William B Zipf

Evaluation of growth hormone release and human growth hormone treatment in children with cranial irradiation-associated short stature

We studied nine children who had received cranial irradiation for various malignancies and subsequently experienced decreased growth velocity. Their response to standard growth hormone stimulation and release tests were compared with that in seven children with classic GH deficiency and in 24 short normal control subjects. With arginine and L-dopa stimulation, six of nine patients who received radiation had a normal GH response (greater than 7 ng/ml), whereas by design none of the GH deficient and all of the normal children had a positive response. Only two of nine patients had a normal response to insulin hypoglycemia, with no significant differences in the mean maximal response of the radiation and the GH-deficient groups. Pulsatile secretion was not significantly different in the radiation and GH-deficient groups, but was different in the radiation and normal groups. All subjects in the GH-deficient and radiation groups were given human growth hormone for 1 year. Growth velocity increased in all, with no significant difference in the response of the two groups when comparing the z scores for growth velocity of each subjects bone age. We recommend a 6-month trial of hGH in children who have had cranial radiation and are in prolonged remission with a decreased growth velocity, as there is no completely reliable combination of GH stimulation or release tests to determine their response.

Sexual precocity in association with septo-optic dysplasia and hypothalamic hypopituitarism.

Sexual precocity in association with abnormalities of the central nervous system is well known, but its occurrence with hypothalamic hypopituitarism is most unusual. We report five females with septo-optic dysplasia, blindness, and multiple pituitary tropic hormone deficiencies: all were growth hormone and adrenocorticotropic hormone deficient; two had diabetes insipidus; one had sexual precocity, and one had early pubertal maturation, whereas three were prepubertal and responded to administration of synthetic gonadotropin-releasing hormone. These children retained ability to secrete gonadotropins despite the presence of anterior hypothalamic disease. Experimental data from primates plus our observations on these patients raise questions about the role of the anterior hypothalamus in gonadotropin secretion in man.

Characterization of alterations in glucose and insulin metabolism in Prader-Willi subjects

Obesity is a common component of non-insulin-dependent diabetes mellitus (NIDDM) and plays an important role in the development of insulin resistance and hyperinsulinemia. Prader-Willi syndrome (PWS) has been associated with morbid obesity and an increased propensity for early development of NIDDM. It has been assumed that the etiology for this increased rate of NIDDM is related to the morbid obesity and concomitant insulin resistance, but this remains controversial. To shed light on the glucoregulatory mechanisms in PWS, we studied both pediatric and adult PWS patients with normoglycemia. The objectives of our study were (1) to examine glucose, insulin, and C-peptide responses to oral (OGTT) and intravenous (IVGTT) glucose tolerance tests; (2) to characterize acute first- and second-phase insulin secretion during an IVGTT; (3) to assess hepatic insulin extraction (HIE) and insulin clearance (IC) in PWS subjects; and (4) to determine whether beta-cell function in PWS is age-dependent. These results in PWS were compared with values obtained in age-, sex-, and body mass index (BMI)-matched non-PWS obese controls. Three groups were studied. Group I consisted of nine PWS subjects under the age of 13 years and 22 age-, sex-, weight-, and puberty stage-matched obese subjects who underwent OGTT. Group II consisted of 14 adult PWS subjects and 10 age-, weight-, and BMI-matched obese adults who underwent OGTT. Group III consisted of nine adult PWS subjects and eight age-, sex-, and weight-matched obese adults who underwent frequently sampled IVGTT (FSIVGTT). During the OGTT in the pediatric group, fasting (86 +/- 3 v 89 +/- 2 mg/dL), peak (144 +/- 11 v 147 +/- 4 mg/dL), and total area under the curve (AUC) (6,984 +/- 1,320 v 6,963 +/- 615 mg/dL x min) glucose levels were not significantly different in PWS versus obese children, respectively. In contrast, fasting (20 +/- 6 v 37 +/- 4 microU/mL), peak (114 +/- 24 v 214 +/- 23 microU [correction of mU]/mL), and total AUC (12,673 +/- 2,176 v 26,734 +/- 2,608 microU/mL microU/mL min) insulin levels were significantly lower in pediatric PWS. During the OGTT in the adult groups, neither fasting insulin (16.7 +/- 2.8 v 13.5 +/- 2.5 microU/mL) nor total AUC for insulin (10,664 +/- 1,955 v 11,623 +/- 1,584 microU/mL x min) were significantly different in adult PWS and obese groups. During the IVGTT in adults, both first-phase (138 +/- 42 v 454 +/- 102 microU/mL x min) and second-phase (295 +/- 66 v 1,015 +/- 231 microU/mL x min) insulin release were significantly reduced in PWS subjects despite similar glucose levels. Similarly, first-phase (8.6 +/- 2.3 v 21 +/- 4.6 ng/dL x min) and second-phase (47 +/- 4.6 v 75 +/- 14 ng/dL x min) C-peptide responses were also significantly reduced in PWS subjects. In contrast, mean HIE and IC was 33% higher in PWS subjects versus obese controls (15.4 +/- 1.5 v 10.3 +/- 1.6). Similarly, poststimulation HIE and IC was significantly greater (5.2 +/- 0.8 v 2.4 +/- 0.4) in the PWS group compared with the obese group (P < .01). In summary, this study demonstrates that nondiabetic PWS subjects manifest (1) a reduced beta-cell response to glucose stimulation, (2) a significantly increased HIE compared with obese controls, and (3) a dissociation of obesity and insulin resistance, in contrast to normal obese subjects. We conclude that glucoregulatory mechanisms are different in obese PWS versus non-PWS subjects.

