Paul M. Martha

Acceleration of Growth Rate in Growth Hormone-Deficient Children Treated with Human Growth Hormone-Releasing Hormone

ABSTRACT: Twenty-four growth hormone-deficient children were treated with growth hormone releasing hormone-40 (GHRH) for 6 months or longer. GHRH (1 to 4 μg/kg of body weight per dose) was administered subcutaneously every 3 h (n = 10); or every 3 h overnight only (n = 10); or by twice daily injections (n = 4). Twenty-one children had an increase in growth rate during GHRH treatment. The growth velocities (mean ± SD; cm/yr) before and during treatment were, respectively: every 3 h 3.5 ± 1.4 versus 10.0 ± 2.2, p = 0.0001; overnight only 3.4 ± 1.0 versus 6.2 ± 2.1, p = 0.008; twice daily injections 3.2 ± 1.8 versus 7.9 ± 2.4, p = 0.06. Using these three modes of GHRH administration, different total daily amounts of GHRH were administered. Regression analysis of average daily dose versus growth velocity revealed a correlation coefficient (r) value of 0.57, p = 0.004. Sixteen children received extended treatment for periods varying from 9 to 30 months. Of these, seven children were treated continuously for 9 months with pump overnight only and 5 for 12 months with pump every 3 h. Their growth velocities were sustained at a similar rate as those observed at 6 months. Six children received both twice daily and three hourly treatments consecutively. The growth velocities were similar during both treatments. Eleven children developed circulating antibodies to GHRH during treatment, however, all 11 had accelerated growth rates during GHRH therapy. GHRH can stimulate growth hormone secretion and its biologic effects to accelerate linear growth in children with growth hormone deficiency. Further studies are required to characterize the optimal dose and frequency of administration.

Dual Hormonal Replacement With Insulin and Recombinant Human Insulin-Like Growth Factor I in IDDM: Effects on glycemic control, IGF-I levels, and safety profile

OBJECTIVE To examine if dual replacement with insulin and rhIGF-I, recombinant human insulin-like growth factor I (rhIGF-I) may be safe and result in improved metabolic control and reduced insulin usage. RESEARCH DESIGN AND METHODS Forty-three patients with IDDM were randomized to receive a daily injection of rhIGF-I (80 mcg/kg s.c.) or placebo while on conventional insulin therapy for 4 weeks. Insulin was adjusted in the attempt to achieve predetermined goal glycemic values. Free and total IGF-I, four daily blood glucoses, and HbA1c were measured. RESULTS Before randomization, placebo and rhIGF-I groups exhibited low plasma levels of free and total IGF-I, which increased toward normal levels during the treatment period only in the rhIGF group. The regression curve obtained from the average of daily blood glucose measurements indicated that the glycemic profile, overlapping in the lead-in period, exhibited a downward trend in the rhIGF-I group during the treatment period. Mean blood glucose level during the last 10 days of treatment was lower in the rhIGF-I groups (174 ± 37 vs. 194 ± 32 mg/dl). HbA1c level was reduced by more than one-half percent more in the rhIGF-I group (−1.85%) than in the control group (−1.3%). The dose of regular insulin was significantly lower in the rhIGF-I group (0.2 ± 0.1 vs. 0.28 ± 0.1 U · kg−1 · 10 days−1 in the placebo group; P < 0.05). CONCLUSIONS rhIGF-I in combination with conventional insulin treatment ameliorated the low plasma total and free IGF-I levels and was well tolerated in IDDM. There was a trend toward improved glycemic control, while the regular insulin dose was significantly decreased.

Variations of Pulsatile Growth Hormone Release in Healthy Short Prepubertal Boys

ABSTRACT: Overnight growth hormone (GH) concentrations obtained by frequent venous sampling of 20 healthy, short prepubertal boys were evaluated using the objective pulse detection algorithm, CLUSTER. The resulting pulsatile characteristics were compared with those of 11 healthy prepubertal boys of normal stature and with those of nine prepubertal children with documented GH deficiency. Although no significant differences of pulsatile GH release were found between the normal and short subjects, a subset of the short prepubertal boys with significantly delayed skeletal ages had subnormal sum of GH pulse areas and sum of GH pulse amplitudes. The finding of a significant correlation in all subjects between growth velocity and the sum of GH pulse amplitudes is important, as the results are compatible with the hypothesis that alterations of amplitude-modulated GH release underlie the pathophysiology of suboptimal growth in some short prepubertal children.

