Biomedical subjects
Publications and source records attributed to S A Chalew.
Preliminary laboratory and clinical studies suggest that the clinical onset of type 1 diabetes can be delayed or prevented in high-risk individuals. The NIH sponsored Diabetes Prevention Trial Type 1 is currently underway to determine whether prevention is possible using insulin to alter the autoimmune process.
Several studies have suggested that testosterone may have a direct, GH-independent effect on growth. In order to assess possible mechanism(s) whereby testosterone exerts its growth-promoting effect, we evaluated its effect on growth mediators of the GH-IGF-I axis, in both the liver and the epiphyseal growth plate (EGP). Testosterone was administered to peripubertal rats and the responses of mRNA of GH receptor, IGF-I, IGF-I receptor and IGF-binding proteins-1 and -3 (IGFBP-1 and IGFBP-3) as well as circulating IGF-I were evaluated in two time-related models: over 12 h after a single injection (short-term study) and 10 days after continuous administration (long-term study). Rats in the short-term study were castrated and were killed 1, 4, 6 and 12 h post injection. Rats in the long-term study were divided into two groups: castrated vs castrated and hypophysectomized, in order to assess the effect of testosterone in the presence and absence of GH. mRNA levels were determined by RNase protection assay, and serum IGF-I by RIA. Testosterone enhanced weight gain in the rats treated for 10 days, a change that was similar in the presence or absence of GH. This effect was relatively small, however, by comparison with the total weight gained without testosterone. Testosterone had no effect on hepatic IGF-I mRNA abundance but induced a reduction in circulating IGF-I levels, in both the short- and long-term study. Testosterone had no effect on hepatic GH receptor and IGFBP-3 mRNA levels but resulted in a transient, short-term elevation in IGFBP-1 mRNA levels that was maximal 4 h post injection. In the EGP, neither testosterone administration nor hypophysectomy had any effect on IGF-I and IGF-I receptor mRNA levels. However, testosterone increased GH receptor mRNA abundance after 10 days of continuous administration in hypophysectomized rats only. These data suggest that the effect of testosterone on growth (as assessed by weight gain) is small and is not mediated by changes in hepatic gene expression of IGF-I, IGF-I receptor, IGFBP-1, IGFBP-3 or circulating IGF-I. At the EGP, the testosterone effect on linear growth is not mediated through changes in mRNA abundance of IGF-I and IGF-I receptor. The small but significant elevation of GH receptor mRNA levels in hypophysectomized rats may suggest a testosterone-mediated augmentation of a GH effect at the target organ.
Serum phosphate (PO4) levels and the tubular threshold for PO4 corrected for glomerular filtration (TP/GF) are age-dependent, being higher in children than in adults. We evaluated the effect of age on the response to infusion of parathyroid hormone(1-34) (PTH) in healthy children (n = 8) and adults (n = 12). In addition, six patients with pseudohypoparathyroidism (PHP) and two with PTH deficiency (hypoparathyroidism [HP]) were also studied. At baseline, TP/GF in normal subjects was inversely correlated with urinary cyclic adenosine monophosphate corrected for glomerular filtration (UcAMP/GF) (P < .0359). After PTH administration in the controls, UcAMP/GF was inversely correlated with TP/GF (P < .0007) and directly correlated with maximal fractional extraction of PO4 (FEP) (P < .0002). The slope of the regression of TP/GF (P < .0076) and FEP (P < .0034) with UcAMP/GF was steeper in children than in adults. Two HP patients had high PTH-stimulated UcAMP/GF levels, but stimulated TP/GF and FEP were not changed commensurate with levels that would expected from the normative data. In six patients with PHP, PTH-stimulated TP/GF was also correlated with peak UcAMP/GF (r = .96, P < .002). PHP patients could be distinguished from normal controls based on the combination of low peak FEP or high TP/GF together with low peak UcAMP/GF. Thus, in normal subjects, the phosphaturic response to PTH is correlated with the increase in urinary cAMP and is age-dependent, with a greater decrease of TP/GF in children than in adults.
