Is the urinary neutrophil gelatinase-associated lipocalin concentration in children and adolescents with type 1 diabetes mellitus different from that in healthy children?

Introduction: Diabetic kidney disease (DKD) is one of the major microvascular complications of type 1 diabetes mellitus (T1DM). Some studies suggest that changes of renal tubular components emerge before the glomerular lesions thus introducing the concept of diabetic tubulopathy with urinary neutrophil gelatinase-associated lipocalin (uNGAL) as a potential marker of DKD. This concept was not confirmed in all studies. Materials and methods: In 198 T1DM patients with median age 15 years and diabetes duration over one year, an albumin/creatinine ratio (ACR) was determined and uNGAL measured in spot urine sample. Urine samples for ACR and uNGAL were also collected in the control group of 100 healthy children of similar age. Results: There was no significant difference in uNGAL concentration or uNGAL/creatinine between T1DM children and healthy subjects (6.9 (2.8-20.1) ng/mL vs 7.9 (2.9-21.0) ng/mL, P = 0.969 and 6.8 (2.2-18.4) ng/mg vs 6.5 (1.9-13.4) ng/mg, P = 0.448, respectively) or between T1DM subjects with albuminuria A2 and albuminuria A1 (P = 0.573 and 0.595, respectively). Among T1DM patients 168 (85%) had normal uNGAL concentrations, while in 30 (15%) patients uNGAL was above the defined cut-off value of 30.9 ng/mL. There was no difference in BMI, HbA1c and diabetes duration between patients with elevated uNGAL compared to those with normal uNGAL. Conclusions: We found no significant difference in uNGAL concentration or uNGAL/creatinine between T1DM children and healthy subjects or between albuminuria A2 and albuminuria A1 T1DM subjects. Therefore, uNGAL should not be recommended as a single marker for detecting diabetic kidney disease in children and adolescents.

Challenges and pitfalls of youth-onset type 2 diabetes.

The incidence and prevalence of youth-onset type 2 diabetes mellitus (T2DM) are increasing. The rise in frequency and severity of childhood obesity, inclination to sedentary lifestyle, and epigenetic risks related to prenatal hyperglycemia exposure are important drivers of the youth-onset T2DM epidemic and might as well be responsible for the early onset of diabetes complications. Indeed, youth-onset T2DM has a more extreme metabolic phenotype than adult-onset T2DM, with greater insulin resistance and more rapid deterioration of beta cell function. Therefore, intermediate complications such as microalbuminuria develop in late childhood or early adulthood, while end-stage complications develop in mid-life. Due to the lack of efficacy and safety data, several drugs available for the treatment of adults with T2DM have not been approved in youth, reducing the pharmacological treatment options. In this mini review, we will try to address the present challenges and pitfalls related to youth-onset T2DM and summarize the available interventions to mitigate the risk of microvascular and macrovascular complications.

Association between cardiorespiratory fitness level and insulin resistance in adolescents with various obesity categories.

BACKGROUND: An association between cardiorespiratory fitness (CRF) and insulin resistance in obese adolescents, especially in those with various obesity categories, has not been systematically studied. There is a lack of knowledge about the effects of CRF on insulin resistance in severely obese adolescents, despite their continuous rise. AIM: To investigate the association between CRF and insulin resistance in obese adolescents, with special emphasis on severely obese adolescents. METHODS: We performed a prospective, cross-sectional study that included 200 pubertal adolescents, 10 years to 18 years of age, who were referred to a tertiary care center due to obesity. According to body mass index (BMI), adolescents were classified as mildly obese (BMI 100% to 120% of the 95th percentile for age and sex) or severely obese (BMI ≥ 120% of the 95th percentile for age and sex or ≥ 35 kg/m2, whichever was lower). Participant body composition was assessed by bioelectrical impedance analysis. A homeostatic model assessment of insulin resistance (HOMA-IR) was calculated. Maximal oxygen uptake (VO2max) was determined from submaximal treadmill exercise test. CRF was expressed as VO2max scaled by total body weight (TBW) (mL/min/kg TBW) or by fat free mass (FFM) (mL/min/kg FFM), and then categorized as poor, intermediate, or good, according to VO2max terciles. Data were analyzed by statistical software package SPSS (IBM SPSS Statistics for Windows, Version 24.0). P < 0.05 was considered statistically significant. RESULTS: A weak negative correlation between CRF and HOMA-IR was found [Spearman's rank correlation coefficient (rs) = -0.28, P < 0.01 for CRFTBW; (rs) = -0.21, P < 0.01 for CRFFFM]. One-way analysis of variance (ANOVA) revealed a significant main effect of CRF on HOMA-IR [F(2200) = 6.840, P = 0.001 for CRFTBW; F(2200) = 3.883, P = 0.022 for CRFFFM]. Subsequent analyses showed that obese adolescents with poor CRF had higher HOMA-IR than obese adolescents with good CRF (P = 0.001 for CRFTBW; P = 0.018 for CRFFFM). Two-way ANOVA with Bonferroni correction confirmed significant effect of interaction of CRF level and obesity category on HOMA-IR [F(2200) = 3.292, P = 0.039 for CRFTBW]. Severely obese adolescents had higher HOMA-IR than those who were mildly obese, with either good or poor CRF. However, HOMA-IR did not differ between severely obese adolescents with good and mildly obese adolescents with poor CRF. CONCLUSION: CRF is an important determinant of insulin resistance in obese adolescents, regardless of obesity category. Therefore, CRF assessment should be a part of diagnostic procedure, and its improvement should be a therapeutic goal.