Atenolol enhances growth hormone release to exogenous growth hormone-releasing hormone but fails to alter spontaneous nocturnal growth hormone secretion in boys with constitutional delay of growth

ABSTRACT: We tested the hypothesis that selective β1-adrenergic blockade will enhance growth hormone (GH) secretion in boys with constitutional delay of growth in response to both exogenously administered growth hormone-releasing hormone as well as to endogenous GH-releasing hormone pulsations. The study group comprised eight healthy, short, prepubertal boys ranging from 7 2/12 to 15 0/12 yr old with bone ages delayed 15 to 42 months. All had demonstrated GH levels of greater than 10 ng/ml following a pharmacologic or physiologic stimulus. During two consecutive nights, blood samples were withdrawn every 20 min for GH determination between 2000 and 0800 h. Immediately after each 0800 h blood withdrawal, 1 μg/kg of GH-releasing hormone (1–40)-OH was administered intravenously to each subject and blood was withdrawn every 15 min for an additional 2 h. During the day before the second overnight sampling period each subject received atenolol, 25 mg orally, at 1030 and 1600 h to induce β-adrenergic blockage. The six subjects in whom β-adrenergic blockade could be documented had enhanced GH release after GH-releasing hormone administration on the atenolol treatment day both in terms of higher peak GH levels achieved p < 0.05) as well as greater total GH secretion (3916 ± 701 versus 5624 ± 986 ng/ml min, p < 0.01). In contrast, there were no differences in endogenous, unstimulated nocturnal GH pulse characteristics between study and control days. In particular, there were no changes in number of GH pulses, mean 12-h GH concentrations, mean GH pulse height, amount of GH secreted in pulses, mean interpulse GH levels, or total area under the GH versus time curve.

Improvement of HbA1c without increased hypoglycemia in adolescents and young adults with type 1 diabetes mellitus treated with recombinant human insulin-like growth factor-I and insulin. rhIGF-I in IDDM Study Group.

OBJECTIVE A 12-week trial with insulin and rhIGF-I compared to insulin and placebo was conducted in patients with type 1 diabetes mellitus aged 11-66 years. We present the efficacy and safety data pertinent to the younger subset of participants (11-21 years). STUDY DESIGN The patients were randomized to receive s.c. insulin and either placebo or rhIGF-I at one of the following doses (microg/kg): 40 a.m./40 p.m., 80 a.m./40 p.m. or 80 a.m./60 p.m.). RESULTS The average decrease of HbA1c from baseline was higher (-1.3 +/- 0.2%) in the rhIGF-I treated group compared to the placebo group (-0.6 +/- 0.3%; p <0.05). This was associated with a significant decrease in daily insulin dose (U) of both Regular (rhIGF-I: -7 +/- 1; placebo: -1 +/- 1; p <0.01) and NPH (rhIGF-I: -4 +/- 2; placebo: +5 +/- 3; p <0.05). The incidence of hypoglycemia and weight gain were not increased. Edema, jaw pain and tachycardia were associated with rhIGF-I treatment, particularly at doses higher than 40 microg/kg b.i.d. Dose-related early worsening of retinopathy was observed in 11/55 patients in the rhIGF-I group, with resolution in the majority of them in the follow-up photographs. CONCLUSIONS These findings suggest a possible role for rhIGF-I co-therapy in adolescents and young adults with type 1 diabetes mellitus.

Growth Hormone Secretory Dynamics During Puberty

Growth hormone (GH) is released in an intermittent, pulsatile manner in the fetus and on throughout life. GH is first detectable in the human fetal pituitary by week 9 of gestation (1). Premature infants have higher circulating concentrations of GH compared to term infants. Quantitative analysis of GH secretory profiles (see below) indicates an elevation in production rate, burst amplitude, and mass of GH secreted per burst in premature compared with term infants. The simultaneously derived half-lives of disappearance do not differ between these two groups of newborns; thus, augmented secretion rather than decreased clearance accounts for the differences in circulating GH concentrations. Taken together, the data suggest that increased GH secretory activity in premature infants reflects an increase in hypothalamic GH releasing hormone (GHRH) activity and/or reduced somatostatin (SRIH) tone (2).

