Persistently high glucose levels in young children with type 1 diabetes.

OBJECTIVES: The aim of the study was to characterize glucose levels and variability in young children with type 1 diabetes (T1D). METHODS: A total of 144 children of 4-10 yr old diagnosed with T1D prior to age 8 were recruited at five DirecNet centers. Participants used a continuous glucose monitor (CGM) every 3 months during an 18-month study. Among the 144 participants, 135 (mean age 7.0 yr, 47% female) had a minimum of 48 h of CGM data at more than five of seven visits and were included in analyses. CGM metrics for different times of day were analyzed. RESULTS: Mean hemoglobin A1c (HbA1c) at the beginning and end of the study was 7.9% (63 mmol/mol). Fifty percent of participants had glucose levels >180 mg/dL (10.0 mmol/L) for >12 h/d and >250 mg/dL (13.9 mmol/L) for >6 h/d. Median time <70 mg/dL (3.9 mmol/L) was 66 min/d and <60 mg/dL (3.3 mmol/L) was 39 min/d. Mean amplitude of glycemic excursions (MAGE) was lowest overnight (00:00-06:00 hours). The percent of CGM values 71-180 mg/dL (3.9-10.0 mmol/L) and the overall mean glucose correlated with HbA1c at all visits. There were no differences in CGM mean glucose or coefficient of variation between the age groups of 4 and <6, 6 and <8, and 8 and <10. CONCLUSIONS: Suboptimal glycemic control is common in young children with T1D as reflected by glucose levels in the hyperglycemic range for much of the day. New approaches to reduce postprandial glycemic excursions and increase time in the normal range for glucose in young children with T1D are critically needed. Glycemic targets in this age range should be revisited.

Metabolic effects of oral versus transdermal 17ß-estradiol (E2): a randomized clinical trial in girls with Turner syndrome.

CONTEXT: The long-term effects of pure 17ß-estradiol (E2) depending on route of administration have not been well characterized. OBJECTIVE: Our objective was to assess metabolic effects of oral vs transdermal (TD) 17ß-E2 replacement using estrogen concentration-based dosing in girls with Turner syndrome (TS). PATIENTS: Forty girls with TS, mean age 16.7 ± 1.7 years, were recruited. DESIGN: Subjects were randomized to 17ß-E2 orally or TD. Doses were titrated using mean E2 concentrations of normally menstruating girls as therapeutic target. E2, estrone (E1), and E1 sulfate (E1S) were measured by liquid chromatography tandem mass spectrometry and a recombinant cell bioassay; metabolites were measured, and dual-energy x-ray absorptiometry scan and indirect calorimetry were performed. MAIN OUTCOME: Changes in body composition and lipid oxidation were evaluated. RESULTS: E2 concentrations were titrated to normal range in both groups; mean oral dose was 2 mg, and TD dose was 0.1 mg. After 6 and 12 months, fat-free mass and percent fat mass, bone mineral density accrual, lipid oxidation, and resting energy expenditure rates were similar between groups. IGF-1 concentrations were lower on oral 17ß-E2, but suppression of gonadotropins was comparable with no significant changes in lipids, glucose, osteocalcin, or highly sensitive C-reactive protein between groups. However, E1, E1S, SHBG, and bioestrogen concentrations were significantly higher in the oral group. CONCLUSIONS: When E2 concentrations are titrated to the normal range, the route of delivery of 17ß-E2 does not affect differentially body composition, lipid oxidation, and lipid concentrations in hypogonadal girls with TS. However, total estrogen exposure (E1, E1S, and total bioestrogen) is significantly higher after oral 17ß-E2. TD 17ß-E2 results in a more physiological estrogen milieu than oral 17ß-E2 administration in girls with TS.

Response of fractional synthesis rate (FSR) of fibrinogen, concentration of D-dimer and fibrinolytic balance to physical activity-based intervention in obese children.