A challenging case of an adolescent and young adult patient with high-risk acute lymphoblastic leukemia: the need for a multidisciplinary approach: a case report.

BACKGROUND: Adolescents and young adults diagnosed with acute lymphoblastic leukemia are treated according to pediatric-based regimens to achieve better results. However, implementation of intensive chemotherapy protocols in this age group is associated with increased treatment-related toxicities, affecting almost every organ and system. In this case, the focus of our interest was on rather rare entities: steroid-induced psychosis that seldom develops in children and adolescents, and choroid plexus hemosiderosis, infrequently identified as a first sign of iron overload. CASE PRESENTATION: The aim of this paper is to present a challenging case of a 15-year-old Caucasian male patient treated for high-risk acute lymphoblastic leukemia and who experienced various adverse incidents during intensive chemotherapy, thus necessitating a high-quality multidisciplinary approach. Slow minimal residual disease clearance was an additional concerning issue. Induction and re-induction were complicated by steroid-induced hyperglycemia that required multiple-week insulin. During consolidation, acute kidney injury on the basis of chronic kidney disease was verified, demanding subsequent drug dose modifications. By the end of re-induction, after dexamethasone cessation, infrequent steroid-induced psychosis, presented as incoherent speech, aggressive behavior, and mood swings, required intensive psychiatric support. Neurological evaluation of seizures revealed uncommon choroid plexus hemosiderosis by brain magnetic resonance imaging, warranting appropriate selection of iron chelation therapy in the context of preexisting nephropathy. Ultimately, iron deposits of moderate intensity were verified by liver magnetic resonance imaging, while heart tissue remained intact. The early diagnosis and adequate treatment of aforementioned difficult toxicities resulted in complete recovery of the patient. CONCLUSIONS: Treating adolescents with high-risk acute leukemia and multiple therapy-related morbidities remains a challenge, even in the era of extensive and effective supportive therapy. Superior survival rates might be achieved by prompt recognition of both frequent and rarely encountered adverse episodes, as well as well-timed and appropriate management by a well-coordinated multidisciplinary team.

Establishing paediatric reference intervals for thyroid function tests in Croatian population on the Abbott Architect i2000.

INTRODUCTION: Evaluation of thyroid function is often requested and therefore defining paediatric reference intervals (RIs) is of vital importance. Currently, there is a distinct lack of paediatric RIs for thyroid function tests in Croatia. Thus, we established RIs for thyroid stimulating hormone (TSH), total triiodothyronine (TT3), total thyroxine (TT4), free triiodothyronine (FT3) and free thyroxine (FT4) in the Croatian paediatric population. MATERIALS AND METHODS: Reference intervals were calculated from 397 apparently healthy children, aged from 2 days to < 19 years. Serum samples were analysed for thyroid function tests on the Abbott Architect i2000. Age- and sex-specific 95% RIs with 90% confidence intervals were established according to Clinical and Laboratory Standards Institute guidelines. To express the magnitude of sex and age variation, standard deviation ratio (SDR) was calculated using two-level nested ANOVA. The criterion for considering partitioning reference values was set to SDR > 0.3. RESULTS: All thyroid function tests required age partitioning, confirmed by SDR above 0.3. There was no need for sex partitioning, confirmed by SDR below 0.3. Still, FT3 was partitioned due to visually noticeable sex related difference for the oldest group (12 years to < 19 years). CONCLUSION: This is the first study to establish RIs for thyroid function tests in the Croatian paediatric population. We propose RIs for widely used Abbott platform, thus giving laboratories method- and population-specific paediatric RIs for thyroid function tests that should improve clinical test interpretation.

