Short-Term Effects of Growth Hormone on Lipolysis, Glucose and Amino Acid Metabolism Assessed in Serum and Microdialysate of Healthy Young Men.

OBJECTIVE: We investigated direct effects of a therapeutic growth hormone dose on lipolysis, glucose and amino acid metabolism. METHODS: This crossover microdialysis trial involved six healthy male volunteers receiving single subcutaneous injections of both growth hormone (0.035 mg/kg) and placebo (0.9% sodium chloride). The investigation comprised three test days with standard diet. The first day served for adaptation, the second and third one for determining study data during 9 night hours with or without growth hormone. Abdominal subcutaneous microdialysate and blood were continuously collected and forwarded to a separate room next door where hourly taken samples were centrifuged and frozen until analysed. RESULTS: Growth hormone achieved the peak serum level after 3 h followed by a plateau-like course for the next 6 h. Glycerol in microdialysate started to rise 2 h following growth hormone injection achieving significance compared to placebo after 9 h (P<0.05). Serum glycerol increased 4 h after growth hormone administration achieving significance after 6 h (P<0.05). Glucose and amino acid concentrations showed neither in microdialysate nor in serum significant differences between growth hormone and placebo. Serum values of insulin and C-peptide revealed no significant difference between growth hormone and placebo. SUMMARY AND CONCLUSION: As the result of a high single subcutaneous dose of GH, persistent lipolysis can be shown in continuously collected microdialysate and blood, but no indication for gluconeogenesis or protein anabolism.

Evaluating the four most important salivary sex steroids during male puberty: testosterone best characterizes pubertal development.

Background During pubertal development in healthy boys, increased levels of different sex steroids occur which are responsible for sexual maturation and physical changes. However, relationships between various sex hormones and pubertal development stages have not been sufficiently studied. Methods The investigation included 165 normal boys (mean age 12.7±2.8 years, mean body mass index [BMI] 19.6±4.2 kg/m2). Pubic hair (PH) stages were stratified by Tanner and testicular volume (TV) by means of the Prader orchidometer and assigned to the prepubertal, pubertal and postpubertal development phase. Four different sex steroids (testosterone [TE], dehydroepiandrosterone [DHEA]/dehydroepiandrosterone-sulfate [DHEAS], androstenedione (AE), 17-hydroxyprogesterone [17-OHP]) were measured in saliva by enzyme-linked immunosorbent assay (ELISA) and as serum total steroids by different assays (radioimmunoassay [RIA], chemiluminescence immunoassay [CLIA], electrochemiluminescence immunoassay [ECLIA]). Validation of saliva-based ELISA tests included data related to inter- and intra-assay coefficients of variation (CVs), recovery and linearity. Results Using Spearman rank correlation, salivary steroids significantly correlated (p<0.001) with pubertal development: TE (TV r=0.74 and PH stages r=0.72), DHEA (r=0.58 and 0.62), AE (r=0.38 and 0.45) and 17-OHP (r=0.42 and 0.43). Correlations between salivary and serum concentrations of steroids were also statistically significant (p<0.001). Binomial logistic regression analysis revealed significant correlations between salivary TE and pubertal maturation during the development phases of prepuberty-puberty and puberty-postpuberty. Inclusion of further salivary steroids did not improve analysis results. Conclusions Salivary TE permits a good non-invasive characterization of pubertal maturation stages. The consideration of further salivary sex steroids did not improve diagnostic accuracy.

Transfer of Topical Testosterone to Subcutaneous Microdialysate, Blood and Saliva in Healthy Young Men.

