Rare Antagonistic Leptin Variants and Severe, Early-Onset Obesity.

Hormone absence or inactivity is common in congenital disease, but hormone antagonism remains controversial. Here, we characterize two novel homozygous leptin variants that yielded antagonistic proteins in two unrelated children with intense hyperphagia, severe obesity, and high circulating levels of leptin. Both variants bind to the leptin receptor but trigger marginal, if any, signaling. In the presence of nonvariant leptin, the variants act as competitive antagonists. Thus, treatment with recombinant leptin was initiated at high doses, which were gradually lowered. Both patients eventually attained near-normal weight. Antidrug antibodies developed in the patients, although they had no apparent effect on efficacy. No severe adverse events were observed. (Funded by the German Research Foundation and others.).

Type 1 diabetes in children and adolescents is not associated with a reduced prevalence of atopy and allergic diseases.

BACKGROUND: Type 1 diabetes mellitus (T1D) as well as allergies in childhood have increased worldwide during the last 2 decades. The reasons for this increase are still unknown but early life origins are being discussed, such as dietary and hygiene factors that may play a role in the development of both diseases. The aim of this study was to compare the prevalence of allergies in children with and without T1D and to define potential influencing factors. MATERIALS AND METHODS: Data were collected from 104 patients with T1D (n = 104; mean age 11.4 ± 4.4 years; m/f: 77/27) and 104 healthy controls (CG) (n = 104; mean age 11.4 ± 4.3 years; m/f: 77/27). A questionnaire on allergic symptoms was obtained from each individual. In parallel, ImmunoCAP tests to detect specific allergen sensitization were performed. RESULTS: Allergen sensitization rates were not significantly different between both groups (T1D: 42% vs CG 38%; P = 0.625). In both groups, a comparable number of patients reported allergic symptoms in the questionnaire (T1D: 20% vs CG 26%; P = 0.43). Allergen sensitization and allergic symptoms were independent of breastfeeding, pets at home or diabetes duration. However, in T1D, fewer family members smoked (T1D: 10% vs CG 56%; P < 0.001). CONCLUSIONS: The present cohort study shows the same prevalence of allergy and atopy in a pediatric diabetes population compared to healthy controls. Diabetes per se does not seem to influence the development of allergies.

Only minor changes in thrombin generation of children and adolescents with type 1 diabetes mellitus - A case-control study.

BACKGROUND: Micro- and macrovascular diseases are frequent complications in patients with diabetes. Hypercoagulability may contribute to microvascular alterations. OBJECTIVE: In this study, we investigated whether type 1 diabetes in children is associated with a hypercoagulable state by performing a global function test of coagulation - the thrombin generation assay. SUBJECTS: 75 patients with type 1 diabetes aged between 2 and 19years were compared to an age-matched healthy control group. Diabetes patients were divided into high-dose and low-dose insulin cohorts with a cut-off at 0.8Ukg-1d-1. METHODS: Measurements were performed with platelet poor plasma using Calibrated Automated Thrombography and 1 pM or 5 pM tissue factor. Additionally, we quantified prothrombin fragments F1+2, thrombin-antithrombin complex, prothrombin, tissue factor pathway inhibitor, and antithrombin. RESULTS: Patients with type 1 diabetes exhibited a significantly shorter of lag time as well as decreased thrombin peak and endogenous thrombin potential compared to control subjects with 5 pM but not with 1 pM tissue factor. In high-dose insulin patients peak thrombin generation was higher and time to peak shorter than in low-dose patients. Thrombin-antithrombin complex was decreased in patients with type 1 diabetes, whereas prothrombin fragments F1+2 was comparable in both groups. Thrombin generation parameters did not correlate with parameters of metabolic control and the duration of diabetes. CONCLUSIONS: Taken together, we found only minor changes of thrombin generation in children and adolescents with type 1 diabetes which - in contrast to type 2 diabetes - do not argue for a hypercoagulable state.

Do children and adolescents with type 1 diabetes mellitus have a higher frequency of parietal cell antibodies than healthy controls?