Effects of Tolbutamide on Growth and Body Composition of Nondiabetic Children with Cystic Fibrosis

Previously, we reported that nondiabetic children with cystic fibrosis show a blunted insulin response to a meal stimulus. In the study presented here, using tolbutamide, we determined the effects of augmented insulin secretion/action on height and lean body mass of children with cystic fibrosis. Twelve subjects (mean ± SEM age, 11.0 ± 0.5 y) were studied for three 4-mo periods: 1) pretreatment, 2) treatment, consisting of 750 mg/d of tolbutamide, and 3) posttreatment. Before the pretreatment period, insulin response to a meal stimulus was evaluated in relation to three doses of tolbutamide: 0, 250, and 500 mg. Growth was monitored during each period, and incremental changes in lean body mass were calculated from height data. To validate the change in lean body mass based on height measurements, we determined lean body mass in seven subjects during the treatment period by using a criterion method (H218O). Growth velocity (cm/4 mo) significantly increased (p < 0.05) during the treatment (2.58 ± 0.31) compared with the pretreatment period (0.88 ± 0.20). The increase in lean body mass calculated from height was greater during the treatment (1.61 ± 0.29 kg/4 mo) than during the pretreatment period (0.44 ± 0.18 kg/4 mo) (p < 0.05). There was also a significant increase (p < 0.05) in lean body mass during the treatment as measured with H218O (1.91 ± 0.65 kg/4 mo). Acute administration of either 250 or 500 mg of tolbutamide reduced (p < 0.05) the area under the glucose concentration curve in response to a meal compared with the control condition of no tolbutamide. However, there was no significant effect of tolbutamide on plasma insulin levels. We conclude that short-term tolbutamide therapy more than doubled linear growth and increased lean body mass accretion 4-fold in slowly growing children with cystic fibrosis, possibly by improving the tissue response to insulin. (Pediatr Res 30: 309–314, 1991)