BACKGROUND: Physical activity-induced reduction in obesity-related hyperfibrinogenemia in children has been reported. The underlying mechanisms remain elusive. Further, the effect of such interventions on fibrinolysis in children is scarce. OBJECTIVES: To investigate in obese children, before and after a physical activity-based intervention: (i) the mechanistic role of fractional synthesis rate (FSR) of fibrinogen in the reduction of hyperfibrinogenemia; and (ii) the changes in fibrinolytic factors. METHODS: Subjects included 21 (age > 14 < 18 years; Tanner stage, IV-V) children (15 obese, BMI >95%tile for age and sex and six lean, BMI <85%tile). After baseline measurements of FSR of fibrinogen, and concentrations of fibrinogen, D-dimer, PAI-1 and t-PA in all children, studies were repeated after a 3-month randomized controlled physical activity-based lifestyle intervention in obese children only. RESULTS: FSR of fibrinogen was higher (P = 0.002) in the obese (vs. lean) group, which was reduced (P = 0.001) after intervention. This almost completely accounted for the reduction in obesity-related hyperfibrinogenemia. High levels of D-dimer decreased (P = 0.001) after intervention, whereas fibrinolysis was not enhanced. CONCLUSIONS: The direct reduction in the FSR of fibrinogen and the remarkable correlation between the magnitudes of reduction in fibrinogen FSR and concentration signify a mechanistic role for FSR in the regulation of physical activity-induced reversal of hyperfibrinogenemia in obese children. The congruent reductions in the FSR of fibrinogen and the concentrations of fibrinogen and D-dimer in response to intervention despite depressed fibrinolysis suggest an overall improvement in the hypercoagulable state in obese children with physical activity-based lifestyle intervention.

Can glutamine and growth hormone promote protein anabolism in children with cystic fibrosis?

To determine whether recombinant human growth hormone (rhGH), glutamine (GLN) or a combination of both agents can enhance protein synthesis in cystic fibrosis (CF) patients, six 9.6 +/- 0.5-year-old prepubertal children (4 M, 2 F) with CF and stable lung disease with undernutrition (weight/height <50th percentile) or delayed growth (height <5th percentile) received stable isotope infusions, in the postabsorptive state and on 4 separate study days: (a) at baseline, and after a 4-week treatment with either, (b) oral GLN (0.7 g/kg/day), (c) rhGH (0.3 mg/kg/week, SC), or (d) both GLN and rhGH. Four-hour infusions of (13)C-leucine were used to assess leucine appearance rate (Ra, an index of protein breakdown), oxidation (Ox), and non-oxidative leucine disposal (NOLD, an index of protein synthesis). Results are expressed as changes (%) from baseline:We conclude that in children with CF: (1) due to high inter-subject variability, oral glutamine does not significantly enhance protein gain; (2) rhGH has significant anabolic effects which are mediated by stimulation of protein synthesis, and (3) glutamine does not enhance the effect of rhGH.

Growth hormone and sex steroids. Interactions in puberty.

Dynamic interactions among growth hormone, IGF-1, and sex steroidal hormones have a major role in the achievement of full height potential and the body composition changes in adolescence. Testosterone and estrogen affect the growth hormone neuroendocrine rhythms, and growth hormone, in turn, potentiates many of the metabolic actions of the sex steroids. Leptin is also thought to have a key regulatory role in the process of sexual development in the child, but the precise nature of these interactions is unclear. The targeted replacement of hormonal deficiencies in puberty and manipulation of the timing of pubertal maturation have resulted in better strategies to treat profoundly short children during this period; however, more research is needed to determine the consequences of such approaches in aspects of metabolism other than linear growth.

Recombinant human growth hormone and recombinant human insulin-like growth factor I diminish the catabolic effects of hypogonadism in man: metabolic and molecular effects.

