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OBJECTIVES: In a contemporary cohort of youth with type 1 diabetes, we examined the interval between episodes of severe hypoglycemia (SH) as a risk factor for recurrent SH or hypoglycemic coma (HC). METHODS: This was a large longitudinal observational study. Using the DPV Diabetes Prospective follow-up data, we analyzed frequency and timing of recurrent SH (defined as requiring assistance from another person) and HC (loss of consciousness or seizures) in 14 177 youths with type 1 diabetes aged <20 years and at least 5 years of follow-up. RESULTS: Among 14 177 patients with type 1 diabetes, 72% (90%) had no, 14% (6.8%) had 1 and 14% (3.2%) >1 SH (HC). SH or HC in the last year of observation was highest with SH in the previous year (odds ratio [OR] 4.7 [CI 4.0-5.5]/4.6 [CI 3.6-6.0]), but remained elevated even 4 years after an episode (OR 2.0 [CI 1.6-2.7]/2.2 [CI 1.5-3.1]). The proportion of patients who experienced SH or HC during the last year of observation was highest with SH/HC recorded during the previous year (23% for SH and 13% for HC) and lowest in those with no event (4.6% for SH and 2% for HC) in the initial 4 years of observation. CONCLUSIONS: Even 4 years after an episode of SH/HC, risk for SH/HC remains higher compared to children who never experienced SH/HC. Clinicians should continue to regularly track hypoglycemia history at every visit, adjust diabetes education and therapy in order to avoid recurrences.

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Antenatally, glucose maintenance takes place via transplacental transfer from mother to fetus. In the third trimester, the amount of glucose transported increases, while glycogen and fat stores are developed. After delivery a continuous and sufficient glucose supply for vital organs and brain is essential. In term infants hormonal and metabolic adaption is well-coordinated, involving adrenal gland, pancreas and liver. However, in preterm infants, mainly during first week of life, there is a high risk of abnormalities in glucose homeostasis. Due to limited glycogen and fat stores, hypoglycaemia may occur which is avoided by continuous glucose infusion. An underestimated risk is hyperglycaemia due to a combination of relative insulin deficiency and insulin resistance, associated with increased mortality and morbidity. Management of hyperglycaemia is one of the topics in neonatology and is still being discussed controversially. This review approaches different therapeutic strategies and gives an overview about the current recommendations in the literature.

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BACKGROUND: Diabetic ketoacidosis (DKA) is a frequent acute complication at onset of type 1 diabetes. It is assumed that increased public awareness about diabetes symptoms may reduce DKA rate at diabetes onset. To investigate the time-dependent trend in DKA prevalence we analysed the frequency and determinants of DKA at disease onset over 15 years in pediatric patients. PATIENTS AND METHODS: The prevalence of DKA at disease onset was analysed in individuals aged ≤18 years treated for the first time from 1995-2009 within 7 days after diagnosis in pediatric centers. Simple and multiple logistic regression analysis was performed to investigate influencing factors on DKA prevalence. Change of the probability of ketoacidosis over years were modelled in the logistic regression as linear trend. RESULTS: 16 562 individuals from 170 institutions were studied with a mean age of 9.2 ± 4.2 years. DKA (pH <7.3) was present in 20.8% of patients without a significant trend between 1995 and 2009 (p=0.222). DKA prevalence was higher in children ≤5 years (26.3%) and in the age group 10-15 years (21.7%) than in individuals aged 5-10 years (16.4%) and 15-18 years (16.9%, p<0.001). Girls had DKA more often than boys (21.2% vs. 19.3%, p=0.002). DKA frequency was increased in individuals with migration background (26.5% vs. 19.2%, p<0.001). CONCLUSIONS: DKA prevalence at diabetes onset was constant at about 21% during the last 15 years. Very young children, pubertal adolescents, girls and individuals with migration background are at higher risk for DKA at diagnosis. To prevent DKA earlier diagnosis of type 1 diabetes is warranted especially in these patient groups.

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Premature pubarche in boys is a rare manifestation of McCune-Albright syndrome (MAS). In all cases published so far, it has always been attributed to an excessive testosterone production in the testicles. For the first time we describe a boy with MAS and evidence of premature pubarche of extragonadal origin. Apart from fibrous dysplasia of the forehead and a growth hormone- and prolactin-producing pituitary adenoma, the boy presented with premature pubarche at the age of 6 years and 11 months. The size of his testicles was only 2 ml at that time and remained thus despite a progression of his pubic hair to Tanner stage IV at the age of 10 years. In the basal blood analysis testosterone was not significantly elevated. However, androstenedione and DHEAS were elevated in the serum, and in repetitive 24-hour urine samples DHEAS metabolites were markedly elevated. We therefore concluded that the patient's premature pubarche might have originated in an increased production of DHEAS. This increased production might be due to an activating mutation of a hormone receptor in the zona reticularis of his adrenal glands leading to an increase in sulfotransferase activity and excessive DHEAS production.