Elevated Hepatic Glucose Production in Children with Cystic Fibrosis

ABSTRACT: We hypothesized that elevated hepatic glucose output (HGO) may occur in children with cystic fibrosis (CF) as an early sign of declining insulin secretion and that tolbutamide therapy would correct the defect. We studied eight glucose-tolerant CF patients ([Xmacr ] ± SD, 9.1 ± 1.9 y) and five healthy controls (9.0 ± 1.6 y). Fasting glucose, insulin, and insulin-connecting peptide concentrations were not different in the CF and control subjects; however, meal stimulation tests in the CF patients suggested that insulin secretion was defective in the fed state. HGO (mg · kg−1 body weight · min−1) was 26% higher in the CF patients (4.2 ± 0.7 versus 3.1 ± 0.6 in HC) (p = 0.016). When normalized for fat-free mass (mg · kg fat-free mass−1 · min−1), HGO was 27% higher in CF (4.9 ± 0.8 versus 3.8 ± 0.5) (p = 0.015). However, when expressed as a function of resting energy expenditure (mg · kcal−1), HGO was not significantly different in CF (121 ± 22) versus healthy controls (116 ± 30). In seven of the CF group, HGO was re-assessed after a 2-h glucose infusion at a rate of 0.90 ± 0.02 mg · kg−1 · min−1. HGO was suppressed (p < 0.05) by an amount equal to 103 ± 18% of the glucose infusion rate. Finally, in five CF patients, HGO was re-measured after 2 wk of oral therapy with tolbutamide (750 mg/d). Tolbutamide did not affect HGO (fasting or during the glucose infusion). In conclusion, fasting HGO was elevated in the CF patients in proportion to energy expenditure.

Feeding-Induced Changes in Energy Expenditure in Children With Cystic Fibrosis

Seven children with cystic fibrosis (aged 7 to 12 years) were studied in the fasted and fed states. Using a primed, constant, intravenous infusion of NaH13CO3, the rate of appearance of CO2 (RaCO2) was estimated. Net CO2 excretion (VCO2) was also measured. Energy expenditure was calculated using the food quotient. RaCO2 (mean +/- SD) (mumol.kg-1.min-1) in the fasted and fed states (297 +/- 59 and 359 +/- 67) was 117% and 105% of VCO2 (259 +/- 48 and 352 +/- 72). Feeding induced a 23% and a 37% increase in RaCO2 and VCO2, respectively, and respective 19% and 33% increases in energy expenditure (p < .05). Measurement of CO2 production by isotopic dilution is a useful index of group changes in energy expenditure, including those induced by feeding.

Cholesteryl ester transfer and cholesterol esterification in type 1 diabetes: relationships with plasma glucose.

Abstract The activities of two crucial enzymes of reverse cholesterol transport, cholesterol ester transfer protein (CETP) and lecithin:cholesterol acyltransferase (LCAT), and their relationships with lipid profile and fasting plasma glucose were examined in 35 type 1 diabetic children. The CETP and LCAT activities were significantly lower (p<0.05) in the 4 subjects with normal fasting plasma glucose levels (<6.39 mmol/l) than in the 28 with high plasma glucose levels (CEPT activity, 10.63±3.81 vs. 32.18±13.94 nmol/ml h; LCAT activity, 25.52±4.53 vs. 39.52±12.52 nmol/ml h; both p<0.05). The subjects with high plasma glucose levels also had higher total and LDL-cholesterol than those with normal glucose levels. CETP activity was positively correlated with fasting plasma glucose, CETP concentration, LCAT activity, total cholesterol, free cholesterol, LDL-C, and LDL-cholesterol ester, while negatively correlated with cholesteryl ester to free cholesterol ratio, LDL triglyceride to protein ratio, and LDL triglyceride to cholesteryl ester ratio. LCAT activity was found to positively correlate with CETP activity, total cholesterol, free cholesterol. LDL-C, CETP concentration, and LDL-cholesteryl ester, while it negatively correlated with cholesteryl ester to free cholesterol ratio. The results observed in type 1 diabetic subjects suggest that (1) accelerated LCAT and CETP activities may result in the accumulation of LDL-cholesteryl ester; and (2) fasting plasma glucose may be a major determinant of CETP activity.

