Context: Children with severe IGF-I deficiency due to congenital or acquired defects in GH action have short stature that cannot be remedied by GH treatment.
Objectives: The objective of the study ...was to examine the long-term efficacy and safety of recombinant human IGF-I (rhIGF-I) therapy for short children with severe IGF-I deficiency.
Design: Seventy-six children with IGF-I deficiency due to GH insensitivity were treated with rhIGF-I for up to 12 yr under a predominantly open-label design.
Setting: The study was conducted at general clinical research centers and with collaborating endocrinologists.
Subjects: Entry criteria included: age older than 2 yr, sd scores for height and circulating IGF-I concentration less than −2 for age and sex, and evidence of resistance to GH.
Intervention: rhIGF-I was administered sc in doses between 60 and 120 μg/kg twice daily.
Main Outcome Measures: Height velocity, skeletal maturation, and adverse events were measured.
Results: Height velocity increased from 2.8 cm/yr on average at baseline to 8.0 cm/yr during the first year of treatment (P < 0.0001) and was dependent on the dose administered. Height velocities were lower during subsequent years but remained above baseline for up to 8 yr. The most common adverse event was hypoglycemia, which was observed both before and during therapy. It was reported by 49% of treated subjects. The next most common adverse events were injection site lipohypertrophy (32%) and tonsillar/adenoidal hypertrophy (22%).
Conclusions: Treatment with rhIGF-I stimulates linear growth in children with severe IGF-I deficiency due to GH insensitivity. Adverse events are common but are rarely of sufficient severity to interrupt or modify treatment.
GH replacement therapy has been shown to improve abnormalities in body composition, bone mineral density (BMD), lipid profile, and other changes resulting from GH deficiency (GHD) in adults. There ...is, however, need to determine appropriate dosing in young adults who were treated for GHD as children, to bridge the interval between childhood (in which relatively high doses are used) and older adulthood (in which only lower doses are tolerated). This multicenter, randomized, double-blind, placebo-controlled study compares the safety and efficacy of two doses of GH (25 and 12.5 μg/kg·d) with placebo, maintained for 2 yr, in adults with GHD who were treated as children and were off GH for at least 1 yr (mean, 5.6 yr).
The 64 treated subjects were less than 35 yr of age (mean, 23.8 yr) and had maximum serum GH responses, on retesting less than 5 μg/liter (mean, 0.7 μg/liter). At baseline, 22% had spine BMD below −2 sd, 59% were overweight or obese, and 45% had serum total cholesterol more than 200 mg/dl. A significant dose response was seen for percent increase in spine BMD at 24 months (mean of 1.3%, 3.3%, and 5.2% in the placebo, 12.5-, and 25-μg/kg·d groups, respectively, P = 0.018). Both GH-treated groups had similar changes in body composition at 6 months (decreased fat mass, increased lean mass); however, some gains were subsequently lost in the lower dose group. A significant decrease in low-density lipoprotein cholesterol was seen only in the higher GH dose group. Significant changes were not observed in quality of life and echocardiographic measures. The groups were similar with regard to adverse events and laboratory measurements, except for a higher incidence of edema in the GH-treated groups.
We conclude that this dose-response study confirms the benefits of GH-replacement therapy in GHD adults and indicates that, to achieve treatment goals in younger adults, higher doses may be needed than those generally used in older adults.
Both starvation and sepsis are characterized by growth hormone (GH) insensitivity, which leads to a reduction in circulating insulin-like growth factor (IGF)-I. Because of the anabolic properties of ...this growth factor, its decline may contribute to the growth arrest and the catabolic reaction observed in starvation and sepsis. This review focuses on the mechanisms responsible for the reduction in circulating IGF-I and impairment of GH responsiveness that occur during starvation and sepsis. A clearer understanding of the complex nature of GH resistance should lead to the development of new therapeutic strategies aimed at restoring the beneficial effects of anabolic agents such as GH and IGF-I.
