Iwona Pietrzak

Sulfonylurea improves CNS function in a case of intermediate DEND syndrome caused by a mutation in KCNJ11

Background A 12-week-old female presented with neonatal diabetes. Insulin therapy alleviated the diabetes, but the patient showed marked motor and mental developmental delay. The patient underwent genetic evaluation at the age of 6 years, prompted by reports that mutations in the KCNJ11 gene caused neonatal diabetes.Investigations Genomic sequencing of the ATP-sensitive potassium (KATP) channel gene KCNJ11 and in vitro functional analysis of the channel defect, and single-photon emission CT imaging before and after glibenclamide therapy.Diagnosis Genetic evaluation revealed a missense mutation (His46Leu) in KCNJ11, which encodes the Kir6.2 subunit of the KATP channel, conferring reduced ATP sensitivity. Functional studies demonstrated that the mutant channels were strongly inhibited by the sulfonylurea tolbutamide.Management Sulfonylurea (glibenclamide) treatment led to both improved glucose homeostasis and an increase in mental and motor function.

Insulin sensitivity in Type 1 diabetic children and adolescents.

Aim  To estimate insulin sensitivity in Type 1 diabetic children and adolescents, and assess the relationship between insulin sensitivity and clinical markers of adiposity and parameters of the metabolic syndrome.

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

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.

Wolfram syndrome in the Polish population: novel mutations and genotype–phenotype correlation

Objective  Wolfram syndrome is a rare form of diabetes mellitus associated with optic atrophy and disorders of different organs (e.g. diabetes insipidus, hearing loss, ataxia, anaemia and many others). This syndrome is caused by recessive mutations in the wolframin gene (WFS1) localized on chromosome 4p16·1. The aim of this study was to identify the causative mutations in WFS1 in a group of Polish patients with suspected Wolfram syndrome.

Delayed recognition of Wolfram syndrome frequently misdiagnosed as type 1 diabetes with early chronic complications.

AIMS Improvements in diagnostic methods and greater genetic awareness have brought remarkable progress in the recognition of monogenic forms of diabetes, including Wolfram syndrome (WFS). WFS is diagnosed based on clinical criteria of coexistence of diabetes mellitus and optic atrophy, and confirmed by molecular analysis; however, the condition is still sometimes misdiagnosed. To begin to understand the reasons for misdiagnosis, we conducted a retrospective analysis of WFS patients who were originally misdiagnosed. MATERIALS AND METHODS The medical histories of 13 pediatric patients with clinical misdiagnosis of type 1 diabetes and early chronic complications made in the years 1995-2010 and who were subsequently correctly diagnosed with WFS based on genetic testing in 2008-2011 were analyzed. RESULTS The average age of the patients at diabetes onset was 5 (4.4-6.3) years, and the mean HbA1c level at diagnosis was 9.1±2.3%. Initially, all of these patients were treated as having type 1 diabetes with progressive visual impairment despite good metabolic control (mean HbA1c 7.5±1.3%). Diagnosis of optic atrophy was made at an average age of 9 (5.9-11.5) years, which corresponds to 4 years after diabetes recognition (p=0.002). At the time of genetic analysis, the average age of the patients was 16 (12-18.7) years, which corresponds to 7 years after recognition of coexistence of diabetes mellitus and optic atrophy (p=0.007). CONCLUSIONS Delays of at least 7 years occurred before recognition of WFS among a cohort of pediatric patients with diabetes. All patients with WFS were primarily misdiagnosed as having type 1 diabetes.

Switching to Sulphonylureas in Children With iDEND Syndrome Caused by KCNJ11 Mutations Results in Improved Cerebellar Perfusion

OBJECTIVE Activating mutations in the KCNJ11 gene, encoding the Kir6.2 subunit of the KATP channel, result in permanent neonatal diabetes mellitus. They also may cause neurologic symptoms such as mental retardation and motor problems (iDEND syndrome) and epilepsy (DEND syndrome). Sulphonylurea (SU) treatment is reported to alleviate both the neurologic symptoms and diabetes in such cases. The study aimed to establish the magnitude and functional basis of the effect of SUs on the neurologic phenotype in children with iDEND using neuroimaging before and after insulin replacement with glibenclamide. RESEARCH DESIGN AND METHODS To localize and quantify the effect of glibenclamide administration, we performed single-photon emission computed tomography in seven patients with different mutations in KCNJ11. In five patients, measurements before and after initiation of SU treatment were performed. RESULTS Significant changes in single-photon emission computed tomography signal intensity after transfer to SU therapy were restricted to the cerebellum, consistent with previous data showing high Kir6.2 expression in this brain region. Cerebellar perfusion improved for both left (P = 0.006) and right (P = 0.01) hemispheres, with the mean improvement being 26.7 ± 7.1% (n = 5). No patients showed deterioration of cerebellar perfusion on SU therapy. Electrophysiological studies revealed a good correlation between the magnitude of KATP channel dysfunction and the clinical phenotype; mutant channels with the greatest reduction in adenosine 5′-triphosphate inhibition were associated with the most severe neurologic symptoms. CONCLUSIONS We conclude it is likely that at least some of the beneficial effects of SU treatment on neurodevelopment in iDEND patients result from improved cerebellar perfusion.