SEXUAL PRECOCITY IN ASSOCIATION WITH SEPTO-OPTIC DYSPLASIA (SOD) AND HYPOTHALAMIC HYPOPITUITARISM

Sexual precocity arises frequently from a CNS disturbance but its association with hypothalamic hypopituitarism Is most unusual. We report 5 girls with SOD and multiple tropic hormone deficiencies; all were GH and ACTH def. and 2/5 had sexual precocity while 3 were prepubertal and responded to IV GnRH. This finding contrasts sharply with other patients with multiple tropic hormone def. who have severely blunted or absent responses to GnRH. Case 1 diagnosed at 2 mos. with ADH def., presented at 7 4/12 yrs with midpubertal development, menarche, bone age 13.5 yrs, height age 9 yrs, and growth increment of 20 cm/last 2 yrs. GH and ACTH def. were documented by arginine/L-dopa and IV metapyrone tests. Basal serum Prl values were 31-42 ng/ml. Pelvic exam was normal and brain scan showed no mass. Case 2 presented at 16 yrs before GnRH testing was available, with short stature (HA 8 yrs), optic nerve dysplasia and regular menstrual periods since 10 yrs. Case 5 also was ADH def.; only case 3 was TSH def.These Interesting cases illustrate selective retention of gonadotropin secretion despite presumed anterior hypothalamic dysfunction. Their congenital anomalies may have resulted in sexual precocity by interference with tonic inhibitory effects of the CNS.

Sandwich enzyme-linked immunosorbent assay for plasma cholesteryl ester transfer protein concentration

OBJECTIVES Cholesteryl ester transfer protein (CETP) mediates the transfer of HDL cholesterol to apoB-containing lipoproteins. Its mass and activity are increased in several pro-atherogenic conditions. The objective of this study is to develop a cost- and time-effective sandwich ELISA for plasma CETP concentration. DESIGN AND METHODS Monoclonal anti-CETP, TP20, was used as the capture antibody, while the other biotinylated monoclonal anti-CETP, TP2, was used for detection. The results were expressed in an arbitrary unit, ng biotin-TP2 bound per microl plasma. Plasma CETP concentrations, activities and their relationship were assessed in 35 IDDM children. RESULTS The assay had an intra-assay CV of 8.75% and an inter-assay CV under 10%. Plasma CETP concentration of these subjects ranged from 0.36-1.89 ng biotin-TP2/microL. CETP concentration was significantly correlated with CETP activity (r = 0.51, p < 0.01). CONCLUSION The sandwich ELISA we have developed carried sufficient sensitivity for assaying plasma CETP concentration in human.

Risk factors for coronary heart disease in type 1 diabetic children: the influence of apoE phenotype and glycemic regulation

The effects of apolipoprotein E (apoE) phenotype and glycemic regulation on plasma levels of lipids and lipoproteins, low density lipoprotein (LDL) composition, LDL particle size, and LDL oxidation were examined in 35 type 1 diabetic children aged 5-12 years. All subjects were classified according to glycemic regulation (HbA(1c)<8% vs. HbA(1c)>8%). ApoE phenotypes were identified by isoelectric focusing (IEF) followed by immunoblotting. Results from two-way analysis of variance (ANOVA) showed that subjects with apoE 4/3 and HbA(1c)>8% had higher concentrations of total cholesterol (TC), LDL-cholesterol (LDL-C), and LDL-cholesterol ester (LDL-CE) than subjects with the same apoE phenotype and HbA(1c)<8%. LDL particles in all subjects were classified as the subclass pattern A. Both LDL particle size and susceptibility of LDL to oxidation were not different among subjects stratified by apoE phenotype. In conclusion, children with type 1 diabetes mellitus included in this study did not have high-risk lipoprotein profiles at this early stage of life. However, there was some indication that those with the apoE 4/3 phenotype were more likely to have more favorable lipid profiles when HbA(1c) levels were <8%.