Severe gonadal androgen deficiency can have profound catabolic effects in man. Hypogonadal men develop a loss of lean body mass, increased adiposity, and decreased muscle strength despite normal GH and insulin-like growth factor I (IGF-I) concentrations. We designed these studies to investigate whether GH or IGF-I administration to male subjects with profound hypogonadism can diminish or abolish the catabolic effects of testosterone deficiency. Moreover, we also examined the nature of the interactions among GH, IGF-I, and androgens in specific genes of the im system. A group of 13 healthy subjects (mean age, 22 +/- 1 yr) was studied at baseline (D1) and 10 weeks after being made hypogonadal using a GnRH analog (GnRHa; D2). At 6 weeks from baseline they were started on either recombinant human (rh) IGF-I (60 microg/kg, sc, twice daily) or rhGH (12.5 microg/kg, sc, daily) for 4 weeks. On each study day subjects had infusions of L-[(13)C]leucine; indirect calorimetry; isokinetic dynamometry of the knee extensors; determination of body composition (dual energy x-ray absortiometry) and hormone and growth factor concentrations, as well as percutaneous muscle biopsies. Their data were compared with those of previously studied male subjects who received only GNRHA: Administration of rhIGF-I and rhGH to the hypogonadal men had similar effects on whole body metabolism, with maintenance of protein synthesis rates, fat oxidation rates, and fat-free mass compared with the eugonadal state, preventing the decline observed with hypogonadism alone. This was further amplified by the molecular assessment of important genes in muscle function. During rhIGF-I treatment, im expression of IGF-I declined, and IGF-binding protein-4 increased, similar to the changes during GnRHa alone. However, rhGH administration was associated with a marked increase in IGF-I and androgen receptor messenger ribonucleic acid concentrations in skeletal muscle with a reciprocal decline in IGF-binding protein-4 expression in the hypogonadal men. The gene expression for myostatin did not change. These effects were accompanied by a much greater increase in plasma IGF-I concentrations after rhIGF-I (225 +/- 32 vs. 768 +/- 117 microg/L) compared with the concentrations achieved during rhGH (217 +/- 20 vs. 450 +/- 19 microg/L). We conclude that 1) rhGH and rhIGF-I both may be beneficial in preserving lean body mass and sustaining rates of protein synthesis during states of severe androgen deficiency in man; 2) GH may affect the im IGF system via an a paracrine, local production of IGF-I; 3) androgens may be necessary for the full anabolic effect of GH/IGF-I in man. These hormones, particularly GH, may play a role in the treatment of hypogonadal men rendered hypogonadal pharmacologically or those unable to take full testosterone replacement. The latter requires further study.

Growth hormone therapy in the glucocorticosteroid-dependent child: metabolic and linear growth effects.

Pharmacological doses of glucocorticosteroids given chronically are associated with a variety of negative side effects which impact the prolonged use of these potent anti-inflammatory agents. They have catabolic effects on protein, resulting in poor tissue healing, an increased incidence of infections and accelerated bone loss. Insulin resistance to both hepatic and peripheral tissues is a common consequence of chronic steroid use, leading at times to impaired carbohydrate metabolism. Steroids affect both the release and the effects of growth hormone (GH) at the target sites, hence becoming functional GH antagonists. When administered to growing children the side effects of glucocorticosteroid treatment are further compounded by a potent and significant suppression of linear growth. Ample experimental and clinical data support a role for GH therapy in counteracting some of the effects of glucocorticosteroids. Using isotope dilution methods we have previously shown that both GH and insulin-like growth factor (IGF)-I can decrease the protein wasting effects of prednisone administration in man. IGF-I has also been shown to enhance type I collagen formation in hydrocortisone-treated human osteoblasts. GH (through IGF-I) significantly enhances linear growth; thus, in states of "functional" GH deficiency, such as that observed in chronic steroid use, GH may also have a potentially beneficial effect. Studies in children on chronic prednisone doses with cystic fibrosis, chronic renal failure or juvenile rheumatoid arthritis have all shown beneficial effects on linear growth after prolonged GH therapy. Data from a recent study of ours using GH in children with steroid-dependent inflammatory bowel disease showed that GH treatment was associated with increased lean body mass, decreased adiposity and increased linear growth. Marked increases in IGF-I concentrations and in kinetic measures of bone calcium accretion (using calcium tracers) were also observed, without any deterioration of disease activity scores or carbohydrate tolerance. In conclusion, GH therapy may play a role in the treatment of children on chronic steroids both as a growth promoting agent and as an anabolic agent on whole body protein and bone. Longer term studies will be needed to better define the safety and efficacy of this approach.

High dose recombinant human growth hormone (GH) treatment of GH-deficient patients in puberty increases near-final height: a randomized, multicenter trial. Genentech, Inc., Cooperative Study Group.