Glucose-Stimulated Insulin Release by Individual Pancreatic β Cells: Potentiation by Glyburide

Abstract To investigate the effect of glyburide on insulin secretion by individual β cells from normal rats, we employed a reverse hemolytic plaque assay. Pancreata were harvested from female Wistar-Furth rats, the pancreatic islets isolated, and the latter dispersed into single cells. These cells were mixed with protein A-coated ox erythrocytes, the mixture was placed in a Cunningham chamber in the presence of insulin antiserum, and the cells were exposed to the various test substances. Having developed hemolytic plaques around the insulin-secreting cells with complement, the percentage of plaque-forming cells was determined and the plaque areas (reflecting the amount of insulin secreted) were quantitated. For the purpose of validation, we demonstrated that (i) plaque-forming (but not non-plaque-forming) cells could be identifed as insulin secreting by an independent immunofluorescent technique, (ii), plaques did not form if insulin antiserum was deleted from the preparation, (iii) plaques failed to develop if insulin antiserum was preabsorbed with insulin, and (iv) incubation with non-protein A-coated RBC or omission of complement resulted in no plaque formation. In addition, both the percentage of plaque-forming cells and the mean plaque area increased upon exposure to glucose (0.75–20 mM) in a concentration-dependent manner at 5- and 60-min incubation times. Moreover, somatostatin suppressed the percentage of plaque-forming cells and diminished the mean plaque area of cells which continued to secrete insulin in response to glucose. Exposure of cells to 100 nM glyburide in the presence of 5 mM or 20 mM glucose had no effect on the percentage of plaque-forming cells present at 5 min or 60 min. Similarly, glyburide did not alter mean plaque area at 5 or 60 min when cells were co-incubated with 5 mM glucose. However, mean plaque area was markedly enhanced at 5 and 60 min in response to glyburide and 20 mM glucose.

Growth and Body Composition in Children with Growth Hormone Insensitivity Treated with Recombinant Insulin-like Growth Factor I (IGF-I) † 407

Growth and Body Composition in Children with Growth Hormone Insensitivity Treated with Recombinant Insulin-like Growth Factor I (IGF-I) † 407

A SINGLE DOSE OF RECOMBINANT HUMAN IGF-I (rhIGF-I) DOES NOT AFFECT URINARY EXCRETION OF NITRIC OXIDE METABOLITES IN IDDM. 560

Several studies have shown the potential importance of nitric oxide (NO) in the regulation of peripheral vascular resistance in diabetes. The discovery that IGF-I induces NO production by endothelial cells suggests that IGF-I may be an important regulator of vascular tone in vivo via nitric oxide release from the vascular endothelium and may play a role in control of renal hemodynamics in physiologic and pathologic conditions. We have previously reported that the excretion of NO metabolites(NO2+NO3=NOx) is not significantly different in IDDM compared to controls (n=9; age range 3-17 years). The aim of this study was to evaluate urinary excretion of NOx in response to a single rhIGF-I (n=9; 80 mcg/Kg Sc) or placebo injection (n=9). Urinary excretion of NOx was measured during hospital admission in the 12-hour period preceding and following rhIGF-I or placebo administration in 18 subjects with IDDM without nephropathy (age range 8-16 years, IDDM duration 1-10.5 years, 5 pre-pubertal/13 pubertal). Mean glycosylated hemoglobin was high(11.7±1.9%; nI 4.4-6.1%) while on conventional insulin therapy. Urinary NO3 was reduced to NO2 by E. Coli reductase and total NO2 was analyzed using the Griess reagent. Records were kept by the nurses and accuracy of the collection was validated by creatinine excretion (correlation between creatinine and urinary NO, r=0.51; p<0.01). The data(mean±SD) were analyzed by Students t-test. A single injection of rhIGF-I did not affect the urinary excretion of NO metabolites. As previously reported, the mean nitric oxide excretion was not significantly different from that observed in controls and did not increase with IDDM duration. Further studies are necessary to evaluate the influence of chronic rhIGF-I administration on nitric oxide metabolism. This study was partially funded by Genentech Inc. and NY State Health Research Council.Table

A LONGITUDINAL ASSESSMENT OF ESTROGEN LEVELS DURING NORMAL PUBERTY IN BOYS AS DETERMINED BY AN ULTRA-SENSITIVE BIOASSAY. † 532A

A LONGITUDINAL ASSESSMENT OF ESTROGEN LEVELS DURING NORMAL PUBERTY IN BOYS AS DETERMINED BY AN ULTRA-SENSITIVE BIOASSAY. † 532A