Anna Wędrychowicz

Insulin-Like Growth Factor-1 and Its Binding Proteins, IGFBP-1 and IGFBP-3, in Adolescents with Type-1 Diabetes mellitus and Microalbuminuria

Background/Aims: Numerous clinical and experimental studies suggest that growth factors may contribute to the development of diabetic microvascular complications. The aim of the study was to test the hypothesis that in adolescents with type-1 diabetes mellitus and microalbuminuria (MA) there are specific disorders of serum insulin-like growth factor-1 (IGF-1) and concentrations of its binding proteins, IGFBP-1 and IGFBP-3, that could be of importance in the pathogenesis of microvascular diabetic complications. Methods: 25 adolescents with MA, 24 adolescents with diabetes without complications, and 17 controls were examined. There were no differences with regard to age, puberty stage, HbA1c and body mass index between the groups examined. Two of the patients in the first group also had diabetic retinopathy. Serum fasting concentrations of IGF-1 and overnight urine albumin concentrations were measured by radioimmunoassay, IGFBP-1 and IGFBP-3 concentrations by immunoradiometric assay and HbA1c by high-performance liquid chromatography methods. Diabetic patients were examined by an experienced ophthalmologist and neurologist. The data were analyzed using Kruskal-Wallis ANOVA and multiple regression analysis. Results: Significantly lower IGF-1 concentrations were found in adolescents with diabetes and MA compared to diabetic patients without complications and healthy contemporaries. IGFBP-1 concentrations were significantly higher and IGFBP-3 concentrations were statistically lower in diabetic patients with MA than in patients without complications. Conclusions: The IGF-IGFBP system is deranged in adolescents with type-1 diabetes mellitus and MA. Our results suggest the participation of circulating IGFBP-1 in the origin of diabetic complications. It could be also possible that IGFBP-3 takes part in the protection from them.

Continuous Improvement after Multiple Mesenchymal Stem Cell Transplantations in a Patient with Complete Spinal Cord Injury

Interruption of spinal cord (SC) continuity leads to functional loss below the lesion level. The purpose of this study was to evaluate the safety and efficacy of bone marrow nucleated cell (BMNC) and multiple mesenchymal stem cell (MSC) transplantations in spinal cord injury (SCI). A patient with total SC interruption at the Th2-3 level underwent experimental therapy with BMNC and MSC transplantations followed with intensive neurorehabilitation treatment. At admission, 6 h after SCI, the patient was scored ASIA A, had a Th1 sensation level, paraplegia with sphincter palsy, and was without the ability to control trunk movement. Neurophysiology examination showed bilateral axonal damage to the motor and sensory neural fibers with no motor unit potentials or peripheral motor nerve conduction in the lower extremities. The standard therapy had been applied and had not produced any positive results. The patient was treated with autologous BMNCs injected intravenously (3.2 × 109) and intrathecally (0.5 × 109) 10 weeks after the SCI and with five rounds of MSCs every 3-4 months (1.3-3.65 × 107) administered via lumbar puncture. Total number of transplanted MSC cells during the course of treatment was 1.54 × 108. There were no complications related to transplantations and no side effects related to the therapy during 2 years of treatment. The ASIA score improved from A to C/D (from 112 to 231 points). The sensation level expanded from Th1 to L3-4, and the patients ability to control the body trunk was fully restored. Bladder filling sensation, bladder control, and anal sensation were also restored. Muscle strength in the left lower extremities improved from plegia to deep paresis (1 on the Lovett scale). The patients ability to move lower extremities against gravity supported by the movements in quadriceps was restored. The patient gained the ability to stand in a standing frame and was able to walk with the support of hip and knee ortheses. Magnetic resonance imaging (MRI) revealed that at the Th2/Th3 level, where the hemorrhagic necrosis was initially observed, small tissue structures appeared. Our results suggest that repeated intrathecal infusions of MSCs might have the potential to produce clinically meaningful improvements for SCI patients.