OBJECTIVE: We evaluated percutaneous penetration of topical testosterone and subsequent transfer to subcutaneous tissue, blood and saliva. METHODS: This microdialysis trial involved eight healthy male volunteers. Five participants received a single dose of 50 mg testosterone gel on the abdominal skin and three untreated participants served as controls. Two microdialysis probes were inserted percutaneously into the abdominal subcutaneous adipose tissue. On the skin above one probe, testosterone gel was applied (ipsilateral side). A second control probe was inserted on the contralateral side. For the determination of total and free testosterone, samples of subcutaneous microdialysate, serum, and saliva were collected over six hours, frozen, and analysed using ELISA procedures. RESULTS: Testosterone values in the ipsilateral microdialysate of treated subjects increased significantly within 6 h after gel application compared to controls. Salivary testosterone levels showed a rapid increase within 20 min after transdermal application followed by a plateau phase with tenfold increased testosterone levels. Microdialysate testosterone of the contralateral site started to rise moderately within the normal range 1 h after administration of testosterone gel whereas total and free testosterone serum concentrations increased within 2 h in each case followed by a plateau phase. SUMMARY AND CONCLUSION: Single topical administration of testosterone gel leads to a continuous increase of testosterone in the subcutaneous ipsilateral microdialysate. Rapid salivary testosterone increase happens after gel administration followed by tenfold increased testosterone plateau values. Despite continuous influx, testosterone concentrations in serum, saliva, and contralateral microdialysate show a plateau formation thus avoiding testosterone excess.

Decrease of small dense LDL and lipoprotein-associated phospholipase A2 due to human growth hormone treatment in short children with growth hormone deficiency and small for gestational age status.

BACKGROUND: Growth hormone deficiency (GHD) and small for gestational age (SGA) status are associated with cardiovascular risks. We therefore, investigated antiatherogenic effects of growth hormone (GH). METHODS: Subfractions of low-density lipoprotein (LDL) and high-density lipoprotein (HDL), lipoprotein-associated phospholipase A2 (Lp-PLA2), and high-sensitivity C-reactive protein (hsCRP) were measured at baseline, after 8 and 52 weeks of GH treatment in 51 short children born SGA (n=33) or with GHD (n=18). RESULTS: The overall group showed post-treatment reductions of LDL cholesterol (LDL-C) (p=0.016), small-dense LDL cholesterol (sdLDL-C, p<0.001), Lp-PLA2 (p<0.001), and hsCRP (p=0.005), but increase of HDL2a cholesterol (HDL2a-C, p=0.025). SGA children revealed significant correlations between Lp-PLA2 and LDL-C and sdLDL-C both before and after GH, significant reductions of sdLDL-C, Lp-PLA2, hsCRP, and an increase of HDL2a-C. GHD children showed the same lipid responses, though not significantly. CONCLUSIONS: Children with GHD or born SGA may benefit from GH by growth acceleration and reduction of cardiovascular long-term risks.

Non-High-Density Lipoprotein Cholesterol in Children with Diabetes: Proposed Treatment Recommendations Based on Glycemic Control, Body Mass Index, Age, Sex, and Generally Accepted Cut Points.

Percentile-based non-high-density lipoprotein cholesterol levels were analyzed by glycemic control, weight, age, and sex of children with type 1 diabetes (n = 26,358). Ten percent of all children and 25% of overweight adolescent girls require both immediate lipid-lowering medication and lifestyle changes to achieve non-high-density lipoprotein cholesterol levels <120 mg/dL and cardiovascular risk reduction.

Decreased levels of homoarginine and asymmetric dimethylarginine in children with type 1 diabetes: associations with cardiovascular risk factors but no effect by atorvastin.

OBJECTIVES: To investigate homoarginine and asymmetric dimethylarginine (ADMA) in controls compared to children with type 1 diabetes (T1D) and if homoarginine and ADMA are affected by atorvastatin. METHODS: Homoarginine and ADMA levels of 28 T1D patients were compared to levels of 41 controls. In T1D patients, homoarginine and ADMA were determined at baseline, 1 year, and 2 years at daily 10 mg atorvastatin or placebo within a double-blind study. RESULTS: At baseline, both homoarginine and ADMA were lower (p<0.001) in T1D patients compared to controls. In T1D patients, homoarginine and ADMA were not influenced by atorvastatin. Inverse correlations between homoarginine and HbA1c (p<0.001) and between ADMA and systolic blood pressure (p=0.005) and pulse pressure (p=0.003) were shown. CONCLUSIONS: Homoarginine and ADMA levels are decreased and associated with cardiovascular risk factors in children with T1D without being affected by atorvastatin.