GH production rates markedly increase during human puberty, mostly as an amplitude-modulated phenomenon. However, GH-deficient children have been dosed on a standard per kg BW basis similar to prepubertal children. This randomized study was designed to compare the efficacy and safety of standard recombinant human GH (rhGH) therapy (group I, 0.3 mg/kg x week) vs. high dose therapy (group II, 0.7 mg/kg x week) in GH-deficient adolescents previously treated with rhGH for at least 6 months. Ninety-seven children with documented evidence of GH deficiency (peak GH in response to stimuli, <10 ng/mL), with either organic or idiopathic pathology, were recruited. Both groups were matched for sex (group I, 42 males and 7 females; group II, 41 males and 7 females), age [group I, 14.0+/-1.6 (+/-SD) yr; group II, 13.7+/-1.6], standardized height (group I, -1.4+/-1.1; group II, -1.2+/-1.1), bone age (group I, 13.1+/-1.3 yr; group II, 13.1+/-1.3) etiology, maximum stimulated GH, previous growth rate, and midparental target height. All subjects were in puberty (Tanner stage 2-5) at study entry. Of the 97 subjects enrolled, 45 were treated for 3 yr or more; 48 completed the study. Of the subjects who discontinued the study, the most common reason was satisfaction with their height, although others discontinued for adverse events or personal reasons. The frequency of patients who discontinued was the same in both groups. The primary efficacy analysis was the difference between dose groups for near-adult height, defined as the height attained at a bone age of 16 yr or more in males and 14 yr or more in girls; all subjects who qualified were included in the analysis. This difference was statistically significant at 4.6 cm by analysis of covariance (ANCOVA; P < 0.001; n = 75). For subjects who received at least 4 yr of rhGH treatment, the difference between dose groups at that time point was 5.7 cm (by ANCOVA, P = 0.024; n = 20). The mean height SD score at near-adult height was -0.7+/-0.9 in the standard dose group and 0.0+/-1.2 in the high dose group. At 36 months the cumulative change in height (centimeters) was 21.5+/-5.3 cm (group I) vs. 25.1+/-4.9 (group II; P < 0.001, by ANCOVA); the change in Bayley-Pinneau predicted adult height was 4.8+/-4.2 cm (group I) vs. 8.4+/-5.7 (group II; P = 0.032). Median plasma IGF-I concentrations at baseline were 427 microg/L (range, 204-649) in group I and 435 microg/L (range, 104-837) in group II; at 36 months they were 651 microg/L (range, 139-1079) in group I vs. 910 microg/L (range, 251-1843) in group II (P = NS). No difference in change in bone age was detected between groups at any interval. High dose rhGH was well tolerated, with a similar safety profile as standard dose treatment and no difference in hemoglobin A1c or glucose concentrations between groups. In summary, compared to conventional treatment, high dose rhGH therapy in adolescents 1) increased near-adult height and height SD scores significantly, 2) did not increase the rate of skeletal maturation, and 3) appears to be well tolerated and safe. In conclusion, high dose rhGH therapy may have a beneficial effect in adolescent GH-deficient patients, particularly those who are most growth retarded at the start of puberty.

Growth hormone stimulation testing in both short and normal statured children: use of an immunofunctional assay.

