OBJECTIVE: To evaluate the interaction between serum free insulin, insulin-like binding protein (IGFBP)-1 and leptin concentrations during puberty in insulin-dependent diabetes mellitus (IDDM). DESIGN: Adolescent patients with IDDM (n=101, age >9 years, duration >2 years) from the Outpatient Clinic of the Department of Pediatrics at Oulu University Hospital, and non-diabetic controls, were recruited to the study. Free insulin, IGFBP-1, leptin and insulin antibody concentrations were measured from a fasting serum sample. RESULTS: Free insulin concentrations were lower in the patients than in the controls (4.3+/-2.3 mU/l compared with 6.5+/-3.1 mU/l, P<0.001), and there was an inverse correlation between free insulin and fasting blood glucose in the boys with diabetes (r=-0.53, P<0.001), whereas a positive correlation was observed between free insulin and leptin concentrations in the girls with diabetes (r=0.30, P=0.020). The IGFBP-1 concentrations were greater in the patients than in the controls (16.5+/-10.6 microg/l compared with 4.0+/-3.3, P<0.001), and they correlated significantly with blood glucose (r=0.63, P<0.001) and free insulin (r=-0.35, P<0.001). No significant difference was observed in the leptin concentrations between the patients and controls overall, despite greater total body fat in the girls with diabetes compared with the control girls. CONCLUSIONS: Adolescents with IDDM are characterised by morning hypoinsulinaemia and high circulating IGFBP-1 concentrations, which may contribute to insulin resistance and impaired metabolic control during puberty. The mechanism behind the increased total body fat in the postpubertal female patients remains to be determined.
PH Riihimaa, M Knip, A Ruokonen, and P Tapanainen
Wendy L Awa, E Fach, D Krakow, R Welp, J Kunder, A Voll, A Zeyfang, C Wagner, M Schütt, B Boehm, M de Souza, and R W Holl
To characterize the clinical phenotype of type 2 diabetes mellitus (T2DM) with respect to age, gender, and BMI.
Anonymized data of 120 183 people with T2DM from the German/Austrian multicenter Diabetes Patienten Verlaufsdokumentation database were analyzed based on chronological age or age at diagnosis (0–19, 20–39, 40–59, 60–79, and ≥80 years). Age, gender, and BMI comparisons with clinical phenotype were made using χ 2 and Kruskal–Wallis tests (SAS V9.2).
Of all the patients, 51.3% were male, average age was 67.1±12.7 years, and average disease duration was 9.9±9.1 years. More girls than boys were diagnosed during adolescence and more men than women during adulthood (20–60 years). No gender differences existed when age at diagnosis was ≥60 years. Patients were obese on average (BMI: 30.5±6.1 kg/m2) and had significantly higher BMI values than German population peers. The BMI gap was widest in the younger age categories and closed with increasing age. Adult women were significantly more obese than men. Obese patients more often had elevated HbA1c (≥7.5%), hypertension or dyslipidemia (irrespective of age), microalbuminuria (adults), or retinopathy (elderly) than nonobese patients. More men than women (20–60 years) had hypertension, dyslipidemia, or microalbuminuria while more women than men (≥60 years) had hypertension or dyslipidemia.
During puberty, more girls than boys were diagnosed with T2DM while during adulthood males predominated. T2DM manifested at comparatively lower BMI in males, and younger patients were more obese at diagnosis. Age, gender, and BMI were also associated with poor metabolic control and cardiovascular disease comorbidities/complications.
Beate Karges, Joachim Rosenbauer, Paul-Martin Holterhus, Peter Beyer, Horst Seithe, Christian Vogel, Andreas Böckmann, Dirk Peters, Silvia Müther, Andreas Neu, Reinhard W Holl, and on behalf of the DPV Initiative
To investigate rates and risk factors of hospital admission for diabetic ketoacidosis (DKA) or severe hypoglycemia in young patients with established type 1 diabetes.