OBJECTIVES: Parietal cell antibodies (PCA) are markers of autoimmune gastritis (AG). AG can lead to hypergastrinemia and iron-deficiency anaemia (IDA). Compared to healthy controls, adults with type 1 diabetes mellitus (T1DM) show a higher prevalence of PCA (1% vs 20%). The aim of the present study was to evaluate the frequency of PCA in children and adolescents with T1DM compared to healthy controls and the clinical and biochemical markers. PATIENTS AND METHODS: We studied 170 patients (87 boys) with T1DM (mean age 12.9 years) and 101 healthy controls (49 boys; mean age 13.0 years). PCA, free T4, free T3, thyroid-stimulating hormone (TSH), and thyroid antibodies were measured in all of the patients. In addition, gastrin, pepsinogen I, iron, ferritin, vitamin B12, and folate were measured in patients with T1DM only. Gastroscopy was carried out in patients with T1DM having high (>100 U/mL) PCA levels. RESULTS: The frequency of PCA in patients with T1DM was 5.29% compared to 1.98% in healthy controls (not significant). PCA was strongly correlated to both thyroid peroxidase antibodies (TPOAb) and gastrin levels (P = 0.001). IDA was present in 4 of 9 patients from the PCA-positive group compared to 4 of 160 patients from the PCA-negative group. Hypergastrinemia was found in 2 PCA-positive patients. Histopathologically, 1 of 4 patients showed early symptoms of AG. CONCLUSIONS: Children and adolescents with T1DM have a lower frequency of PCA than is reported for adults. Compared to healthy controls, they seem to be at increased risk for developing PCA, in particular if positive for TPOAb, but overt clinical disease is rare in children with T1DM.

The influence of physical activity on ghrelin and IGF-1/IGFBP-3 levels in children and adolescents with type 1 diabetes mellitus.

OBJECTIVES: The aim of the study was to determine the influence of regular physical activity on ghrelin and IGF-1/IGFBP-3 levels during a diabetes camp. METHODS: Twenty-eight children and adolescents (14 boys; mean age 12.1 yr) with type 1 diabetes mellitus (T1DM, mean duration of diabetes 4.8 yr) attending a 2-wk diabetes camp that features increased regular physical activities have been studied. Serum levels of ghrelin (total and acylated), growth hormone (GH), insulin-like growth factor-1 (IGF-1), insulin-like growth factor-bindng protein-3 (IGFBP-3) and insulin were measured in fasting state on day 1 and day 14. Improvement of metabolic control was documented by haemoglobin A1c (HbA1c). Glucose levels and insulin doses were determined daily. RESULTS: Mean insulin dosage decreased from 0.87 to 0.78 U/kg/d, mean HbA1c levels decreased from 8.6 to 8.3%, but the changes were not statistical. There was a significant decline in total ghrelin. IGFBP-3 and IGF-1 decreased also significantly. Total basal ghrelin was inversely related to the change in IGFBP-3. CONCLUSIONS: We hypothesize an association between ghrelin and metabolic control in T1DM. Higher ghrelin levels might be associated with poor metabolic control. The dynamic of IGFBP-3 levels appears to be under the influence of basal ghrelin concentrations in T1DM.

Late sequela after treatment of childhood low-grade gliomas: a retrospective analysis of 69 long-term survivors treated between 1983 and 2003.

The aim of the present study was to evaluate the spectrum of late effects in a large cohort of pediatric patients with low-grade gliomas (WHO grade I and II) during an observation period of 20 years. Eighty-seven patients with low-grade gliomas grouped according to tumor location (cerebellum: n=28; cerebral hemispheres: n=21; central midline: n=15; brainstem: n=12; tectum: n=5; other locations: n=6) were evaluated for tumor- and/or treatment-related late effects by analysis of medical and computer records, and personal interviews. Seventy patients underwent neurosurgery, 29 patients received additional radiotherapy and 20 additional chemotherapy. Median follow-up of survivors is 96 months with an overall survival of 79% (cerebellum: 89%; cerebral hemispheres: 95%; central midline: 80%; brainstem: 25%; tectum: 100%; other locations: 66%). Chronic medical problems (mild ataxia to multiple severe neuroendocrine deficits) are observed in 100% of patients with brainstem/central midline tumors and in 40-50% of patients with low-grade gliomas of other locations. Endocrine deficiencies were observed in 15/17 (88%) of long-term survivors who received radiotherapy. In contrast, none of the patients who underwent surgery only had endocrine deficiencies. Seven long-term survivors (10.1%) are severely disabled with permanent need of medical help. Tumor- and treatment-related late effects are common in patients with low-grade gliomas with the most severe occurring in patients with brainstem or central midline tumors. As long-term survival is excellent in patients with low-grade gliomas except for tumors located in the brainstem, future treatment studies should focus on avoiding long-term late effects.