Decrease In IGF-I Research Articles

The porcine insulin-like growth factor-I gene: characterization and expression of alternate transcription sites

Genomic DNA encoding the 5' region of the porcine IGF-I gene was cloned and sequenced and shown to be highly homologous to that of man, rats and sheep. Two leader exons (exons 1 and 2), which are alternately spliced to exon 3 (encoding part of the mature IGF-I molecule), were identified by RNase protection analysis. In both cases, transcription initiates upstream from exons 1 and 2 at multiple dispersed start sites to yield two distinct IGF-I mRNA transcript classes (1 and 2) which differ in the precursor peptides predicted from their individual leader sequences. The expression of class 1 and 2 transcripts was measured in liver and muscle RNA from two groups of 2-month-old pigs whose energy status had been manipulated within physiological limits to produce marked differences in plasma IGF-I levels and growth rates. For this purpose, RNase protection probes were developed that contained the individual leader exons 1 and 2 linked separately to the common exon 3, so that class-specific and total IGF-I gene expression could be determined in a single assay. At normal plasma IGF-I concentrations (200 ng/ml), class 1 and 2 transcripts comprised 81 and 19% respectively of total liver IGF-I mRNA, while at a lower plasma concentration (90 ng/ml) the corresponding values were 95 and 5% respectively. Although both classes of transcript declined with the decrease in plasma IGF-I, the relative drop in levels of class 2 transcripts (84%) was substantially greater than that of class 1 (54%). In longissimus dorsi, cardiac and soleus muscles IGF-I mRNA was predominantly of class 1 and did not change in response to decreased plasma IGF-I. This suggests that liver-derived endocrine IGF-I has an important function in the regulation of muscle growth and that class 2 IGF-I transcripts are more sensitive to conditions that promote optimal growth.

LACK OF SUPPRESSION OF SERUM IGF-I AFTER SEX HORMONE SUPPRESSION IN TRUE AND PSEUDO PRECOCIOUS PUBERTY

Association of delayed puberty and low serum IGF-I is observed in GH deficiency and chronic malnutrition, while advanced central puberty and high IGF-I is seen in children after long time exposure to high levels of sex hormones(SH). While some workers have reported a decrease of serum IGF-I during therapy of precocious puberty (PP)with GnRHa, others have shown no change. We have studied 7 children with PP, 4 with central PP(2 boys aged 3.5 and 7.5 y, 2 girls aged 6.1 and 5.6 y) and 3 with simple virilizing CAH (mean±SD age 5.7±2.1, bone age 12.9±1.2 y), both before and 2 to 7 months after SH suppression (SHS) with either long acting GnRHa or hydrocortisone. Serum IGF-I, LH, FSH, testosterone (T) and estradiol (E2) were measured by RIA. A GnRH test was carried out in the 3 patients with CAH. Before SHS, serum IGF-I and T (boys) or E2 (girls) were 1.52 ± 0.4 U/ml (5 to ] 11-y-old normal: 0.72±0.4) and 13.7±8.6 nmol/L or 230 pmol/L, respectively (mean±SD or mean of duplicate). After SHS, values were 1.78±0.92 and 0.93±0.14 or 10.5. IGF-I did not decrease in any patient, while SH decreased in all of them. Maximal LH and FSH responses to GnRH in CAH were 1.60±1.1 and 0.88+±.54 before SHS, and 9.27±2.25 and 6.46±2.45 U/L 2 to 12 months after SHS, respectively. Testicular enlargement and clinical evidence of central PP developed in CAH patients after SHS. It is concluded that after SHS to prepubertal values, serum IGF-I remains high in either central PP or CAH, suggesting that SH induce a maturational change in IGF-I values. Since after SHS in CAH, the GnRH test acquires a pubertal pattern of response, IGF-I might be involved in the process of maturation of the gonadostat.

COMPARATIVE STUDY OF SOMATOSTATIN ANALOG VS. ESTROGEN IN TALL GIRLS (N = 20)

The treatment of constitutional tall stature in adolescent girls is based on high doses of Estrogen (Ethinyl Oestradiol - EE - 200 to 500 μg/day). Known vascular and metabolic risks led us to the use of other therapeutic means based on the reduction of GH secretion with Somatostatine Analog (SMS 201-995). This work consisted in comparing the results of a randomized protocol (SMS vs. EE) and the therapeutic efficiency of both medications.20 girls aged 11 or more (n = 12.1 ± 0,8 years) at the start of puberty (S2, P2 or S2, P3) whose prognostic height was more than 180 cm (Bayley Pinneau - BP) were treated upon request (and after randomization) either with SMS (100 μg twice a day SC) or with EE (200 μg daily + progesterone). A dosage of IGF1 (UI/ml) and a study of spontaneous GH secretion with the calculation of the 24h GH integrated concentration (24h IC ng/ml/min) were assessed before treatment and after 6 months of treatment. All twenty girls have now reached 6 months of treatment and will have been through 1 year of treatment by June 1993.Mean parental height was 186.0 ± 5.3 cm for fathers and 173.3 ± for mothers. Mean height at the start of treatment was + 3.3 SDS and growth velocity (GV) during the year before treatment was 7.8 ± 1.5cm. There was no significant difference between the two groups in CA, BA, parental height, prior GV, pubertal development and height prognosis.These preliminary results showed a greater efficiency of SMS than EE: Reduction of growth rate by 65% vs. 46%. significant decrease of IGF1 and 24h IC (whereas EE increased these two parameters). Side effects were observed by EE: 1 case ot hypertension and 1 case of hypercholesterolemia required to discontinue treatment, with SMS a vesicular microlithiasis having subsided with desoxycholic acid and did not lead to therapeutic discontinuation.