In total, 31 330 patients with type 1 diabetes (median age 12.7 years) from the Diabetes Patienten Verlaufsdokumentation (DPV) Prospective Diabetes Registry treated between 2011 and 2013 in Germany were included.
Admission rates for DKA (pH <7.3 or bicarbonate <15 mmol/l) and severe hypoglycemia (requiring assistance from another person) were calculated by negative binomial regression analysis. Associations of DKA or hypoglycemia with patient and treatment characteristics were assessed by multivariable regression analysis.
The mean admission rate for DKA was 4.81/100 patient-years (95% CI, 4.51–5.14). The highest DKA rates were observed in patients with HbA1c ≥9.0% (15.83 (14.44–17.36)), age 15–20 years (6.21 (5.61–6.88)) and diabetes duration of 2–4.9 years (5.60 (5.00–6.27)). DKA rate was higher in girls than in boys (5.35 (4.88–5.86) vs 4.34 (3.95–4.77), P=0.002), and more frequent in migrants than in non-migrants (5.65 (4.92–6.49) vs 4.57 (4.23–4.93), P=0.008). The mean admission rate for severe hypoglycemia was 1.45/100 patient-years (1.30–1.61). Rates were higher in migrants compared to non-migrants (2.13 (1.72–2.65) vs 1.28 (1.12–1.47), P<0.001), and highest in individuals with severe hypoglycemia within the preceding year (17.69 (15.63–20.03) vs patients without preceding hypoglycemia 0.42 (0.35–0.52), P<0.001). Differences remained significant after multivariable adjustment.
The identification of at-risk individuals for DKA (patients with high HbA1c, longer diabetes duration, adolescents, girls) and for severe hypoglycemia (patients with preceding severe hypoglycemia, migrants) may facilitate targeted diabetes counselling in order to prevent these complications.
Satu Seppä, Tanja Kuiri-Hänninen, Elina Holopainen, and Raimo Voutilainen
Puberty is the period of transition from childhood to adulthood characterized by the attainment of adult height and body composition, accrual of bone strength and the acquisition of secondary sexual characteristics, psychosocial maturation and reproductive capacity. In girls, menarche is a late marker of puberty. Primary amenorrhea is defined as the absence of menarche in ≥ 15-year-old females with developed secondary sexual characteristics and normal growth or in ≥13-year-old females without signs of pubertal development. Furthermore, evaluation for primary amenorrhea should be considered in the absence of menarche 3 years after thelarche (start of breast development) or 5 years after thelarche, if that occurred before the age of 10 years. A variety of disorders in the hypothalamus–pituitary–ovarian axis can lead to primary amenorrhea with delayed, arrested or normal pubertal development. Etiologies can be categorized as hypothalamic or pituitary disorders causing hypogonadotropic hypogonadism, gonadal disorders causing hypergonadotropic hypogonadism, disorders of other endocrine glands, and congenital utero–vaginal anomalies. This article gives a comprehensive review of the etiologies, diagnostics and management of primary amenorrhea from the perspective of pediatric endocrinologists and gynecologists. The goals of treatment vary depending on both the etiology and the patient; with timely etiological diagnostics fertility may be attained even in those situations where no curable treatment exists.
V Barrios, J Argente, MT Munoz, J Pozo, JA Chowen, and M Hernandez
OBJECTIVE: To analyze the possible utility of measuring acid-labile subunit (ALS) in some types of pathologies in which the IGF system is altered and to compare it with the clinical implications of measurements of other components of this axis. DESIGN AND METHODS: We studied serum ALS concentrations in 20 children with normal variants of short stature (NVSS) at diagnosis and 24 with growth hormone deficiency (GHD), 18 obese patients and 18 girls with anorexia nervosa at diagnosis and during a follow-up period. RESULTS: In patients with GHD and anorexia nervosa, mean ALS concentrations were significantly reduced, but there was a high percentage of overlap with control values. At diagnosis, ALS concentrations were normal in obese patients and children with NVSS. During follow-up, these values normalized in children with GHD who were treated with GH, tended to normalize in those with anorexia nervosa who showed weight gain, and did not change in obese children upon weight loss. However, ALS measurement was less accurate than that of IGF-I or IGF binding protein (IGFBP)-3 in diagnosis of GHD. The correlations found between ALS and some IGF system components at diagnosis either decreased or were non-significant during follow-up of these clinical conditions. CONCLUSION: ALS adds little information to that obtained with IGF-I and IGFBP-3 determinations.