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OBJECTIVE: Discomfort during insulin injection and self-monitoring of blood glucose (SMBG) is a potential obstacle in diabetes therapy, but its prevalence and extent in relation to clinical variables is uncertain. RESEARCH DESIGN AND METHODS: We prospectively assessed treatment-associated discomfort and pain in an unselected cohort of patients (60 boys and 52 girls; mean age 14.6+/-3.0 years, mean A1C 8.0+/-1.4%) with type 1 diabetes and multiple daily self-injections of insulin, using visual analogue/verbal rating scales (range, 0-10) and a six-item questionnaire. RESULTS: Pain during insulin injection was absent to very low in 91.9% of patients, and its intensity was independent of age, gender, diabetes duration, current A1C, injection volume, or type of insulin. Injection was more unpleasant than SMBG in 64.2% of patients (mean difference of pain score, 1.0+/-1.7, p<0.0001). Injection into the upper arm was less painful than into the thigh and abdomen. Surprisingly, painlessness of injection and SMBG was not judged an important treatment goal by 22.0 and 32.9% of patients, respectively. Logistic difficulties (41.2% of responses) and time requirements (23.8%), but not pain (10.1%), were considered most relevant problems. CONCLUSIONS: In young patients with access to optimized diabetes care, pain during insulin injection and SMBG is infrequent or mild, and not widely perceived as problematic, thus encouraging the use of multiple daily injection treatment.

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OBJECTIVE: To investigate clinical and laboratory markers of pubertal development in a large sample of obese children and adolescents. METHODS: Analysis of parameters of sexual maturation in 1232 obese individuals (582 boys) aged 6-18 years (mean 13.0+/-2.42 years). Clinical evaluation of pubertal stage and determination of bone age in a subset (227 patients). RESULTS: Mean Height--standard deviation scores (height-SDS) was positive during childhood and reached zero approximately at age 14 years followed by a turn to negative mean height-SDS in both genders. Accordingly, bone age was accelerated until age 14. No significant differences in average time points of occurrence of pubic hair stages PH 2 to PH 4 in boys and PH 2 to PH 5 in girls were observed as compared to references of the First Zurich Longitudinal Study. In girls, breast stage B 3 was reached earlier (11.6 vs 12.2 years, P=0.03). In boys, mean volume of testis revealed no significant deviation from reference. Mean dehydroepiandrosterone sulfate (DHEAS) levels were elevated in boys (within age ranges 8-10 years and 12-16 years, P<0.02) and in girls (within age ranges 6-8 years and 12-18 years, P<0.005) and mean testosterone levels in boys >12 years were lower as compared to reference ranges (all P-values <0.0001). CONCLUSION: The study data suggest normal development of pubarche and gonadarche in obese German boys and normal timing of pubarche in girls. Breast development in obese girls seems to be slightly advanced. In obese boys, an obvious dissociation of clinical and laboratory parameters of pubertal development was observed. Despite significantly increased height-SDS and increased DHEAS levels, gonadal development was normal and testosterone levels were decreased. Elevated DHEAS levels in both genders may contribute to the acceleration of bone maturation, a lower final body height and could increase cardiovascular risk.

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AIM: Insulin glargine is a long-acting insulin analogue with favourable clinical characteristics. We studied a slim 24-year-old female with Type 1 diabetes who repeatedly experienced severe hypoglycaemia after switching from NPH insulin to insulin glargine at identical daily doses. METHODS: Clinical examination and high-resolution ultrasound. RESULTS: The patient frequently placed her injections into muscle tissue, followed by unexpected rapid insulin action. After correction of her injection technique, hypoglycaemia did not recur. CONCLUSIONS: The long-acting kinetics of insulin glargine require precipitation in the subcutaneous tissue. Therefore, each patient's injection technique should be carefully checked when treatment with insulin glargine is initiated, particularly in young and lean individuals.

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Endoglin/CD105 is a membrane protein involved in the TGF-beta receptor signalling pathway. Endoglin expression has been reported to be selective for a few cell types, in particular endothelial cells, although a number of conflicting reports have been published. In this study, we performed a detailed analysis of endoglin expression in human lung tumors and different tumor and endothelial cell lines, employing reverse-transcriptase-polymerase-chain reaction as well as immunoblotting and immunohistochemistry using verified antibodies to endoglin. Our data show a clearly preferential expression of both endoglin mRNA and protein in endothelial cells. In tumors, endoglin expression was strongly elevated in the angiogenic endothelium at the tumor edges. In agreement with this observation, we find a clear correlation between endoglin expression and markers of proliferation, such as cyclin A and Ki-67, suggesting that endoglin expression is linked to cell-cycle regulation. These findings not only resolve some of the discrepancies in the literature, but also provide the basis for further applications making use of its selective localization and expression in the tumor vasculature.

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