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Eight short patients with normal 24-hour integrated concentration of growth hormone by continuous withdrawal (IC-GH) received 6 months of GH therapy, followed by 6 months off. GH therapy increased growth rate (+2.9 cm/yr), repeated IC-GH (sixfold), and IGF-1 concentration (twofold). Posttreatment growth reverted to the pretreatment rate. Thus increased growth rate and IGF-1 concentration is associated with supraphysiologic IC-GH after injection.
Growth hormone (GH)-binding protein (GHBP) and GH secretion are potential mediators of linear growth in children. To study the relationship between these variables, we measured GHBP activity, peak stimulated GH (PKGH), and 24-hour integrated GH concentration (ICGH) in 76 children referred for evaluation of growth. Linear growth was expressed as an age- and sex-specific growth rate standard deviation score (GRSD), which was calculated from sequential height measurements in the 6-month period immediately before GH testing. Using multiple regression models, we found that the relationship between GHBP and growth (GRSD) depended on height (height standard deviation [HGTSD] expressed as an age- and sex-specific z score) controlling for ICGH or PKGH. In further analysis of this relationship, we divided the subjects by HGTSD in subsequent analyses. In 19 children of normal stature (HGTSD > -2), GRSD increased with GH concentration (measured both as PKGH and ICGH: P <.013,R2 = .56) but decreased with higher levels of GHBP (P < .005,R2 = .62). In contrast, for 57 subjects with severe short stature (HGTSD < or = -2), GRSD could not be predicted from GHBP, GH secretion, HGTSD, or interaction involving these variables. These data suggest the hypothesis that under normal conditions, GHBP and GH level may be important predictors of growth rate in children.
We measured the ratio of GH by radioreceptor assay (RRA) using IM-9 cells to its radioimmunoassay (RIA) level in: (a) 25 children and young adults with normal growth (controls); (b) 7 poorly growing children with GH neurosecretory dysfunction (GHND) who had normal stimulated GH but subnormal integrated concentration of GH (IC-GH) who responded to GH therapy; (c) 4 poorly growing children who had both normal stimulated GH and IC-GH but did not respond to GH therapy (GHNR - GH responder), and (d) 7 poorly growing patients with normal stimulated, and IC-GH who responded to GH therapy (GHR - GH responder). The RRA/RIA ratio of the GHND group was 1.3 +/- 0.4 similar to that of the control group - 1.3 +/- 0.3. The mean RRA/RIA ratio of the 7 GHR patients was 0.6 +/- 0.5, significantly lower than the controls and the GHND patients (p < 0.05). The RRA/RIA ratios of the 4 GHNR patients was not different from the controls. We conclude that: (1) GH binding is normal in GHNR and GHND patients and (2) RRA/RIA ratio below the normal range as measured by IM-9 cell GH RRA in short, poorly growing children with normal GH secretion, was a predictor of the response to GH therapy.
The recent finding of an activating mutation in the Gs alpha protein, the protein that couples receptors to stimulation of adenylate cyclase, from endocrine and nonendocrine tissues of patients with McCune-Albright syndrome (MAS) suggests that alterations in adenylate cyclase activity may account for the clinical abnormalities in these patients. Many patients with MAS have hypophosphatemia. This may result from the presence of the activating Gs alpha mutation in proximal renal tubules or the elaboration of a phosphaturic factor from fibrous dysplasia. We, therefore, sought to characterize renal cAMP generation and phosphate handling in MAS patients. Intravenous infusion of PTH is a classic clinical test used to evaluate hormonal responsiveness of renal proximal tubule adenylate cyclase and examine PTH-dependent phosphate clearance. We performed PTH infusion in 6 MAS patients, 10 normal subjects, and 6 patients with pseudohypoparathyroidism (PHP). The basal urinary cAMP (UcAMP) level in the MAS group [5.5 +/- 2.6 nmol/dL glomerular filtration (GF)] was elevated (P < 0.05) compared to those in both normal subjects (3.2 +/- 1.2 nmol/dL GF) and patients with PHP (1.9 +/- 0.6 nmol/dL GF). However, PTH-stimulated peak UcAMP (15.0 +/- 7.0 nmol/dL GF) and the peak/basal UcAMP ratio (3.1 +/- 1.7) in MAS were significantly lower than the respective values in normal subjects (30.8 +/- 16.9 nmol/dL GF and 9.3 +/- 2.9; P < 0.05 for both) and were statistically similar to the blunted levels in PHP (respectively, 3.1 +/- 1.5 nmol/dL GF and 2.0 +/- 1.7). By contrast, the PTH-induced phosphaturic response in MAS patients was similar to that in the normal subjects. Our study provides clinical evidence that MAS patients have altered renal adenylate cyclase activity, manifested by an elevated basal UcAMP, but a blunted UcAMP response to PTH stimulation. These observations are presumably due to a mutation in the Gs alpha protein in the renal tubules. Despite the blunted UcAMP excretion, the phosphaturic response to PTH in MAS patients is intact.