CE Fluck, J Deladoey, S Nayak, O Zeller, P Kopp, and PE Mullis
OBJECTIVE: To study clinical, morphological and molecular characteristics in a Swiss family with autosomal dominant familial neurohypophyseal diabetes insipidus (adFNDI). PARTICIPANTS AND METHODS: A 15-month-old girl presenting with symptoms of polydipsia and polyuria was investigated by water deprivation test. Evaluation of the family revealed three further family members with symptomatic vasopressin-deficient diabetes insipidus. T1-weighted magnetic resonance images of the posterior pituitary were taken in two affected adult family members and molecular genetic analysis was performed in all affected individuals. RESULTS: The water deprivation test in the 15-month-old child confirmed the diagnosis of vasopressin-deficient diabetes insipidus and the pedigree was consistent with autosomal dominant inheritance. The characteristic bright spot of the normal vasopressin-containing neurophypophysis was absent in both adults with adFNDI. Direct sequence analysis revealed a new deletion (177-179DeltaCGC) in exon 2 of the AVP-NP II gene in all affected individuals. At the amino acid level, this deletion eliminates cysteine 59 (C59Delta) and substitutes alanine 60 by tryptophan (A60W) in the AVP-NP II precursor; interestingly, the remainder of the reading frame remains unchanged. According to the three-dimensional structure of neurophysin, C59 is involved in a disulphide bond with C65. CONCLUSIONS: Deletion of C59 and substitution of A60W in the AVP-NP II precursor is predicted to disrupt one of the seven disulphide bridges required for correct folding of the neurophysin moiety and thus disturb the function of neurophysin as the vasopressin transport protein. These data are in line with the clinical and morphological findings in the reported family with adFNDI.
E Hammer, K Kutsche, F Haag, K Ullrich, R Sudbrak, RP Willig, T Braulke, and B Kubler
OBJECTIVE: It has been suggested that mono-allelic deletion of the IGF-I receptor gene is causally related to severe intrauterine and postnatal growth deficiency whereas no IGF-I resistance was observed in the patients' fibroblasts. The expression and regulation of the growth-modulating IGF binding proteins (IGFBPs) have been investigated in serum and fibroblasts of a short girl with mono-allelic loss of the distal long arm of chromosome 15 (15q26.1-qter). PATIENT AND METHODS: The mono-allelic loss of the IGF-I receptor (IGF1R) gene was confirmed in a child with prenatal and severe postnatal growth retardation by fluorescence in situ hybridization, and was evaluated on the protein level in fibroblasts of the patient by FACS analysis and IGF cross-linkage. Additionally, expression of IGFBPs and cell-mediated degradation of IGFBP-3 were examined in the patient's fibroblasts. RESULTS: Levels of GH, IGF-I, and IGFBP-3 were above the 95th percentile in the serum of the 3-year-old girl with a mono-allelic deletion of the IGF1R gene, suggesting IGF-I resistance. In the patient's fibroblasts the IGF-I receptor concentration was half that in control cells. Whereas the pattern of secreted IGFBPs in response to IGFs was not altered, the abundance of secreted IGFBPs was higher in the patient's cells than in controls. Moreover, fibroblast-mediated degradation of 125I-labeled IGFBP-3 appears to be reduced in the patient's fibroblasts. The higher abundance of IGFBPs in the patient's fibroblasts might be responsible for the lack of IGF-I-stimulated [alpha-1-14C]methylaminoisobutyric acid transport. CONCLUSION: Our results suggest that the expression and regulation of IGFBPs in tissues from patients with mono-allelic deletion of the IGF-I receptor gene may lead to IGF sequestration and contribute to IGF-I resistance and growth retardation.