Associations between Bone, Fat Tissue and Metabolic Control in Children and Adolescents with Type 1 Diabetes Mellitus

AIMS To investigate the relationship between bone-derived osteocalcin (OC), osteoprotegerin (OPG), Receptor Activator of Nuclear Factor NF-ĸB ligand (RANKL), and fat tissue-derived leptin and adiponectin with a clinical outcome of type 1 diabetes mellitus (T1DM) in children and adolescents. METHODS 78 patients (43 girls and 35 boys), aged 11.5±4.3 years with T1DM and 11 age- and BMI-matched controls were included into the study. Patients were divided into 3 groups according to HbA1c level, I - below 7% [53 mmol/mol], II - 7-9% [53-75 mmol/mol] and III - above 9% [75 mmol/mol]. Blood samples for biochemical measurements were drawn at 8.00 AM, when the patients were in a fasting state. HbA1c was measured by the standardized IFCC method. OC, OPG, RANKL, leptin and adiponectin were measured by ELISA. ANOVA, and multiple regression analysis were used for statistical analysis. RESULTS Significant differences in leptin and osteocalcin levels between groups with different HbA1c values were observed (p=0.03, p=0.04). Multiple regression analysis adjusted for age showed that serum OC and leptin negatively correlated with HbA1c levels (r=-0.22, p=0.004 and r=-0.27, p=0.0001, respectively). In contrast, serum OPG correlated positively with HbA1c (r=0.26, p=0.02) as well as with adiponectin (r=0.26, p=0.02) and RANKL (r=0.27, p=0.02) levels. The correlation of OC with HbA1c was the strongest in group I - patients with good metabolic control of DM (r=-0.43, p=0.03). In that group, in multiple regression analysis adjusted for age and BMI leptin correlated positively with daily dose of insulin (r=0.52, r=0.009). In group II and III in multiple regression analysis adjusted for age and BMI OC correlated negatively with leptin (r=-0.37, p=0.01). CONCLUSIONS Our data suggest significant relationships between bone, fat tissue and glucose metabolism in pediatric patients with T1DM. The results can confirm that poor metabolic control is associated with reduced bone formation. On the other hand fat and bone tissue can influence glucose metabolism, potentiality in insulin-dependent manner. From these data leptin or OC may be potentially used as additional therapeutic agents for T1DM.

Like-Triple Diabetes as First Manifestation of MODY2 in an Overweight Teenager With Transient Multiple Antibodies

Patients with heterozygous inactivating mutations in the gene encoding glucokinase, which causes type 2 maturity-onset diabetes of the young (MODY2), have mild fasting hyperglycemia that usually remains considerably stable during life and requires only diabetic diet as treatment. Atypical course of disease is uncommon. An 11-year-old, prepubertal, Caucasian overweight boy (BMI 22.5 kg/m2) with gynecomastia/steatomastia and diabetes was diagnosed on the basis of an oral glucose tolerance test without any typical symptoms (2-h blood glucose 215 mg/dL). Insulin levels were quite high (fasting 17.1 IU/mL, 2-h 114 IU/mL). Since 6 years of age he had been treated for Asperger syndrome, currently with risperidone. His family history was positive for diabetes in the previous three generations. At the time of diabetes diagnosis, dyslipidemia with elevated total cholesterol (212 mg/dL), triglycerides (150 mg/dL), and LDL cholesterol (133.1 mg/dL) was observed. Diabetes autoantibodies were significantly positive: islet antigen 2 antibodies …

Diabetes Mellitus after Allogeneic Hematopoietic Stem Cell Transplantation

Survivors of pediatric hematopoietic stem cell transplantation (HSCT) are known to be at risk of developing endocrine abnormalities, but occurrence of diabetes mellitus (DM) is a relatively recent observation. We present a 17.5-year-old girl with DM after high-dose radio- and chemotherapy followed by allogeneic HSCT for the treatment of acute lymphoblastic leukemia, diagnosed when she was 10 years old. In the posttransplantation period, multiple acute and chronic complications occurred. Among them, we observed graft versus host disease requiring corticosteroid therapy, pancreatitis and some endocrine complications like primary hypothyroidism, growth hormone deficiency and hypergonadotropic hypogonadism. DM with some components of metabolic syndrome-like insulin resistance, high arterial blood pressure and dyslipidemia developed during the first year after HSCT. Five years later, a trend towards increased requirement of insulin with deterioration in metabolic control of DM was observed, despite a normal level of C-peptide and negative diabetes autoantibodies. After the addition of metformin to continuous subcutaneous insulin infusion in the therapy of DM, an improvement in metabolic control was observed. Due to the possible mechanism of insulin resistance which is associated with impaired insulin receptors after HSCT procedure, metformin with insulin appears to be effective in the treatment of this type of diabetes.