OBJECTIVE: To evaluate the effect of a standard dose of injected recombinant growth hormone on the integrated concentrations of growth hormone and insulin. DESIGN: Integrated concentrations were studied in patients receiving growth hormone therapy before and on the day of injection. SETTING: Pediatric endocrine clinic and diagnostic unit. PATIENTS: Twelve growth hormone-deficient patients with poor linear growth and deficient growth hormone response to provocative stimulation and/or 24-hour integrated concentration. INTERVENTION: Patients received subcutaneous injections of 0.06 mg/kg of growth hormone three times a week in the evenings at approximately 8 PM. Integrated concentrations were measured again approximately 6 months after the start of therapy at the time of a growth hormone injection. MEASUREMENTS AND RESULTS: Mean growth hormone dose administered was 2.0 +/- 0.5 mg. Integrated concentration of growth hormone was 2.2 +/- 0.9 micrograms/L before therapy. The integrated concentration of growth hormone after treatment (14.6 +/- 4.2 micrograms/L) was significantly higher than that before treatment and that of normally growing children (P < .001). After injection, peak growth hormone level was 53.7 +/- 24.1 micrograms/L; time to peak growth hormone level, 4.8 +/- 1.2 hours; constant of elimination, 0.24 +/- 0.06 per hour; half life, 3.0 +/- 0.7 hours; area under the curve, 328 +/- 85 (microgram.h)/L; clearance rate, 107.6 +/- 34.3 mL/min (3.2 +/- 0.8 mL/min per kilogram based on weight, 95.2 +/- 24.2 mL/min per meter squared based on surface area). There was no relationship between integrated concentration of growth hormone or pharmacokinetic variables after treatment and the growth response to 6 months' therapy. Integrated concentration of insulin before treatment was 19.0 +/- 10.9 mU/L, which was significantly lower than that after injection of growth hormone (33.4 +/- 9.5 mU/L; n = 9, P < .0008). CONCLUSIONS: Integrated concentrations of growth hormone after an injection of 0.06 mg/kg of growth hormone are considerably higher than spontaneous integrated concentrations of growth hormone observed in normally growing children, and associated with a rise in insulin secretion. These changes may be pertinent in patients with underlying insulin resistance or when higher doses of growth hormone are used for therapy.
OBJECTIVE: To compare the 24-hour integrated concentrations of plasma growth hormone with growth hormone levels in a simultaneously collected sample of urine. SETTING: Pediatric endocrine diagnostic unit. PATIENTS: Forty-six children (41 male and five female) aged 6 to 19 years underwent measurement of integrated concentrations of growth hormone and simultaneous urine collection. MEASUREMENTS AND RESULTS: Integrated concentration of plasma growth hormone was correlated with urinary growth hormone levels from both the 24-hour (r = .67; P < .0001) and 12-hour overnight (r = .52; P < .001) measurements. Peak growth hormone response to paired stimulation was not correlated with either the 24-hour (r = .26; P < .23; n = 28) or 12-hour (r = .16; P < .48; n = 28) urinary growth hormone levels. The mean 24- and 12-hour urinary growth hormone levels for the patients with normal integrated concentrations of growth hormone were significantly higher than those in patient groups having subnormal integrated concentrations of growth hormone (P < .05). However, there was considerable overlap in the 12- and 24-hour urinary growth hormone levels between the patients with normal and those with subnormal integrated concentrations of growth hormone. Only one patient who had subnormal integrated concentrations of growth hormone had a 24-hour urinary growth hormone level higher than 9 ng, and none had a 12-hour urinary growth hormone level higher than 7 ng. The mean 12- and 24-hour urinary growth hormone levels were significantly higher in patients who received growth hormone injection than in those with normal spontaneous integrated concentrations of growth hormone and had no overlap with patients who had subnormal integrated concentrations of growth hormone. CONCLUSIONS: (1) Urinary and integrated concentrations of plasma growth hormone are correlated; (2) patient diagnoses based on integrated plasma growth hormone levels exhibit a high degree of overlap of urinary growth hormone; and (3) urinary growth hormone levels can serve to monitor compliance with growth hormone therapy.