Effects of melatonin implants on insulin-like growth factor 1 in male red deer ( Cervus elaphus)

Red deer stags have a seasonal pattern of growth, alternating between periods of summer weight gain and winter weight loss that are influenced by photoperiod and by exogenous melatonin. A seasonal pattern of plasma insulin-like growth factor 1, also influenced by photoperiod, underlies the seasonal growth pattern. The present studies aimed to determine the influence of exogenous melatonin, administered at various times of the year, on plasma IGF1 in adult red deer stags in New Zealand at 45°S. In one study, 7-year-old stags ( N = 9) were allocated to one of three treatment groups, either control or subcutaneous melatonin (3 × 18-mg coated implants (Regulin) per month) from November to February or from December to February. Blood was sampled, the stags were weighed, and antler status was recorded over 17 months. Melatonin treatment advanced the seasonal patterns of rise and fall of plasma IGF1 and of weight gain and loss. The cessation of melatonin treatment in February produced early antler casting and a second (out-of-season) antler and increased IGF1. In a second study, 4-year-old stags ( N = 30) were allocated to one of six treatment groups as follows: three melatonin implants per month for 6 consecutive months beginning on 22 June, i.e., winter solstice, 4 August, 16 September, and 23 October; three melatonin implants per month for 12 months beginning on 22 June; and an untreated group. All animals were sampled as before for 12 months. Melatonin treatment beginning in July and August did not prevent the seasonal peak in IGF1, but the amplitude was lowered and antler casting delayed. In contrast, melatonin treatment beginning in September and October advanced the seasonal decrease in plasma IGF1, thus the duration of elevated IGF1 was shortened. In the stags treated with melatonin for 1 year, the amplitude of the IGF1 peak was reduced but the seasonal pattern was unaffected. Treatment with melatonin tended to reduce antler size and liveweight gain in all groups. The results indicate that the effect of melatonin treatment on IGF1 differs in June and December. Initially melatonin does not influence the seasonal increase in IGF1 although its amplitude is lowered. Later melatonin treatment advances the seasonal decrease in IGF1 to shorten the duration of elevated IGF1. Melatonin treatment uncoupled antler growth from the IGF1 seasonal pattern either by delaying casting or advancing cleaning to give a decreased antler size.

Decreased serum insulin-like growth factor-I associated with growth failure in newborn lambs with experimental cyanotic heart disease.

To determine whether chronic hypoxemia results in alterations in endocrine function that may contribute to growth failure, we measured growth hormone (GH), somatomedins (insulin-like growth factors I and II, IGF-I and IGF-2), hepatic growth hormone receptors, and circulating IGF-binding proteins IGFBP-3 and IGFBP-2 in 12 newborn lambs with surgically created pulmonic stenosis and atrial septal defect, and in 10 controls. During chronic hypoxemia (oxygen saturation of 60-74% for 2 wk), weight gain was 60% of control (hypoxemic, 135 +/- 20 vs. control, 216 +/- 26 g/d, P less than 0.02). IGF-I was decreased by 43% (hypoxemic 253.6 +/- 29.3 SE vs. control 448.0 +/- 75.5 ng/ml, P = 0.01), whereas GH was unchanged (19.9 +/- 5.1 vs. 11.9 +/- 3.0 ng/ml, NS). The increase in IGF-1 was associated with a decrease in IGFBP-3 (hypoxemic, 5.09 +/- 1.25 vs. control, 11.2 +/- 1.08 arbitrary absorbency units per mm (Au.mm), P less than 0.01), and increase in IGFBP-2 (0.47 +/- 0.03 vs. 0.19 +/- 0.13 Au.mm, P less than 0.05), but no significant downregulation of hepatic GH receptors (hypoxemic, 106.1 +/- 20.1 vs. control, 147.3 +/- 25.9 fmol/mg, NS). Thus, chronic hypoxemia in the newborn is associated with a decrease in IGF-I and IGFBP-3 in the face of normal GH. This suggests peripheral GH unresponsiveness, similar to protein-calorie malnutrition or GH receptor deficiency dwarfism, but mediated at a level distal to the hepatic GH receptor.