Algorithm-based cholesterol monitoring in children with type 1 diabetes.

OBJECTIVE: To facilitate child-specific and diabetes-related cholesterol control, we developed a monitoring algorithm derived from population-based reference values. STUDY DESIGN: Low-density lipoprotein (LDL)-, non-high-density lipoprotein (HDL)-, and HDL cholesterol percentile values were calculated for children with type 1 diabetes (T1D) and their peers without T1D within algorithm-based categories of sex, age: 1-10 vs >10-<18 years, body mass index: <90th vs ≥90th percentile, and hemoglobin A1c <6%, 6%-<7.5%, 7.5%-9%, >9%. Analyses included 26 147 patients sampled from a German/Austrian population-based registry for T1D (Diabetes Documentation and Quality Management System) and 14 057 peers without diabetes participating in the national Health Interview and Examination Survey for Children and Adolescents in Germany. RESULTS: Reference percentile values for cholesterol were derived as a diagnostic algorithm aimed at supporting long-term cholesterol control. Taking account of a patient's sex, age-group, weight-, and hemoglobin A1c-category, the flowcharts of the algorithm developed separately for LDL-, non-HDL-, and HDL cholesterol allow comparing his/her cholesterol levels with population-based reference percentile values of peers without T1D. CONCLUSIONS: The population-based algorithmic approach applied to LDL-, non-HDL-, and HDL cholesterol allows referencing children with T1D with regard to their peers without T1D and, if necessary, suggests corrections of glycemic control to optimize long-term cholesterol levels.

Marked increase of final height by long-term aromatase inhibition in a boy with idiopathic short stature.

Growth hormone (GH) is the most frequently used treatment in children with idiopathic short stature (ISS). Aromatase inhibitor (AI) therapy is still in an experimental state, and both final height (FH) and long-term efficacy data in ISS have not been published. We present a 14.5-year-old boy with ISS and a height of 142.7 cm [standard deviation score (SDS) -2.79]. Based on the baseline bone age (BA) of 13.5-14 years, his predicted adult height (PAH) by Bayley/Pinneau was 154 cm (SDS -3.77)-158.2 (SDS -3.15). After a 5-year letrozole monotherapy, FH was 169 cm (SDS -1.57) showing a height difference between PAH and FH from 10.8 to 15 cm. No permanent side effects of the medication have been observed. Both a transient occurrence and a spontaneous recovery of decreased bone mineral apparent density were seen, verified by dual-energy X-ray absorptiometry. Spinal magnetic resonance imaging revealed no vertebral abnormalities. All therapy might be an effective and low-cost alternative to the use of GH. Further controlled trials should prove efficacy and safety of long-term AI therapy in boys with ISS.

Synergistic effects of elevated systolic blood pressure and hypercholesterolemia on carotid intima-media thickness in children and adolescents.

This study aimed to investigate the synergistic effects of elevated systolic blood pressure (SBP) and hypercholesterolemia on carotid intima-media thickness (cIMT). For this study, 60 children with hypercholesterolemia and 40 healthy control children were divided into four subgroups: hypercholesterolemic children with normal (<90th percentile) or elevated (>or= 90th percentile) SBP and control children with normal or elevated SBP. The highest mean and maximal cIMT values were found in the hypercholesterolemic children with elevated SBP and were significantly different from those of all the other groups. The synergistic effects of elevated SBP and hypercholesterolemia lead to a significant increase in cIMT as a subclinical sign of early atherosclerosis.