In order to assess the influence of age, sex, and body mass on plasma cortisol concentrations, we measured the 24-hour Integrated Concentration (IC) of cortisol (F) in 36 obese subjects (16 males, 20 females) aged 5.3-56.4 years, BMI = 35.5 +/- 7.3 kg/m2 and compared with 119 nonobese subjects, body mass indices (BMI) 21.2 +/- 2.7 kg/m2, aged 8.8-66.2 years (55 males, 64 females). Subjects were nondiabetic, normotensive, without history of psychiatric illness, and otherwise in good health. IC studies were performed using a continuous blood withdrawal methodology, and IC-F was assayed from the 24 hour pooled sample by a protein binding method. The effect of age and gender on IC-F was analyzed by multivariate regression. In the nonobese group there was no effect of age or sex on IC-cortisol levels, the mean IC-F = 173.8 +/- 44.1 nmol/L. A statistically significant but weak negative effect of BMI on IC-cortisol (r=-.18, p<0.05) was present. In the obese subjects there was a significant increase in IC-cortisol levels with age IC-F(nmol/L) = 2.76 x age(years) + 85.0 (r2=.36, p<0.0001). IC-cortisol levels tended to be lower in obese males than females when controlled for age (p<0.05). We conclude that in nonobese subjects IC-F levels are independent of age and gender. However, there is a significant increase of IC-cortisol levels with age in obese individuals. The observed increase of IC-cortisol with age may contribute to metabolic complications of obesity.
OBJECTIVE: We assessed the relationship between serum IGFBP-3 levels with IGF-I and quantitative GH secretory status in poorly growing children. DESIGN: We studied the relationship between 24-hour integrated concentration of GH, peak GH to paired sequential stimulation tests, IGF-I and the IGFBP-3 serum levels. PATIENTS: One hundred and two children (82 males, 20 females, age 11.7 +/- 2.7 years) with short stature (height -2.6 +/- 0.7 SDS) were studied. MEASUREMENTS: Quantitative GH secretory status was assessed by the 24-hour integrated GH and by response to arginine and insulin stimulation. GH, IGFBP-3 and IGF-I were measured by radioimmunoassay. To adjust for age and gender, IGFBP-3 levels were converted to SD score. RESULTS: IGFBP-3 SDS was strongly correlated with IGF-I SDS (r = 0.64, P < 0.0001), and weakly with peak GH (r = 0.28, P < 0.0004), but not with the integrated GH concentration (r = 0.07, P < 0.46). IGFBP-3 SDS increased with pubertal maturation (P < 0.0001). There was no difference in mean IGFBP-3 SDS in subgroupings of the patients based on the results of their quantitative GH tests. CONCLUSION: In short children, IGFBP-3 levels increase with puberty, are strongly correlated with IGF-I levels, weakly correlated with peak response to GH stimulation tests, but not correlated with integrated GH. Consequently, diagnostic classifications of patients based on quantitative measurements of GH secretion and IGFBP-3 differ.