Fear of hypoglycemia, a game changer during physical activity in type 1 diabetes mellitus patients.

Hypoglycemia limits optimal glycemic management of patients with type 1 diabetes mellitus (T1DM). Fear of hypoglycemia (FoH) is a significant psychosocial consequence that negatively impacts the willingness of T1DM patients to engage in and profit from the health benefits of regular physical activity (e.g., cardiometabolic health, improved body composition, cardiovascular fitness, quality of life). Technological advances, improved insulin regimens, and a better understanding of the physiology of various types of exercise could help ameliorate FoH. This narrative review summarizes the available literature on FoH in children and adults and tools to avoid it.

CONTINUOUS GLUCOSE MONITORING AND TYPE 1 DIABETES MELLITUS CONTROL IN CHILD, ADOLESCENT AND YOUNG ADULT POPULATION - ARGUMENTS FOR ITS USE AND EFFECTS.

Sensors for continuous glucose monitoring (CGM) in intercellular fluid are used as a contemporary method to achieve better control in type 1 diabetes mellitus (DM), which is best shown through lower glycated hemoglobin (HbA1c) levels.The aim of this study was to assess how many of our patients used CGM (parents were solely financing all the cost of the device) and what was the effect of CGM on the control of DM. Data were retrospectively collected from medical records of patients actively treated at the Division of Endocrinology, Diabetology, Pulmonology and Allergology, Department of Pediatrics, Sestre milosrdnice University Hospital Center. The t-test was used for independent samples to compare the mean levels of HbA1c before and after the inclusion of CGM. CGM was used by 81 (32.1%) of our patients with type 1 DM, of which 43 met the inclusion criteria. The mean HbA1c level 6 months before the introduction of CGM was 8.2%±1.9 and after 12 months of CGM use it was 7.4%±1.2, which was a statistically significant improvement (p=0.026). Furthermore, our results demonstrated that the greatest improvement in HbA1c level was recorded in the groups of young adults (18-25 years) and youngest children (<12 years). We confirmed the efficacy of CGM in achieving better control of type 1 DM by significantly improving HbA1c levels in a population of highly motivated patients.

Time to the Peak, Shape of the Curve and Combination of These Glucose Response Characteristics During Oral Glucose Tolerance Test as Indicators of Early Beta-cell Dysfunction in Obese Adolescents

Objective: Characteristics of the glucose response during oral glucose tolerance test (OGTT) may reflect differences in insulin secretion and action. The aim was to examine whether timing of the glucose peak, shape of the glucose curve and their combination could be indicators of beta-cell dysfunction in obese/severely obese adolescents with normal glucose tolerance (NGT). Methods: Data from 246 obese/severely obese adolescents who completed OGTT were reviewed. Out of 184 adolescents with NGT, 174 could be further classified into groups based on timing of the glucose peak (early/30 minutes vs late/≥60 minutes) and shape of the glucose curve (monophasic vs biphasic). Groups were compared with respect to insulin sensitivity (whole body insulin sensitivity index - WBISI), early-phase insulin secretion (insulinogenic index - IGI) and beta-cell function relative to insulin sensitivity (oral disposition index - oDI). Results: Late glucose peak (p=0.004) and monophasic glucose curve (p=0.001) were both associated with lower oDI after adjustment for age, sex, puberty stage and body mass index z-score. Among obese/severely obese adolescents with NGT, those with coexistent late glucose peak and monophasic glucose curve had lower oDI than those with early glucose peak and biphasic glucose curve (p=0.002). Moreover, a combination of late glucose peak and monophasic glucose curve was the most powerful predictor of the lowest oDI quartile [odds ratio (OR): 11.68, 95% confidence interval: 3.048-44.755, p<0.001]. Conclusion: Late timing of the glucose peak, monophasic shape of the glucose curve and, in particular, a combination of those characteristics during OGTT may indicate early beta-cell dysfunction in obese/severely obese adolescents with NGT.