Influence of food intake, age, gender, HbA1c, and BMI levels on plasma cholesterol in 29,979 children and adolescents with type 1 diabetes--reference data from the German diabetes documentation and quality management system (DPV).

OBJECTIVE: We investigated influences of a 12-h fast, age, gender, body mass index (BMI), hemoglobin A1c (HbA1c) on total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) to provide reference percentiles for TC, LDL-C, and HDL-C of patients with good diabetes control (HbA1c < 7.5%) and normal weight (BMI < 90th percentile). METHOD: A cross-sectional analysis of the diabetes documentation and quality management system using the diabetes data acquisition system for prospective surveillance (DPV) software included 29 979 patients with type 1 diabetes mellitus (T1DM) aged 1-20 yr (52.4% male) from 253 diabetes centers in Germany and Austria. RESULTS: Fasting had no relevant influence on TC, LDL-C, and HDL-C. Multivariate regression analysis revealed strongest dependences of cholesterol on gender and HbA1c followed by BMI and age. Reference cholesterol percentiles of well-controlled and normal weight patients showed TC >or=4.40 mmol/L (170 mg/dL) corresponding to the 50th percentile in females and the 75th percentile in males. LDL-C >or=2.59 mmol/L (100 mg/dL) corresponded to the 50th-75th percentile in females and the 75th percentile in males. CONCLUSIONS: (i) Fasting is no precondition for the determination of TC, LDL-C, and HDL-C; (ii) TC, LDL-C, and HDL-C are strongest associated with gender and HbA1c followed by BMI and age; (iii) Gender- and age-adjusted cholesterol percentiles of well-controlled and normal weight patients with T1DM may serve as reference values and are similar to healthy German children; and (iv) Single target values for TC, LDL-C, and HDL-C based on healthy individuals' data do not sufficiently characterize abnormal cholesterol levels in young patients with T1DM.

Marked smoking-associated increase of cardiovascular risk in childhood type 1 diabetes.

Type 1 diabetes is a generally accepted atherogenic risk factor, and diabetic patients who smoke markedly accelerate the atherosclerotic process. The main intentions of our investigation were to ascertain differences between juvenile active/passive smokers and non-smokers with type 1 diabetes regarding the number and spectrum of cardiovascular risk factors and their associations with smoking. Ninety-two patients were enrolled comprising 19 active/passive smokers (median age 15.9 years) and 73 non-smokers (median age 12.3 years). To determine age-dependent influences we compared age- and gender-matched groups of 12 smokers with 12 non-smokers. Smokers had significantly higher HbA1c, fructosamine, total cholesterol, LDL cholesterol, apolipoprotein B, serum P-selectin, and lower serum L-selectin than non-smokers. However, L-selectin levels were not different between the age-matched smoker and non-smoker groups. A significant positive relation (Spearman rank correlation) was found between smoking and age, HbAlc, fructosamine, total cholesterol, apolipoprotein B, and P-selectin; a negative relationship between smoking and L-selectin. We conclude that smoking in children and adolescents with type 1 diabetes increases the cardiovascular risk through the deterioration of glucose metabolism, lipid profile, and endothelial function. Therefore, smoking diabetic juveniles may increase their number of cardiovascular risk factors from 1, diabetes, by another four factors, i.e. smoking, hyperglycemia, dyslipidemia, and endothelial perturbation.

Early atherosclerosis in childhood type 1 diabetes: role of raised systolic blood pressure in the absence of dyslipidaemia.

