodies a marker of autoimmune thyroiditis in non-obese adults with new-onset diabetes?

Eur J Endocrinol 2014 Apr 14;170(4):651-8. Epub 2014 Mar 14.

Departments of Internal Medicine and Diabetology.

Objective: The diagnosis of autoimmune diabetes in non-obese adults is based on the detection of glutamic acid decarboxylase autoantibodies (GADA), islet cell antibodies (ICA) and antibodies to tyrosine phosphatase (IA-2A). Zinc transporter 8 (ZnT8) has been identified as a new autoantigen in patients with type 1 diabetes mellitus. The coincidence of autoimmune thyroiditis (AITD) with diabetes is common; therefore, screening of TSH and thyroid peroxidase antibodies (ATPO) is recommended during the diagnosis of diabetes. In this study, we determined whether the occurrence of islet autoantibodies is associated with a positive titre of ATPO in newly diagnosed adult-onset autoimmune diabetic patients.

Design And Methods: THE STUDY INVOLVED 80 NON-OBESE ADULTS AGED 44 (INTERQUARTILE RANGE (IQR): 37-51) years with a BMI of 24.0 (IQR: 22.2-26.0) kg/m(2) and new-onset diabetes. The markers of autoimmune diabetes (GADA, ICA, IA-2A and ZnT8A), TSH and thyroid peroxidase antibodies (ATPO) were evaluated.

Results: IN THE STUDY POPULATION, 70% (N=56) OF THE SUBJECTS WERE POSITIVE FOR AT LEAST ONE OF THE FOUR ASSESSED MARKERS OF AUTOIMMUNE DIABETES (83.9% GADA, 62.5% ICA, 42.8% IA-2A AND 33% ZNT8A) AND 37.5% OF THE SUBJECTS WERE POSITIVE FOR ATPO. THE ZNT8A-POSITIVE SUBJECTS HAD HIGHER ATPO TITRES THAN THE ZNT8A-NEGATIVE SUBJECTS (172.7 (IQR: 0.36-410.4) vs 92.4 (IQR: 0-23.7) IU/ml, P=0.001). Based on the assessed islet autoantibodies, the occurrence of positive ZnT8A and GADA was found to be related to a positive titre of ATPO using logistic regression (OR=5.48, 95% CI: 1.65-18.14, P=0.006 and OR=3.42, 95% CI: 1.09-10.71, P=0.03 respectively).

Conclusions: In non-obese adults with new-onset diabetes, the presence of GADA and especially ZnT8 autoantibodies increases the risk of AITD.
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http://dx.doi.org/10.1530/EJE-13-0901DOI Listing
April 2014

Interleukin 18 as a marker of chronic nephropathy in children after anticancer treatment.

Dis Markers 2013 27;35(6):811-8. Epub 2013 Nov 27.

Department of Pediatrics, Oncology, Hematology and Diabetology, Medical University of Lodz, 91-738 Łódź, Poland.

Novel markers of nephrotoxicity, including kidney injury molecule 1 (KIM-1), interleukin 18 (IL-18), and beta-2 microglobulin, were used in the detection of acute renal injury. The aim of the study was to establish the frequency of postchemotherapy chronic kidney dysfunction in children and to assess the efficacy of IL-18, KIM-1, and beta-2 microglobulin in the detection of chronic nephropathy. We examined eighty-five patients after chemotherapy (median age of twelve years). The median age at the point of diagnosis was 4.2 years, and the median follow-up time was 4.6 years. We performed classic laboratory tests assessing kidney function and compared the results with novel markers (KIM-1, beta-2 microglobulin, and IL-18). Features of subclinical renal injury were identified in forty-eight children (56.3% of the examined group). Nephropathy, especially tubulopathy, appeared more frequently in patients treated with ifosfamide, cisplatin, and/or carboplatin, following nephrectomy or abdominal radiotherapy (P = 0.14, P = 0.11, and P = 0.08, resp.). Concentrations of IL-18 and beta-2 microglobulin were comparable with classic signs of tubulopathy (P = 0.0001 and P = 0.05). Concentrations of IL-18 were also significantly higher in children treated with highly nephrotoxic drugs (P = 0.0004) following nephrectomy (P = 0.0007) and abdominal radiotherapy (P = 0.01). Concentrations of beta-2 microglobulin were higher after highly toxic chemotherapy (P = 0.004) and after radiotherapy (P = 0.02). ROC curves created utilizing IL-18 data allowed us to distinguish between children with nephropathy (value 28.8 pg/mL) and tubulopathy (37.1 pg/mL). Beta-2 microglobulin and IL-18 seem to be promising markers of chronic renal injury in children after chemotherapy.
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http://dx.doi.org/10.1155/2013/369784DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3860090PMC
July 2014