Accurate interpretation of the results of GH stimulation tests is of pivotal importance not only in the evaluation of the etiology of growth retardation in children but also in the selection of the best candidates for GH therapy. We performed this study to test a novel immunofunctional GH ( IFGH) assay that makes use of the concept that one GH molecule dimerizes two GH receptors and compared the results with those obtained using two GH assays, the Diagnostic Systems Laboratories ELISA and a Hybritech immunoradiometric assay in 19 children with short stature undergoing routine GH stimulation testing. We also tested 13 normally statured control children to revisit the issue of what constitutes normal GH responses to stimuli, using all three assays and arginine and either L-dopa or insulin-induced hypoglycemia as secretagogues. Concentrations of IGF-I, IGF binding protein-3, and acid labile subunit were measured as well. There was a significant correlation between peak IFGH and Diagnostic Systems Laboratories ELISA GH responses to stimuli (r(2) = 0.93) as well as between the Diagnostic Systems Laboratories ELISA and Hybritech immunoradiometric assay (r(2) = 0.91). There were no significant differences between the short stature and normal group in peak or mean GH concentrations regardless of the assay used; however, the IGF-I, IGF binding protein-3, and acid labile subunit concentrations were substantially lower in the short stature group. There was a wide spectrum of GH concentrations in the normal group; approximately 50% of the children had peak GH concentrations <7 ng/mL, approximately 30% <5 ng/mL, and two pubertal normal subjects peaked to only 2 ng/mL with use of both the ELISA and IFGH assays. We conclude that 1) sensitive GH assays, ELISA and immunoradiometric assay, accurately detect a GH capable of generating a biologic signal comparable to an IFGH and 2) that normal GH stimulation test results can be substantially lower than previously accepted. GH-dependent growth factors may be more sensitive indicators of GH sufficiency than GH concentrations in response to pharmacologic stimuli.

Validation of a structured interview for the assessment of diabetes self-management.

OBJECTIVE: The authors developed and validated a semi-structured interview; the Diabetes Self-Management Profile (DSMP), to measure self-management of type 1 diabetes. The DSMP includes the following regimen components: exercise, management of hypoglycemia, diet, blood glucose testing, and insulin administration and dose adjustment. RESEARCH DESIGN AND METHODS: Families of youths with type 1 diabetes (n = 105) who were entering a controlled trial of intensive therapy (IT) versus usual care (UC) were administered the DSMP Analyses assessed the reliability and validity of the DSMP, including its associations with HbA1c and quality of life. RESULTS: The DSMP total score has adequate internal consistency (Cronbach's alpha 0.76), 3-month test-retest reliability (Pearson correlation, r = 0.67), inter-interviewer agreement (r = 0.94), and parent-adolescent agreement (r = 0.61). DSMP total scores (r = -0.28) and 3 subscales correlated significantly with HbA1c (diet [r = -0.27], blood glucose testing [r = -0.37], and insulin administration and dose adjustment [r = -0.25 ]). Adolescents' reports of self-management did not differ from parental reports. Higher DSMP scores were associated with more favorable quality of life for mothers and youths. CONCLUSIONS: The DSMP is a convenient measure that yields a reliable and valid assessment of diabetes self-management. Compared with extant similar measures, the DSMP is more strongly correlated with HbA1c.

Recombinant human insulin-like growth factor I has significant anabolic effects in adults with growth hormone receptor deficiency: studies on protein, glucose, and lipid metabolism.

The physiological effects of insulin-like growth factor I (IGF-I) on intermediate metabolism of substrates have been extensively studied in a variety of experimental situations in man, and its effects on linear growth of children with GH receptor mutations have proven beneficial. However, there is a paucity of data on the metabolic effects of IGF-I as replacement therapy in adults with GH receptor deficiency (Laron's syndrome). We designed these studies to investigate the in vivo effects of 8 weeks of therapy with recombinant human IGF-I (rhIGF-I) in a unique group of 10 adult subjects with profound IGF-I deficiency due to a mutation in the GH receptor gene (mean +/- SEM age, 29.2 +/- 2.0 yr; 4 males and 6 females). At baseline, patients had infusions of stable tracers, including L-[13C]leucine, [2H2]glucose, and d5-glycerol, as well as indirect calorimetry, assessment of body composition (dual energy x-ray absortiometry), and measurements of growth factor concentrations. Patients were then discharged to receive twice daily rhIGF-I (60 microg/kg, sc) for the next 8 weeks when the studies were repeated identically. Plasma IGF-I concentrations increased during rhIGF-I treatment from 9.3 +/- 1.5 microg/L to 153 +/- 23 (P = 0.0001). There was no change in weight during these studies, but a significant change in body composition was observed, with a decrease in percent fat mass (P = 0.003) and an increase in lean body mass (P = 0.001). These were accompanied by increased rates of protein turnover, decreased protein oxidation, and increased rates of whole body protein synthesis, as measured by leucine tracer methods (P < 0.01). These results are similar to those observed in GH-deficient subjects treated with GH. All measures of lipolytic activity and fat oxidation increased during treatment, with an 18% increase in the glycerol turnover rate (P = 0.04), an increase in free fatty acid and beta-hydroxybutyrate concentrations, and a significant increase in fat oxidation, as measured by indirect calorimetry (P = 0.04). There were significant decreases in insulin concentrations (P = 0.01) and a reciprocal increase in glucose production rates (P = 0.04) during rhIGF-I, yet plasma glucose concentrations remained constant, suggestive of a significant insulin-like action of this peptide. RhIGF-I was well tolerated by all patients. In conclusion, 8 weeks of treatment with rhIGF-I had significant positive effects on body composition and measures of intermediate metabolism independent of GH. These results suggest that, similar to GH treatment of adults with GH deficiency, rhIGF-I may be beneficial as long term replacement therapy for the adult patient with Laron's syndrome.