Sclerostin and its association with insulin resistance in children and adolescents

INTRODUCTION Recent studies have shown that sclerostin, which is mainly known as a negative regulator of bone formation, could play an important role in the crosstalk between bone and glucose metabolism. The aim of this study was to investigate the relationship between sclerostin, other bone and fat related factors as osteocalcin (OC), Receptor Activator of Nuclear Factor NF-қB ligand (RANKL), leptin and adiponectin with glucose metabolism and insulin action in children and adolescents with obesity compared with healthy children and adolescents. METHODS Fifty-five obese children and adolescents, a mean age of 13.2 ± 3.4 yrs., BMI 28.89 ± 5.5 kg/m2, and 26 healthy controls (mean age 13.0 ± 4.3 yrs., BMI 19.96 ± 3.1 kg/m2), sex-, and Tanner stage-matched were included into the study. Fasting blood samples for measurement of sclerostin, glucose, lipid profile, HbA1c, C-peptide, OC, RANKL, leptin and adiponectin, and vitamin D were taken at 8.00 AM. RESULTS Sclerostin, osteocalcin, RANKL, and adiponectin levels did not differ between obese patients and the control group. Leptin and fasting insulin levels were significantly higher in obese subjects compared with controls (p < 0.01, p = 0.01, respectively). A positive correlation between sclerostin and OC (r = 0.417, p = 0.027) and negative correlations between sclerostin and HOMA-IR and between sclerostin and age (r = -0.24, p = 0.045, r = -0.23, p = 0.037, respectively) were found in all of the subjects. Sclerostin did not correlate with HbA1c, lipids, RANKL and fat-derived leptin and adiponectin. Partial correlation analysis adjusted for age, SDS-BMI and Tanner staging only revealed a negative correlation between sclerostin and HOMA-IR (r = -0.3, p = 0.01). In obese patients this correlation was stronger than in the whole group (r = -0.39, p = 0.005). Moreover, a negative correlation between sclerostin and insulin was found in obese patients (r = -0.39, p = 0.006). In the healthy cohort, sclerostin had a negative correlation only with C-peptide (r = -0.79, p = 0.02). CONCLUSIONS Sclerostin could play an important role in the regulation of glucose metabolism in children and adolescents, regardless of other fat and bone-derived factors. In obese young patients its action could be associated with decreasing insulin resistance.

Sclerostin and its significance for children and adolescents with type 1 diabetes mellitus (T1D)

INTRODUCTION Recent studies have shown that sclerostin, which is a negative regulator of bone formation, could play an important role in the crosstalk between bone and glucose metabolism. The role of sclerostin and its link with glucose homeostasis in type 1 diabetes mellitus (T1D) has not been yet studied extensively in children. The aim of this study was to assess sclerostin and its relationship between other bone and fat related factors as well as glucose metabolism in children and adolescents with T1D in comparison to their healthy peers. METHODS Forty patients with T1D, 18 girls, mean age 12.3 ± 4.7 yrs, and 28 healthy as controls (13.1 ± 4.2 yrs), sex and Tanner stage-matched were included into the study. Fasting blood samples for measurement of sclerostin, osteocalcin (OC), leptin, adiponectin, vitamin D, fasting glucose, lipid profile, HbA1c, and C-peptide were taken at 8.00 AM. RESULTS Sclerostin levels were significantly higher in patients with T1D than in the control group (p = 0.04) without significant differences between genders. Pearson correlation coefficients revealed a positive association between serum sclerostin levels and leptin OC (r = 0.59, p < 0.001) and a negative correlation between serum sclerostin levels and leptin (r = -0.32, p = 0.02) in all of the subjects and no significant correlations between sclerostin and adiponectin, 25(OH)D3, nor lipids. In the group of T1D patients a strong positive association between serum sclerostin levels and OC (r = 0.62, p < 0.001), and a negative association between serum sclerostin levels and HbA1c and leptin levels (r = -0.33, p = 0.04; r = -0.33, p = 0.03, respectively) were found. These associations were significant also after adjusting the analysis to the age, SDS-BMI and Tanner staging. In the healthy group after adjustment to age, SDS-BMI and Tanner stage, a negative correlation between sclerostin and C-peptide (r = -0.79, p = 0.02) was found. CONCLUSIONS Our data suggest a possible relationship between sclerostin and glucose metabolism in children and adolescents with T1D. It would be worth to investigate if an increase in sclerostin levels could present as a potential cause of the reduction of bone formation in T1D. Both bone-derived OC as well as fat-derived leptin seems to possibly modulate the participation of sclerostin in metabolic regulation in T1D.