C Ankarberg-Lindgren, E Norjavaara, and KA Wikland
OBJECTIVE: To determine whether there is evidence for impaired testicular function at final height in short boys treated with growth hormone (GH) during their childhood and adolescence. STUDY DESIGN: The analysis was restricted to males who had isolated GH deficiency or idiopathic short stature, and who were included in the Swedish National Registry and the Swedish GH trials. The subjects had to have been treated with GH for at least 4 years; the treatment had to have been started prepubertally, given for at least one year before the onset of puberty and the subjects had to have reached final height. One hundred and eleven boys fulfilled the criteria. METHODS: Testicular volumes were determined by orchidometer in each boy when GH treatment was started and at final height. Samples for testosterone measurements were collected from 77 boys at final height, and were measured by RIA. RESULTS: Each subject had normal testicular size (15 ml or more) and for those in whom concentrations were determined, serum testosterone levels and diurnal rhythm were normal. CONCLUSIONS: The results of our survey do not show evidence of testicular impairment following GH therapy.
M Fukami, N Matsuo, T Hasegawa, S Sato, and T Ogata
OBJECTIVE: To report on auxological data in the combination of SHOX (short stature homeobox containing gene) haploinsufficiency and normal ovarian function. DESIGN: Longitudinal auxological study in a 14 Year 9 Month old Japanese girl with Leri-Weill dyschondrosteosis accompanied by mesomelic short stature, who had a submicroscopic pseudoautosomal deletion involving SHOX, and pubertal development of an almost average tempo. METHODS: Auxological data were assessed by the age-matched standards for Japanese females. RESULTS: The standard deviation scores (SDSs) for height, leg length (LL), and arm span remained below the normal range from childhood and worsened during puberty, whereas those for sitting height (SH) remained within the normal range and stayed almost constant throughout the observation period. Consequently, the SDSs for SH/LL ratio remained above the normal range from childhood and deteriorated during puberty. The decreased pubertal height gain was caused by a diminished pubertal height spurt and abrupt growth cessation shortly after menarche. The SDSs for hand length and palm length remained within the normal range but decreased during puberty, and those for head circumference remained within the normal range and stayed almost constant throughout the observation period. CONCLUSIONS: The results suggest that, in individuals with SHOX haploinsufficiency and normal ovarian function, auxological abnormalities related to mesomelia are evident from childhood and worsen further during puberty because of the skeletal maturing effects of ovarian estrogens.
Carina Ankarberg-Lindgren and Ensio Norjavaara
To test the clinical usefulness of sensitive commercial immunoassays for determination of low 17β-estradiol concentrations in children.
The lower limit of detection and clinical usefulness (functional sensitivity) of three commercial estradiol immunoassays were validated by use of 500 sera from prepubertal and pubertal children and 55 pooled sera. The three immunoassays consisted of two modified direct immunoassays; one RIA (Spectria Estradiol RIA) and one time-resolved fluoroimmunoassay (AutoDELFIA Estradiol), both with increased serum volume in relation to antibody concentration and extended incubation time. In the third method, serum was purified and concentrated using diethyl ether extraction prior to measurement by the modified Spectria Estradiol RIA.
The lower limits of detection and clinical usefulness were 9 and 30 pmol/l for the direct RIA, 11 and 50 pmol/l for the AutoDELFIA, and 4 and 6 pmol/l for serum determined by extraction RIA. When measuring the serum pool originating from girls at breast stages 1–2, the direct RIA and AutoDELFIA resulted in significantly higher 17β-estradiol concentrations when compared with the extraction RIA (+58 and +267%, P<0.001). We found a significant difference in 17β-estradiol concentrations between girls at breast stages 1 (median 6 pmol/l) and 2 (median 16 pmol/l), when quantified by the extraction RIA (P<0.0001) but no difference when quantified with the direct RIA (median values 12 and 14 pmol/l respectively).
For determination of low serum 17β-estradiol concentrations in children, an extraction step prior to commercial immunoassay is needed to achieve clinically useful results.