Estrogen suppression in males: metabolic effects.

We have shown that testosterone (T) deficiency per se is associated with marked catabolic effects on protein, calcium metabolism, and body composition in men independent of changes in GH or insulin-like growth factor I production. It is not clear,,however, whether estrogens have a major role in whole body anabolism in males. We investigated the metabolic effects of selective estrogen suppression in the male using a potent aromatase inhibitor, Arimidex (Anastrozole). First, a dose-response study of 12 males (mean age, 16.1 +/- 0.3 yr) was conducted, and blood withdrawn at baseline and after 10 days of oral Arimidex given as two different doses (either 0.5 or 1 mg) in random order with a 14-day washout in between. A sensitive estradiol (E2) assay showed an approximately 50% decrease in E2 concentrations with either of the two doses; hence, a 1-mg dose was selected for other studies. Subsequently, eight males (aged 15-22 yr; four adults and four late pubertal) had isotopic infusions of [(13)C]leucine and (42)Ca/(44)Ca, indirect calorimetry, dual energy x-ray absorptiometry, isokinetic dynamometry, and growth factors measurements performed before and after 10 weeks of daily doses of Arimidex. Contrary to the effects of T withdrawal, there were no significant changes in body composition (body mass index, fat mass, and fat-free mass) after estrogen suppression or in rates of protein synthesis or degradation; carbohydrate, lipid, or protein oxidation; muscle strength; calcium kinetics; or bone growth factors concentrations. However, E2 concentrations decreased 48% (P = 0.006), with no significant change in mean and peak GH concentrations, but with an 18% decrease in plasma insulin-like growth factor I concentrations. There was a 58% increase in serum T (P = 0.0001), sex hormone-binding globulin did not change, whereas LH and FSH concentrations increased (P < 0.02, both). Serum bone markers, osteocalcin and bone alkaline phosphatase concentrations, and rates of bone calcium deposition and resorption did not change. In conclusion, these data suggest that in the male 1) estrogens do not contribute significantly to the changes in body composition and protein synthesis observed with changing androgen levels; 2) estrogen is a main regulator of the gonadal-pituitary feedback for the gonadotropin axis; and 3) this level of aromatase inhibition does not negatively impact either kinetically measured rates of bone calcium turnover or indirect markers of bone calcium turnover, at least in the short term. Further studies will provide valuable information on whether timed aromatase inhibition can be useful in increasing the height potential of pubertal boys with profound growth retardation without the confounding negative effects of gonadal androgen suppression.

Insulin-like growth factor I and growth hormone (GH) treatment in GH-deficient humans: differential effects on protein, glucose, lipid, and calcium metabolism.