Assessment of interleukin-6, interleukin-8 and interleukin-18 count in the serum of IUGR newborns.

J Matern Fetal Neonatal Med 2014 Jul 29;27(11):1142-5. Epub 2013 Nov 29.

Department of Neonatology, Medical University of Lodz , Lodz , Poland .

Aim: Aim of this study was to assess concentrations of interleukin-6 (IL-6), interleukin-8 (IL-8) and interleukin-18 (IL-18) in the serum of newborns with diagnosed intrauterine growth restriction (IUGR) in comparison to concentrations in serum of newborns with weight appropriate for gestational age (AGA).

Materials: Research was conducted at the Lodz Medical University Clinic of Neonatology during 2010-2011. Surveyed group consisted of 50 hypotrophic full-term infants of single pregnancies (average weight: 2329 ± 287 g); control group, enclosing 50 infants AGA (average weight: 3544 ± 2161 g). Both groups received average Apgar score of 9 points. Concentrations of analysed cytokines were marked between 4-6 hours after birth. The enzyme-linked immunosorbent assay (ELISA) test was used to determine interleukins concentrations. Study was prospective. Statistics on the data were conducted with the Kolmogorov-Smirnov test. Significance level: p < 0.05.

Results: Concentrations of IL-6 and IL-18 were elevated in the IUGR group in a statistically significant manner in comparison to the control group.

Conclusions: An elevated level of IL-6 and IL-18 in the IUGR group, comparing to control group, signifies the existence of inflammation in the process of developing IUGR, therefore, screening tests estimating levels of interleukins as IL-6 and IL-18 might be clinically useful in predicting the occurrence of IUGR and help preventing it.
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http://dx.doi.org/10.3109/14767058.2013.851186DOI Listing
July 2014

Serum tumor necrosis factor-α and interleukin-10 levels as markers to predict outcome of patients with chronic lymphocytic leukemia in different risk groups defined by the IGHV mutation status.

Arch Immunol Ther Exp (Warsz) 2012 Dec 4;60(6):477-86. Epub 2012 Sep 4.

Institute of Hematology and Transfusion Medicine, Indiry Gandhi 14 str, 02-776, Warsaw, Poland.

Tumor necrosis factor (TNF)-α and interleukin (IL)-10 are cytokines involved in the balance between cell-mediated and humoral immunity. We investigated whether serum TNF-α and IL-10 levels have any impact on clinical outcome of patients with chronic lymphocytic leukemia (CLL). TNF-α and IL-10 levels were determined in the serum of 160 CLL patients at the time of diagnosis. The cytokine low-risk group consisted of patients with either TNF-α and IL-10 levels below their medians or those with only one elevated parameter. Both TNF-α and IL-10 levels greater than or equal to their medians defined the cytokine high-risk group. The high-risk patients presented a shorter 3-year treatment-free survival (TFS) than low-risk subjects (15 vs. 69.6 %; p < 0.0001). The high-risk group (p = 0.0002) along with high leukocyte count (p < 0.0001) and unmutated immunoglobulin heavy-chain variable region genes (p < 0.0001) independently predict the risk of progression in patients with Rai stage 0-II. Furthermore, the high-risk group had an independent prognostic impact on shorter TFS both in patients with mutated (24.3 vs. 78.2 %; p < 0.0001) and unmutated (8.2 vs. 49 %; p = 0.004) immunoglobulin heavy-chain variable region genes (IGHV) as compared to the low-risk group. The estimated 5-year overall survival (OS) of high-risk patients was shorter than those in the low-risk group (83.3 vs. 97.1 %; p = 0.003). Multivariate analysis demonstrated the cytokine high-risk group (p = 0.02) followed by Rai stage III-IV (p = 0.048) to be independent factors predicting shorter OS. At diagnosis, TNF-α and IL-10 may predict the outcome of patients with CLL.
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http://dx.doi.org/10.1007/s00005-012-0197-7DOI Listing
December 2012

Increased risk of type 1 diabetes in Polish children - association with INS-IGF2 5'VNTR and lack of association with HLA haplotype.