Eight children with GH insensitivity syndrome were treated with recombinant human insulin-like growth factor I (IGF-I) (80--120 microg/kg sc twice daily) for 6.5--7.5 yr. We previously reported that ...height velocity (HV) improved with treatment (from mean pretreatment HV of 4.0 cm/yr), to 9.3 cm/yr for the first year and 6.2 cm/yr for the second year. HV remained slightly below this during the subsequent years (mean HV: 5.4, 5.5, 5.2, and 4.8 cm/yr during years 3--6). Mean height SD score before therapy was -5.6; and it improved to -4.5, -4.4, and -4.2 after 2, 4, and 6 yr of therapy, respectively. Treatment was accompanied by gain in body weight and fat. Bone age advanced normally in the prepubertal patients, but it advanced more rapidly during the latter years of treatment in those patients undergoing pubertal changes. The growth of spleen and kidneys (determined by ultrasound) was rapid in the first 2--3 yr of therapy. More age- appropriate growth ensued, but six patients had a renal length for height more than 2 SD above the mean at 6--7 yr of treatment. No major adverse changes in biochemical profile were observed. IGF-I-related hypoglycemia occurred early in treatment with the younger patients, but this problem abated as treatment was continued. IGF-I therapy is effective in promoting statural growth in GH insensitivity syndrome patients, but the growth response is neither as intense nor as well-sustained as the growth response to GH among children with GH deficiency.
To investigate whether the anabolic effects of insulin-like growth
factor I (IGF-I) and GH are mediated through regulation of the
ubiquitin (Ub) pathway, we examined the effect of IGF-I (0.35 μg/100
...g) and/or GH (0.3 mg/100 g BW) on the expression of Ub and
Ub-conjugating (E2) enzyme messenger RNAs (mRNAs) in skeletal muscle of
rats made catabolic by treatment with dexamethasone (Dex; 0.5 mg/100 g
BW) for 3 days. Dex caused a significant loss of body and gastrocnemius
weight (14% and 25%, respectively) concurrent with an increase in the
2.8- and 1.2-kb transcripts of Ub (14.3- and 12-fold increases,
respectively), the 1.8- and 1.2-kb transcripts of 14-kDa Ub-conjugating
enzyme (E2–14 kDa; 5.6- and 7.7-fold increases, respectively), the
4.4- and 2.4-kb transcripts of Ub-E2G (6.5- and 8.2-fold
increases, respectively), and the 2E isoform of the 17-kDa E2 mRNA
(3.5-fold increase). Injections of IGF-I in Dex-treated animals
ameliorated the body weight loss, and the gastrocnemius tended to be
heavier. This improvement was also accompanied by a significant
suppression of transcripts for Ub (58% and 66% decreases), E2–14 kDa
(58% and 68% decreases), and Ub-E2G (78% decrease), whereas the 2E
isoform of the 17-kDa E2 was only modestly affected (20% decrease). GH
restored serum IGF-I levels to normal in Dex-treated rats, but had no
effect on the body weight loss or on any of the studied components of
the Ub pathway. Administration of IGF-I to the Dex/GH-treated animals
decreased the activated mRNAs of the Ub pathway in a manner and degree
similar to those observed in the Dex/IGF-I group.
In summary, these results provide evidence that IGF-I regulates the
expression of mRNAs encoding components of the Ub pathway during
catabolism and suggest a possible mechanism for the antiproteolytic
actions of IGF-I. On the other hand, GH, which is believed not to
affect proteolysis but only protein synthesis, had no effect on any of
the mRNAs studied.