We examined the effects of recombinant human (rh) insulin-like growth factor I (IGF-I) vs. rhGH in a variety of metabolic paths in a group of eight severely GH-deficient young adults using an array of contemporary tools. Protein, glucose, and calcium metabolism were studied using stable labeled tracer infusions of L-[1-13C]leucine, [6,6-2H2]glucose, and 42Ca and 44Ca; substrate oxidation rates were assessed using indirect calorimetry; muscle strength was determined by isokinetic and isometric dynamometry of the anterior quadriceps, as well as growth factors, hormones, glucose, and lipid concentrations in plasma before and after 8 weeks of rhIGF-I (60 microg/kg, sc, twice daily), followed by 4 weeks of washout, then 8 weeks ofrhGH (12.5 microg/kg-day, sc); the treatment order was randomized. In the doses administered, rhIGF-I and rhGH both increased fat-free mass and decreased the percent fat mass, with a more robust decrease in the percent fat mass after rhGH; both were associated with an increase in whole body protein synthesis rates and a decrease in protein oxidation. Neither hormone affected isokinetic or isometric measures of skeletal muscle strength. However, rhGH was more potent than rhIGF-I at increasing lipid oxidation rates and improving plasma lipid profiles. Both hormones increased hepatic glucose output, but rhGH treatment was also associated with decreased carbohydrate oxidation and increased glucose and insulin concentrations, indicating subtle insulin resistance. Neither hormone significantly affected bone calcium fluxes, supporting the concept that these hormones, by themselves, are not pivotal in bone calcium metabolism. In conclusion, rhIGF-I and rhGH share common effects on protein, muscle, and calcium metabolism, yet have divergent effects on lipid and carbohydrate metabolism in the GH-deficient state. These differences may allow for better selection of treatment modalities depending on the choice of desired effects in hypopituitarism.

Estrogen treatment and estrogen suppression: metabolic effects in adolescence.

The metabolic consequences of reaching full reproductive maturity in humans involve not only growth hormone (GH) and insulin-like growth factor-I, but also the collaborative interaction of the gonadal sex steroids. Estrogen is critical for completing linear growth. It also inhibits bone resorption, decreases plasma lipid levels and serves as an antiatherosclerotic agent. Our studies show that, in low doses, estrogen increases GH production, increases calcium absorption and decreases bone turnover; however, unlike testosterone, estrogen has no effects as a protein-anabolic agent, at least at the whole body level. Studies of selective estrogen suppression, achieved using a potent aromatase inhibitor, show that estrogen is the main regulator of the gonadotropin axis. In boys, selective aromatase blockade may have a role in delaying epiphyseal fusion. Large placebo-controlled trials will be required to study this effect further.

Pharmacokinetics of insulin-like growth factor I in hypopituitarism: correlation with binding proteins.

We investigated the pharmacokinetics of recombinant human insulin-like growth factor I (rhIGF-I) in growth hormone deficiency (GHD). Nine GHD adults [age 25 +/- 3 (SE) yr] received rhIGF-I (60 microgram/kg sc) twice, 10 h apart, and blood was sampled over 24 h. IGF-I and free IGF-I concentrations increased, whereas IGF binding protein 3 (IGFBP-3) and acid labile subunit (ALS) were unchanged during treatment. There was no correlation between absorption or terminal half-life of IGF-I and IGFBP-3 or ALS, but negative correlations with IGF-I clearance (CL/F) and volume of distribution (V/F). Positive correlations between both IGFBP-3 and ALS and IGF-I maximal concentration (C(max)) and time of C(max) (T(max)) were observed. Compared with normal individuals studied similarly (using 80 microgram/kg), GHD subjects showed a normal absorption half-life, a faster elimination half-life, lower C(max), yet normal T(max) and V/F. In conclusion, GHD is associated with normal absorption and distribution of IGF-I yet faster elimination kinetics. Additionally, IGFBP-3 and ALS concentrations modulate the peak concentrations of IGF-I achieved and correlate reciprocally with its V/F and CL/F, underscoring the critical importance of binding proteins in modulating the bioavailability of IGF-I in vivo in humans.

Profound hypogonadism has significant negative effects on calcium balance in males: a calcium kinetic study.