Immunogenicity of different brands of human insulin and rapid-acting insulin analogs in insulin-naïve children with type 1 diabetes.

Mianowska B, Szadkowska A, Pietrzak I, Zmysłowska A, Wegner O, Tomczonek J, Bodalski J, Młynarski W. Immunogenicity of different brands of human insulin and rapid‐acting insulin analogs in insulin‐naïve children with type 1 diabetes.

Gender and Age – Dependent effect of type 1 diabetes on obesity and altered body composition in young adults

INTRODUCTION AND OBJECTIVE The aim of the study was to evaluate the influence of age and gender on the prevalence of overweight and obesity, body composition and fatty tissue distribution in young adults with type 1 diabetes. MATERIAL AND METHODS 197 patients with type 1 diabetes aged 20-40 years participated in the study. The control group consisted of 138 healthy adults. Body weight, height, waist and hip circumferences were measured. Analysis of body mass composition was performed using the bioimpedance. Study groups were stratified into cohorts aged <30 and 30+ years. RESULTS Overweight and obesity were diagnosed in 35.5% and 13.2% of diabetic patients and in 26.1% and 7.3% of the control group, respectively (p=0.016). In the whole study group, advanced age (OR=1.10; p<0.001) and diabetes mellitus (OR=2.25; p=0.001) predisposed patients to excess body weight. Women had a lower prevalence of overweight and obesity, but a trend toward excessive body mass was observed in diabetic females (OR=1.18; p=0.181). Diabetic females more often had abdominal obesity than control females (mean difference - 19.2%; p=0.020). Higher total body fat mass was found in the diabetic group (p=0.037). Diabetic females had a higher amount of absolute (p<0.001) and relative body fat mass (p=0.002), fat free mass (p=0.007), relative arm (p=0.007), leg (0<0.001) and trunk (p-=0.006) fat mass than control females. Diabetic males showed only higher relative fat mass of the lower limbs compared to control males (p=0.018). CONCLUSIONS Patients with type 1 diabetes develop overweight and obesity in early adulthood more frequently than the general population and are characterized by higher body fat mass. Gender-related differences in body weight and composition in young type 1 diabetic adults were found.

Neonatal diabetes in a child positive for islet cell antibodies at onset and Kir6.2 activating mutation

In contrast to the autoimmune type 1 diabetes, patients with monogenic diabetes due to KCNJ11 mutations do not have pancreatic auto-antibodies at onset. Here we describe a patient diagnosed at the age of 12 weeks that showed ICA at diagnosis, yet has been tested with positive result for KCNJ11 mutation.

Arterial Stiffness, BMI, Dipping Status and ACE D/I Polymorphism in Type 1 Diabetic Children.

THE AIM of the study was to investigate clinical and genetic determinants of arterial stiffness in children and adolescents with type 1 diabetes mellitus. MATERIAL AND METHODS 122 patients (mean age: 16.0±2.35 years), with an average diabetes duration of 5.0 years and without evidence of arterial hypertension were recruited. Ambulatory arterial stiffness index (AASI) was assessed with 24-h automatic blood pressure monitoring. Body weight, height, HbA1c and plasma lipids were measured. Angiotensin I converting enzyme (ACE) gene insertion (I)/deletion (D) polymorphism was analysed. RESULTS Mean AASI equalled 0.22±0.20 and showed significant, positive correlation with age and BMI-SDS. No association was found between AASI and gender, diabetes duration, daily insulin dose, HbA1c and blood lipids concentration. AASI was higher in non-dippers compared to dippers (0.26±0.18 vs. 0.19±0.18, respectively; p=0.04). In a multivariate model AASI was significantly associated with II homozygosity of ACE gene (p=0.007). CONCLUSIONS In type 1 diabetic children and adolescents AASI is correlated with age and BMI-SDS. Non-dipping status and I-allele were associated with higher arterial stiffness.