OBJECTIVE: To assess the usefulness of specific cardiovascular reflex tests in childhood and to estimate the prevalence of cardiovascular reflex abnormalities among children with IDDM. In adults, abnormal cardiovascular reflexes are a frequent complication of diabetes, associated with increased morbidity and mortality. RESEARCH DESIGN AND METHODS: We measured heart-rate responses to deep breathing and standing in ambulatory children with and without IDDM between 6-19 yr of age. A subgroup of the IDDM patients was retested after 1 yr. RESULTS: We found the best techniques for detecting cardiovascular reflex abnormality in children were as follows: to record heart-rate responses to deep breathing either as the change in heart rate corrected for inspiratory heart rate or as the ratio of R-R intervals during expiration and inspiration; and to use the Maximum-minimum ratio for heart-rate responses to standing. HR-DBc was lower in diabetic than nondiabetic children (28.6 +/- 9.2% [n = 248] vs. 33.6 +/- 6.8% [n = 60]; P < 0.0005). Similarly, E:I was lower in children with IDDM than control subjects (1.42 +/- 0.19 [n = 248] vs. 1.52 +/- 0.15 [n = 60]; P < 0.0005). In the IDDM group, 21% of the children had abnormal HR-DBc or E:I responses. HR-STND M/m was lower in children with IDDM than control subjects (1.28 +/- 0.20 [n = 167] vs. 1.38 +/- 0.22 [n = 45]; P < 0.014). Among children with IDDM, 11.4% had abnormal HR-STND M/m responses. Overall, 29% of IDDM children tested abnormal in either HR-DBc or HR-STND M/m; 3% were abnormal in both tests. We found no correlation of HbA1c levels (n = 74) or duration of diabetes with either HR-DB, expiration to inspiration (n = 248), or HR-STND M/m (n = 167). In patients who were reevaluated after 1 yr we found a high correlation of the first and repeat HR-DBc tests (r = 0.47, n = 75, P < 0.0001), E:I (r = 0.53, n = 75, P < 0.0001), and HR-STND M/m (r = .49, n = 37, P < 0.002), but no evidence of an increased number of children with cardiovascular reflex abnormality. CONCLUSIONS: With easily performed HR-DB and HR-STND tests, we detected cardiovascular reflex abnormality in 29% of children with IDDM. We found no correlation of changes in HR-DB and HR-STND with HbA1c or duration of diabetes. These tests provide an objective clinical measurement to monitor autonomic neuropathy in children with diabetes.
OBJECTIVE: To determine the effect of third-party reimbursement on the use of services and indexes of diabetes-related health management among inner-city diabetic patients. RESEARCH DESIGN AND METHODS: Adult diabetic patients (n = 158; 67% women, 33% men) from an inner-city diabetes clinic were categorized by level of third-party medical coverage: complete reimbursement for all services (full); partial reimbursement (part); and no reimbursement (none). Patients were followed for 13 mo. Use of billable medical services, diabetes clinic visits, emergency room visits, and hospital admissions were recorded. Use of a free, day-time diabetes telephone hot line was also documented. Indexes of diabetes-related health management, HbA1, blood pressure, and weight were compared from the beginning and the end of the study. Diabetes complications were scored and tabulated. RESULTS: Univariate analysis showed that patients with full reimbursement were more likely to use services than patients without reimbursement. When the combined effects of reimbursement status, age, sex, type of diabetes, and diabetes complications on use of services were analyzed together in a multivariate analysis, complications was the best predictor of admissions to the hospital and whether a patient called the hot line. IDDM patients and patients with full reimbursement were most likely to have an emergency room visit. Age was the best predictor of diabetes clinic attendance. No difference was noted in blood pressure or weight among the reimbursement groups at the beginning and end of study. However, the trend was toward (P < 0.05) an increase in HbA1 in the none group. CONCLUSIONS: Among inner-city diabetic patients, multiple factors influence use of medical services. Indigent diabetic patients without third-party reimbursement were observed to have a rise in HbA1. These factors should be taken into consideration when planning strategies to prevent diabetes complications and the most effective allocation of health-care resources.
Spontaneous growth hormone (GH) secretion is evaluated by measurement of the 24-hour integrated concentration of GH (24-hour IC-GH), a major diagnostic procedure, or by shorter protocols such as monitoring 6 h during sleep. We have evaluated several possibilities for shortening the procedure by comparing the results of an abbreviated procedure to the 24-hour IC-GH studies. The study population consisted of 50 children with classic GH deficiency (group GHD), determined by provocative testing, and 45 children who had a subnormal secretion of GH (group N), determined by low 24-hour IC-GH but normal GH provocative tests. Twenty-two children of normal height and stature served as a control group. All the children were prepubertal, while there was no overlap between the lower 5th percentile of the 24-hour IC-GH of the control subjects (3.3 micrograms/l) and the upper 97th percentile of the 24-hour IC-GHs of the N and GHD groups (2.9 and 2.7 micrograms/l, respectively), there was a considerable overlap between the IC-GH of control subjects and that of the GHD and N groups measured in all the abbreviated blood withdrawal protocols, except for the 10-hour daytime and the 12-hour nighttime protocols of the GHD patients. It should be noted that there was only a small overlap between the control and the GHD groups during the 12-hour daytime protocol. We have found that the longer the blood collection period the greater the sensitivity and the specificity. We conclude that the 24-hour IC-GH test is the best diagnostic tool for identifying children with subnormal GH secretion.