Endokrynol Pol 2011 ;62(5):436-42

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

Background: Human leukocyte antigens (HLA) complex and INS-IGF2 5'VNTR loci are principal determinants of the risk of type 1 diabetes mellitus (T1DM). Carriage of class III allele is protective, while class I/I homozygosity increases the risk of T1DM.

Material And Methods: HLA and 5'VNTR allele frequencies were summarised and multivariate logistic regression models with interaction evaluation were employed to determine the presence and types of allele effect interdependency. The study group was planned to number 590 children who would undergo genotyping of 5'VNTR and HLA.

Results: 590 patients (302 with T1DM and 288 controls) were recruited. Frequencies of HLA risk alleles were: 117 carriers of DR3-DQ2; 130 carriers of DR4-DQ8 including 43 DR3-DQ2/DR4-DQ8 heterozygotes. In all cases, risk alleles were vastly overrepresented in the T1DM group compared to the controls (p < 0.0001 in all cases). The most frequent protective haplotype was DQB1 × 0602 observed in 24 controls and two T1DM cases (p < 0.001). Class I 5'VNTR homozygotes constituted 58% of the control group (n = 174) and 78% (n = 224) of T1DM patients [OR = 2.63 (95% CI: 1.79-3.57)]. Interactions between 5'VNTR and DR3-DQ2 or DR4-DQ8 variants did not reach statistical significance for risk of developing T1DM (p = 0.54 and 0.24) or age at its diagnosis (p = 0.14 and 0.67 respectively).

Conclusions: Interactions between HLA and 5'VNTR genotype are not of multiplicative character. Class I homozygosity at 5'VNTR is a significant risk factor of T1DM and acts independently from HLA haplotype in determining the actual risk of diabetes in children.
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April 2012

HDL cholesterol as a diagnostic tool for clinical differentiation of GCK-MODY from HNF1A-MODY and type 1 diabetes in children and young adults.

Clin Endocrinol (Oxf) 2011 Sep;75(3):321-7

Department of Pediatrics, Oncology, Hematology and Diabetology, Medical University of Lodz, Lodz, Poland.

Introduction: Confirmation of monogenic diabetes caused by glucokinase mutations (GCK-MODY) allows pharmacogenetic intervention in the form of insulin discontinuation. This is especially important among paediatric and young adult populations where GCK-MODY is most prevalent.

Methods: The study evaluated the utility of lipid parameters in screening for patients with GCK-MODY. Eighty-nine children with type 1 diabetes and 68 with GCK-MODY were screened for triglyceride (TG), total and HDL cholesterol levels. Standardization against a control group of 171 healthy children was applied to eliminate the effect of development. Clinical applicability and cut-off value were evaluated in all available patients with GCK-MODY (n = 148), hepatocyte nuclear factor 1-alpha-MODY (HNF1A MODY) (n = 37) or type 1 diabetes (n = 221).

Results: Lower lipid parameter values were observed in GCK-MODY than in patients with type 1 diabetes. Standard deviation scores were -0·22 ± 2·24 vs 1·31 ± 2·17 for HDL cholesterol (P < 0·001), -0·16 ± 2·14 vs 0·60 ± 1·77 for total cholesterol (P = 0·03) and -0·57 ± 0·97 vs-0·22 ± 0·97 for TG (P = 0·05). Validation analysis confirmed that HDL cholesterol was the best parameter for GCK-MODY selection [sensitivity 87%, specificity 54%, negative predictive value (NPV) 86%, positive PV 56%]. A threshold HDL concentration of 1·56 mm offered significantly better diagnostic efficiency than total cholesterol (cut-off value 4·51 mm; NPV 80%; PPV 38%; P < 0·001). TG did not offer a meaningful cut-off value.