Voluntary fasting is practiced by many humans in an attempt to lose body weight. Conflicting results have been published on the effects of food deprivation on serum lipids. To study the effect of ...acute starvation on serum lipids, 10 nonobese (93-124% of ideal body weight), healthy adults (6 men, 4 women, 21-38 y old) fasted (no energy) for 7 d. Fasting increased total serum cholesterol from 4.90 +/- 0.23 to 6.73 +/- 0.41 mmol/L (37.3 +/- 5.0%; P < 0.0001) and LDL cholesterol from 2.95 +/- 0.21 to 4.90 +/- 0.36 mmol/L (66.1 +/- 6. 6%; P < 0.0001). Serum apolipoprotein B (apo B) increased from 0.84 +/- 0.06 to 1.37 +/- 0.11 g/L (65.0 +/- 9.2%; P < 0.0001). The increases in serum cholesterol, LDL and apo B were associated with weight loss. Fasting did not affect serum concentrations of triacylglycerol and HDL cholesterol. Serum concentrations of insulin-like growth factor-I (IGF-I) decreased from 246 +/- 29 (prefast) to 87 +/- 10 microg/L after 1 wk of fasting (P < 0.0001). We conclude that, in nonobese subjects, fasting is accompanied by increases in serum cholesterol, LDL and apo B concentrations, whereas IGF-I levels are decreased.
Thirty to 60 percent of patients with chronic obstructive pulmonary disease (COPD) are malnourished, and this affects ventilatory muscle function and prognosis for survival adversely. We studied the ...effect of growth hormone (GH) in malnourished patients with COPD (n = 7, mean FEV1 of 1.1±0.2 L, 45±7 percent of predicted values; <90 percent of ideal body weight). The subjects received a balanced diet of 35 kcal/kg with 1 g of protein/kg for 1 week (pre-GH). During the following three weeks, they received the same diet plus subcutaneous injections of recombinant methionyl human GH (0.05 mg/kg daily). The subjects had no significant weight gain during the week of diet alone (0.07±0.11 kg, p = NS) but they had substantial weight gain during the first week of GH treatment (1.37±0.23 kg, p<0.01). Nitrogen balance also improved during GH treatment (+ 1.6±0.7 g/day on diet alone vs +3.8±0.5 g/day on diet plus GH, p<0.02). Maximal inspiratory pressure improved by 27±8 percent after GH treatment (p<0.02). No significant adverse effects occurred. Further study of the potential usefulness of GH in COPD utilizing a placebo-controlled trial is warranted.
The influence of nutrition on growth seems likely to be mediated in part through IGF-I. Restriction of dietary nutrients adversely effects IGF-I synthesis and action at multiple steps, including ...decreased GH receptors, postreceptor defects in GH action, decreased steady state levels of IGF-I mRNA, and attenuation of IGF-I action. In addition, undernutrition affects the IGF binding proteins in ways that vary from one tissue to another. Understanding the alterations in IGFBPs that are caused by nutritional insufficiency may provide insight into the actions of the IGFBPs.
ABSTRACT
Delineating the molecular basis for the metabolic switch from the well‐fed state to starvation is crucial to understanding nutritionally regulated metabolic abnormalities. We have examined ...the molecular events associated with nutrient deprivation, using suppression subtractive hybridization to define the transcriptional programs up‐regulated in rat liver by starvation. Of the genes that displayed significant increases in their hepatic mRNA levels following 48‐h starvation, most could be assigned to one of five major functional classes. We found up‐regulation of genes involved in energy and protein metabolism, genes that respond to stress, and genes encoding nutrient transporters or signaling transducers. The genes with functions in energy and protein metabolism have roles in initiating gluconeogenesis, switching fuel sources from carbohydrates to fatty acids, and protein turnover. A variety of stress response genes, including acute‐phase reactants, exhibited a marked increased in expression, indicating an attempt to restore homeostasis. The expression of several integrated membrane nutrient transporters that supply essential metabolic substrates was increased dramatically. Some known cytosolic signal transducers, likely involved in the metabolic shift from an anabolic to a catabolic state and in the stress response, were significantly enhanced as well. We also observed increased expression of a variety of other known and novel genes. Collectively, our findings indicate that starvation stimulates multiple signaling pathways, which likely lead to extensive metabolic alterations in the liver. These data should serve to enhance our understanding of the molecular mechanisms underlying energy and nitrogen expenditure in the starved state.
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