GH spontaneous peaks and their diagnostic utility have not been previously evaluated by means of a 24-h continuous withdrawal (CW) procedure in children with growth disorders. Using a CW pump, we studied the 24-h spontaneous secretion of GH in 129 prepubertal subjects grouped as follows. The control group (C) consisted of 20 children of normal height and growth rate. Group GHD consisted of 53 patients with classical GH deficiency (48 idiopathic and 5 organic). The NSD group consisted of 36 patients with a growth velocity below 4.5 cm/yr, normal GH response to provocative stimuli (PS), but a mean 24-h GH in the deficient range. Group NSS consisted of 20 short children with normal growth velocity, normal PS, and normal mean 24-h GH concentration. The mean GH levels for the 24-h period were 4.1 +/- 1.7, 1.4 +/- 0.5, 2.1 +/- 0.7, and 4.2 +/- 1.9, respectively, for the C, GHD, NSD, and NSS groups. For each subject, GH levels were determined in 48 0.5-h samples collected during the CW study, and the GH profile was analyzed by the Pulsar computer program. The mean number of peaks was 9.0 +/- 2.5 for C, 9.5 +/- 3.7 for GHD, 10.5 +/- 1.8 for NSD, and 9.5 +/- 3.2 for NSS. There was no statistical difference between groups. The mean amplitude of peaks was 9.8 +/- 8.9 for C, 1.6 +/- 1.0 for GHD, 2.9 +/- 1.3 for NSD, and 9.9 +/- 9.1 for NSS. Mean peak amplitudes in both GHD and NSD were significantly lower than in the C and NSS groups. The presence of peaks of more than 8 micrograms/L during the daytime (0800-2000 h) was a characteristic of children with normal integrated GH concentration (IC-GH) and was seen in 90% of normally growing children but in only 7% of poorly growing children with subnormal IC-GH. There was no significant difference in the number of pulses during the night between C and NSD groups. We conclude that differences in IC-GH between normally growing and poorly growing children are due to a lower amplitude of peaks during the daytime hours.
Obesity in childhood is characterized by subnormal integrated concentrations of growth hormone (IC-GH) and elevated integrated concentrations of insulin (IC-I). We tested whether a reduction of IC-I induced by a low calorie diet would lead to a rise of IC-GH into the normal range for age. Six obese children (body mass index (BMI) 39.1 +/- 9.2 kg/m2) underwent integrated concentration (IC) studies by continuous withdrawal before and again 5-8 weeks after being on a low calorie diet. In response to the diet BMI was lower 34.7 +/- 9.4 kg/m2 (P less than 0.003), and IC-I was considerably reduced, 479 +/- 255 pM initially vs. 109 +/- 109 pM on the diet, P less than 0.0008. IC-GH increased modestly from 1.6 +/- 0.6 micrograms/l initially to 2.4 +/- 0.6 micrograms/l, P less than 0.01 on the diet. None of the patients had repeat IC-GH levels which were above the lower limit of normal for lean children of normal stature (3.2 micrograms/l). Single sample insulin-like growth factor 1 (IGF-1) levels were unchanged: 40.9 +/- 23.1 nM initially vs. 49.7 +/- 25.7 nM (314.6 +/- 197.7 vs. 382.5 +/- 217.0 ng/ml, n.s.). Thus reduction of high insulin concentrations during 5-8 weeks of a low calorie diet has only a small effect on IC-GH in obese children. Factors other than circulating insulin levels are likely to play the major role in mediating the reduced levels of GH observed in obesity.