Phenotype Heterogeneity in Glucokinase–Maturity-Onset Diabetes of the Young (GCK-MODY) Patients

Objective: The aim of the study was to evaluate the clinical phenotypes of glucokinase-maturity-onset diabetes of the young (GCK-MODY) pediatric patients from Southwest Poland and to search for phenotype-genotype correlations. Methods: We conducted a retrospective analysis of data on 37 CGK-MODY patients consisting of 21 girls and 16 boys of ages 1.9-20.1 (mean 12.5±5.2) years, treated in our centre in the time period between 2002 and 2013. Results: GCK-MODY carriers were found in a frequency of 3% among 1043 diabetes mellitus (DM) patients and constituted the second most numerous group of DM patients, following type 1 DM, in our centre. The mean age of GCK-MODY diagnosis was 10.4±4.5 years. The findings leading to the diagnosis were impaired fasting glucose (IFG) (15/37), symptoms of hyperglycemia (4/37), and a GCK-MODY family history (18/37). Mean fasting blood glucose level was 6.67±1.64 mmol/L. In the sample, there were patients with normal values (4/37), those with DM (10/37), and IFG (23/37). In OGTT, 120 min glucose level was normal in 8, diabetic in 2, and characteristic for glucose intolerance in 27 of the 37 cases. Twelve of the 37 cases (32%) were identified as GCK-MODY carriers. In the total group, mean C-peptide level was 2.13±0.65 ng/mL and HbA1c was 6.26±0.45% (44.9±-18 mmol/mol). Thirty-two patients had a family history of DM. DM autoantibodies were detected in two patients. The most common mutations were p.Gly318Arg (11/37) and p.Val302Leu (8/37). There was no correlation between type of mutations and plasma glucose levels. Conclusion: The phenotype of GCK-MODY patients may vary from those characteristic for other DM types to an asymptomatic state with normal FG with no correlation with genotype.

The role of Insulin-like Growth Factor 1, Receptor Activator for Nuclear Factor κB ligand — Osteoprotegerin system, Interleukin 6 and 1β in post-transplantation bone metabolic disease in childhood

INTRODUCTION Bone disorders observed commonly after haematopoietic stem cells transplantation (HSCT) can be caused by several factors,but their detailed pathomechanism is still not well known, especially in childhood.The aim of this study was to evaluate: IGF-I, RANKL-OPG system, IL-6, and IL1β levels and their association with bone mineral density(BMD) in children and adolescents after HSCT. MATERIAL AND METHODS Thirty five patients after allogeneic (N = 21) and autologous (N = 14) HSCT, mean age 8.48 ± 5.18 years, wereincluded in the study. Blood samples were taken before HSCT, on the transplantation day, three and six months after HSCT, then eachyear after HSCT for 2-8 years. RANKL, OPG, and IL-1β, IGF-1, and IL-6 were measured by immunochemistry. Total BMD was evaluatedsix months after HSCT using dual energy X-ray absorptiometry, then annually. RESULTS All Z-core values for BMD were negative in all patients. It was significantly higher in patients after auto HSCT than after allo HSCT.Serum levels of IGF-1 and IL-6 significantly changed after HSCT. IGF-I levels started to increase in the second year after transplantation.IL-6 increased up to 12 months after transplantation. Dynamic although not significant changes of OPG and RANKL levels were observedafter HSCT. RANKL and IGF-1 values correlated with BMD. IL-6 correlated positively with IL-1β but both did not correlate with BMD. CONCLUSIONS Our data indicates that factors influencing bone remodelling change dynamically in the post-transplantation period.It suggests that serum RANKL and IGF-1 levels could be markers of bone metabolism after HSCT in paediatric patients.