Conclusions: HDL cholesterol levels measured in individuals with likely monogenic diabetes may be useful in screening for GCK-MODY and differentiation from T1DM and HNF1A-MODY, regardless of treatment or metabolic control.
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http://dx.doi.org/10.1111/j.1365-2265.2011.04052.xDOI Listing
September 2011

The 5'VNTR proinsulin gene (INS) polymorphism and the functional reserve of β cells in the intravenous glucose tolerance test.

Pediatr Endocrinol Diabetes Metab 2011 ;17(1):5-9

Department of Pediatrics, Medical University of Lodz, Poland.

Introduction: Proinsulin 5'VNTR polymorphism determines susceptibility to type 1 diabetes (T1DM). The authors tested whether it affects intravenous glucose tolerance test (IVGTT) results.

Aim Of The Study: To evaluate a possible relationship between 5'VNTR proinsulin gene (INS) polymorphism and glucose, insulin and C-peptide levels during IVGTT among siblings of children suffering from T1DM.

Material And Methods: Fourteen patients - siblings of children with type 1 diabetes, positive for at least one autoantibody, underwent IVGTT with glucose, insulin and C-peptide concentrations measurement.

Results: Mean age of patients equaled 10.71 ± 4.15 years. Eight individuals were homozygous for class I/I and six were class III/I heterozygotes. No significant differences in blood glucose levels during the IVGTT were observed (p=0.67). However, lower insulin (p=0.03) and C-peptide (p=0.01) levels were observed in I/I homozygotes in post-challenge timepoints. No significant differences were observed in baseline fasting insulin, glucose and C-peptide levels.

Conclusions: The class III allele in the 5'VNTR promoter region of INS is associated with a greater functional reserve of β cells in response to a direct hyperglycemic stimulus in individuals with a familial background of T1DM.
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June 2011

Free fatty acids level may effect a residual insulin secretion in type 1 diabetes.

Pediatr Endocrinol Diabetes Metab 2011 ;17(1):26-9

Department of Pediatrics, Medical University of Lodz, Poland.

Introduction: Recent studies on the pathogenesis of type 1 diabetes (T1DM) show that autoimmune activity in human pancreatic 1-cells is accompanied by abnormalities of fatty tissue metabolism, which is the underlying process in type 2 diabetes.The aim of the study was to determine the correlation between C-peptide concentration, indicating residual insulin secretion, and free fatty acids (FFA) level in children with T1DM.

Material And Methods: We recruited 178 diabetic patients (mean age 10.8 years; M/F 99/79). In all individuals the fasting C-peptide by a radioimmunological method and FFA serum levels using an enzymatic colorimetric method were measured at the onset and after 6 months of the diabetes duration.

Results: Thirty four (19.1%) of the patients had the C-peptide level above the lower limit of normal range (>0.28 pmol/ml) at both time points. FFA level at onset was significantly higher as compared to the level after 6 months of follow-up (38.4+29.4 vs. 28.9 ± 23.1 mg/dl; p=0.0003). However, both values were positively correlated (r=0.31; p=0.0008). Interestingly, a negative correlation was found between FFA and C-peptide measurements at onset (r=-0.19; p=0.01) and at 6th month of the disease (r=-0.18; p=0.02). Moreover, when the C-peptide level was treated as a binominal variable(above and below 0.28 pmol/ml) higher levels of FFA were observed in children with C-peptide deficiency at onset of diabetes (41.1 vs. 29.9 mg/dl; p=0.03) and a similar trend was noticed at 6th month of the disease (31.0 vs. 23.7 mg/dl; p=0.1). No relation of FFA with age at onset, gender,insulin requirement and HbA1c were revealed.

Conclusions: The obtained results, which link the FFA level with residual insulin secretion in T1DM,may serve as further evidence supporting the contribution of fatty tissue metabolism in the patho-genesis of T1DM.
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June 2011