EFFECT OF GROWTH HORMONE THERAPY IN CHILDREN WITH PRADER-WILLI SYNDROME - OUR FIRST EXPERIENCES.

- Prader-Willi syndrome (PWS) is the most common cause of morbid obesity in childhood. It is the consequence of the lack of expression of genes on the paternally inherited 15q11.2-q13 region. Hyperphagia, obesity, short stature, psychomotor retardation and deterioration of behavior predominate in clinical presentation. Recombinant human growth hormone (rhGH) therapy, along with restriction of caloric intake, has become the mainstay in the management of PWS patients. Anthropometric parameters (height, body mass index (BMI)), therapy effect on carbohydrate and lipid metabolism, and occurrence of side effects were monitored in four children with PWS treated with rhGH for ≥2 years at doses of up to 1 mg/m2/day. During the follow-up, the height standard deviation score (SDS) increased in comparison with baseline values, and after ≥2 years of treatment with rhGH it was within the reference range for the general children population. BMI SDS decreased after the first year of treatment, but thereafter increased again; still, the level of BMI SDS was much better in comparison with most children with PWS of the same age and gender. RhGH therapy had no negative effect on glucose and lipid metabolism, nor caused any other adverse effect. Therapy including a customized diet for PWS, along with rhGH therapy, provided a satisfactory growth rate and prevented development of morbid obesity without side effects. This treatment approach would ensure transition of a greater number of PWS patients into adult care, where the multidisciplinary approach in care should be continued.

Regional differences in incidence and clinical presentation of type 1 diabetes in children aged under 15 years in Croatia.

AIM: To determine regional differences in the incidence, incidence trends, and clinical presentation of type 1 diabetes in children under the age of 15 years in Croatia in a 9-year period (1995-2003). METHODS: We included the patients who had been diagnosed with the disease and had started the insulin treatment before they were 15 years old. Regional differences between eastern, central, and southern Croatia were observed. The gross incidence was expressed by the number of newly diagnosed type 1 diabetes patients in 100000 children of the same age and sex per year, ie, for the 0-14 age group, and for the 0-4, 5-9, and 10-14 subgroups. RESULTS: The highest incidence was observed in southern Croatia (10.91 per 100000/y) and the lowest in central Croatia (8.64 per 100000/y), and in eastern Croatia the incidence was 8.93 per 100000/y. All three regions showed a growing incidence trend, which was significant only in eastern and southern Croatia. There was 35.9% of patients with diabetic ketoacidosis in eastern Croatia, 41.7% in central Croatia, and 31.28% in southern Croatia. CONCLUSION: Croatian regions show differences in the incidence, incidence trends, and disease presentation of type 1 diabetes. A further follow-up is needed to establish whether the regional differences are a consequence of the population dynamics in the observed period or they will continue to exist, pointing to differences in environmental risk factors.

Growth disorders in children with type 1 diabetes mellitus.

The aim of the research was to analyze anthropometric variables in children with type 1 diabetes mellitus (DM) in relation with the stage of pubertal development at onset of disease and quality of metabolic control over five-year long observation. Diagnosed children were taller than their peers. This especially referred to age group between 4 and 9.5 years. On the whole, weight of the patients and healthy controls did not differ. However, the diagnosed children had substantially lower weight in puberty than healthy controls. Body mass index was significantly lower in the group of diagnosed children on the whole and in puberty. During a five-year long observation patients have had a significant retardation of growth. However, that retardation referred primarily to patients in prepuberty. Growth retardation was more pronounced with bad metabolic control. Growth was satisfactory if onset of disease had been in puberty. A significant weight gain was observed in patients in puberty whereas in those in prepuberty there was no significant change of body weight at the end of five-year long observation. Metabolic control did not affect observed changes. There were significant differences of anthropometric variables between those suffering from type 1 DM and their peers. The differences depended on the age at onset. The disease had a negative effect on growth with onset in prepuberty, whereas in puberty growth was satisfactory. However, puberty was a period in which patients increased their weight excessively. Prepuberty was a period in which growth had been significantly affected by metabolic control.