The intentions of our investigation were (1) to search for atherogenic risk factors and signs of incipient atherosclerosis in children and adolescents with type 1 diabetes (T1DM) in comparison to well-matched control subjects, (2) to evaluate risk factor associations with carotid intima media thickness (cIMT) in diabetic patients and control subjects, and (3) to acquire a better knowledge of early atherogenesis in children and adolescents with and without T1DM. 94 diabetic children (age median 12.3 years, HbA1c median 7.7%) and 40 non-diabetic controls (age median 12.3 years) were investigated. Mean cIMT was determined using high-resolution B-mode ultrasound with an automated contour identification procedure. Compared to controls, subjects with diabetes had significantly elevated cIMT (p = 0.041) and systolic BP (p = 0.007) but showed a less atherogenic lipid profile. Most markers of inflammation, endothelial function and fibrinolytic activity were higher in diabetic subjects than in controls. Multiple linear regression analysis revealed a significant relationship (r = 0.53, p = 0.036) between bilateral mean cIMT and diverse risk factors in patients with T1DM. Spearman rank correlation showed that diabetes duration (rho = 0.32, p = 0.029), systolic BP (rho = 0.32, p = 0.004), weight (rho = 0.257, p = 0.022), and height (rho = 0.265, p = 0.018) significantly correlated with bilateral mean cIMT in the 94 diabetic patients. In conclusion, in well-controlled type 1 diabetic children systolic BP may be of greater importance than dyslipidaemia in early atherogenesis. BMI, markers of sustained inflammation, endothelial dysfunction and fibrinolytic activity are increased in diabetic versus non-diabetic children but none of them correlates significantly with cIMT. Their prognostic value remains to be determined.

Spectrum and prevalence of atherogenic risk factors in 27,358 children, adolescents, and young adults with type 1 diabetes: cross-sectional data from the German diabetes documentation and quality management system (DPV).

OBJECTIVE: The aim of this data analysis was to ascertain the type and prevalence rate as well as age and sex distribution of cardiovascular risk factors in type 1 diabetic patients up to 26 years of age. RESEARCH DESIGN AND METHODS: Cardiovascular risk factors such as obesity, hypertension, dyslipidemia, poor glycemic control, and smoking were analyzed in 27,358 patients who were divided into three groups (prepubertal, pubertal, and adult) using specifically designed diabetes software for prospective disease documentation. RESULTS: More than half of the patients per age-group had at least one cardiovascular risk factor. Two risk factors were age dependently found in 6.2-21.7% and three or four risk factors in 0.5-4.7%. Elevated values of HbA(1c), total cholesterol, and BMI were found most frequently. Hypertension, smoking, and HDL cholesterol were observed more frequently in males, and elevated BMI, total cholesterol, and LDL cholesterol more often in females. Although 28.6% of the patients had dyslipidemia, merely 0.4% of them received medical treatment, and of the 8.1% of the patients with hypertension, only 2.1% of them were given antihypertensive medication. CONCLUSIONS: With increasing age, a greater number of patients with cardiovascular risk factors were observed. Significant sex differences were seen in the majority of risk factors. Despite the high prevalence of risk factors, only a small minority of patients received antihypertensive or lipid-lowering treatment. Early identification, prevention, and treatment of additional risk factors seem to be necessary, particularly in light of the high incidence of future cardiovascular disease.

Adult-like but regressive increase of intima-media thickness and roughness in a child with type 1 diabetes.

A 12-yr-old Kosovo-Albanian boy with insufficiently controlled type 1 diabetes since his second year of life developed severely increased intima-media thickness (IMT) and roughness (IMR) of the common carotid artery (CCA): max/mean IMT=0.81/0.68 mm and IMR=0.048 mm. Intima-media thickening, comparable with that in a 50- to 60-yr-old healthy adult, decreased within 41 months (max/mean carotid IMT=0.72/0.56 mm and IMR=0.036 mm) by intensive treatment of diabetes. Moyamoya disease (MMD), complicated by cerebral infarction, occurred coincidentally but regressed within 6 months. This case report points out that (i) chronic hyperglycemia in childhood may lead to adult-like increase of carotid IMT/IMR as early signs of subclinical atherosclerosis, (ii) increased carotid IMT/IMR may be regressive by intensive diabetes control, and (iii) a screening examination for carotid IMT/IMR should be considered in patients at high risk of atherosclerosis.