The impact of estrogen deficiency on bone has been extensively studied in the female; however, the effects of androgen deficiency on calcium fluxes in males have been less well characterized. We investigated the effect of short-term, severe androgen deficiency on measures of calcium absorption and kinetics as well as on markers of bone turnover in males. To accomplish this, 11 healthy male volunteers were recruited (mean age 23.3 +/- 0.5 years [SEM], body mass index 25.3 +/- 0.8 kg/m2). They consumed a weight maintenance diet for at least 3 days prior to admission to our Research Unit, with a calcium intake of approximately 1200 mg/day. At baseline (D1), subjects received 42Ca intravenously as well as 44Ca PO mixed with milk or juice. A 29-h urine collection was begun and blood samples collected at frequent intervals for the measurement of the isotopic enrichment of 42Ca and 44Ca using thermal ionization mass spectrometry. Twice daily urine samples were collected for 5 days after the administration of the isotopes. A gonadotropin-releasing hormone agonist (Lupron) was given after D1, again 3 weeks later, and studies repeated identically 4 weeks (D2, n = 6) and 10 weeks from baseline (D3, n = 7) (two subjects completed three studies). Testosterone concentrations were markedly suppressed on both D2 and D3 (-95%, p < 0.006), whereas there were no detectable changes in growth hormone and insulin-like growth factor-1 concentrations. Urinary calcium excretion increased significantly after 4 weeks (43%, p = 0.0007) and 10 weeks (73%, p = 0.003) of sustained hypogonadism. Using a multicompartmental kinetic model, the contribution of oral calcium to the urinary losses was decreased by D3 (-41%, p = 0.01), yet the contribution of bone calcium to urine losses increased by 10 weeks (+11%, p = 0.01). There was a 21% decrease in bone calcium deposition (Vo+) by D3 (p < 0.05) with no significant change in bone resorption rates (Vo-). There was a significant correlation between the decrease in testosterone concentration and the increase in urinary calcium excretion, especially at 10 weeks (R2 = 0.84, p = 0.004). These kinetic changes were accompanied by a decrease in osteocalcin concentrations on D2, with improvements by D3. Urinary N telopeptide, a measure of bone resorption, also increased during the studies. In summary, profound hypogonadism in young males is associated with marked increases in urinary calcium losses, with a greater contribution of bone calcium to those losses and decreased kinetic markers of bone calcium deposition. We conclude that even short-term, severe deficiency in gonadal steroids can have profound negative effects on calcium and bone metabolism in males.

Is glutamine a 'conditionally essential' amino acid in Duchenne muscular dystrophy?

To determine whether whole body protein kinetics are altered in Duchenne muscular dystrophy (DMD), six 9 +/- 1-year-old children with DMD and five weight and height matched controls, received intravenous infusion of L-[1-(13)C]leucine and L-[2-(15)N]glutamine in the post-absorptive state. Glutamine rate of appearance was approximatly 24% lower in DMD boys than in controls (321 +/- 22 vs 425 +/- 37 micromol kg(-1)h(-1), P< 0.05) resulting from a 32% decrease in glutamine de novo synthesis (230 +/- 21 vs 340 +/- 34 micromol kg(-1)h(-1), P< 0.05). Whereas there was no difference between groups in estimates of protein degradation and synthesis, leucine oxidation rate was 44% higher in DMD boys than in controls (23 +/- 2 vs 16 +/- 2 micromol kg(-1)h(-1), P< 0.05). The data suggest that the dramatic mucle mass loss observed in DMD boys is associated with a) significant protein wasting, since increased leucine oxidation reflects a more negative whole body leucine balance, and b) a significant decrease in glutamine availability in the postabsorptive state. Glutamine might therefore be a 'conditionally essential' amino-acid in DMD.

Growth hormone, insulin-like growth factor I and sex hormones: effects on protein and calcium metabolism.

The availability of non-invasive tracer technologies has greatly facilitated the study of the metabolic effects of nutrients and hormones, particularly in children. This brief review examines recent work on the effects of growth hormone (GH), insulin-like growth factor I (IGF-I), testosterone and oestrogen on rates of protein synthesis and degradation and lipolysis, as well as on body composition and bone calcium fluxes in young children and adults. GH acts indirectly on whole body protein pools via IGF-I, but GH appears to act directly on lipolysis. Testosterone stimulates protein synthesis independently of changes in GH concentrations and acts synergistically with GH to enhance whole body metabolism. Oestrogens and androgens both modulate calcium fluxes, enhancing calcium absorption and retention, and thereby underscoring the importance of both groups of hormones in bone calcium metabolism. Further understanding of the physiological role of these hormones during the critical years of adolescence will give us better tools with which to treat disorders of puberty and growth.