Regulation of Insulin-Like Growth Factor (IGF) Binding Proteins in Transgenic Mice with Altered Expression of Growth Hormone and IGF-I

The insulin-like growth factors (IGFs) are present in extracellular fluids bound to specific, high affinity IGF binding proteins (IGFBPs). IGFBPs are believed to mediate IGF transport to tissues and to modulate their actions on target cells. To determine whether IGF-I can modulate IGFBP concentrations in blood and to distinguish the effects of IGF-I from those of GH, we assessed serum IGFBP concentrations in four genotypically distinct groups of sibling transgenic (Tg) mice that differed in respect to their expression of IGF-I and GH. This unique physiological situation was created by crossing IGF-I Tg mice to GH-deficient, dwarf mice in whom somatotrophs were genetically ablated by the expression of a diphtheria toxin transgene in the somatotrophs. Because both Tg mouse lines are hemizygous for their respective transgene, progeny of the cross differ genotypically, according to whether or not they carry one or both transgenes, and phenotypically in regard to their relative expression of IGF-I and GH. GH-deficient mice showed a 15.7-fold decrease in serum IGF-I and a 5.5-fold decrease in serum IGFBP-3, but no change in a serum doublet band of 29,000 to 34,000 Mr, as assessed by ligand blotting. When IGF-I was expressed in the GH-deficient mice, serum levels of IGF-I and IGFBP-3 were 69% and 64% of those in normal sera, respectively. The 29,000 to 34,000 Mr doublet bands also increased. The ternary 150 kilodalton IGF-IGFBP complex, however, was not restored, presumably because IGF-I has no influence on the expression of the acid-labile subunit in this complex. In mice with IGF-I overexpression, serum IGFBP-3 was increased 2.1-fold and the sum of the 29,000 to 34,000 doublet bands was increased 2.9-fold. Immunoblotting showed that the changes in the 29,000 to 34,000 Mr forms observed by ligand blotting appeared to be predominantly due to changes in IGFBP-2. The results show that IGF-I can induce IGFBP-3 and IGFBP-2 independently of GH and that IGF-I is a major controller of these binding proteins.

Response of IGF-1 to nutritional support in malnourished hospital patients: a possible indicator of short-term changes in nutritional status

IGF-1 is a circulating growth factor with hepatic release dependent on nutritional status. To determine if IGF-1 could be a useful nutritional index, 15 malnourished patients were assessed during nutritional support. Patients with protein or protein-calorie malnutrition had lower IGF-1 (39 +/- 7 micrograms/L) than did patients with calorie-only malnutrition (109 +/- 25 micrograms/L, p less than 0.005); transferrin concentrations did not differ between the two groups. Nutritional supplementation produced an increase in IGF-1 (123 +/- 32 micrograms/L, p less than 0.005); the relative increase in IGF-1 (264 +/- 62%, p less than 0.001) exceeded increases in albumin or transferrin (9 +/- 6% and 59 +/- 16%, NS and p less than 0.005, respectively). Reduction or termination of support was followed by a decrease in IGF-1 to 59 +/- 9% of peak values (p less than 0.001) but neither albumin nor transferrin decreased significantly. Changes in IGF-1 were correlated with nitrogen balance (r = 0.45, p less than 0.005). The strong relationship between IGF-1 and nutritional status suggests that IGF-1 determinations may be useful in guiding nutritional therapy in patients whose nitrogen balance is difficult to assess.

Reduction of serum insulin-like growth factor-I by dietary protein restriction is age dependent.

We have determined if dietary protein restriction for 1 wk has differential effects on growth, serum IGF-I, and liver growth hormone receptors at various stages of development. Female Wistar rats were fed a low (5%) protein diet for 7 d at 3, 4, 6, 8, and 12 wk of age, whereas controls were maintained on a normal (15%) protein diet. Body wt gain was impaired in the groups fed the low protein diet, despite normal energy intake, and the effect was attenuated with age. Liver cell number (DNA content) was reduced by low protein feeding in the 3-, 4-, and 6-wk age groups (p less than 0.01), but not in the older animals. Protein restriction caused a dramatic decrease in serum IGF-I in the younger animals (90 and 82% reduction versus normal fed age-matched controls, at 3 and 4 wk, respectively; p less than 0.001), and this effect was progressively attenuated with increasing age (49, 40, and 25% reductions of serum IGF-I at 6, 8, and 12 wk, respectively). Changes in serum IGF-I correlated with those of liver cell number (r = 0.80; p less than 0.001). Total and free liver growth hormone receptors were slightly decreased in the low protein diet groups at 4 (p less than 0.05) and 6 wk (total: p less than 0.001; free: p less than 0.01) but not in the other age groups. The occurrence of profound diet induced reductions in IGF-I without proportional reductions in liver GH receptors suggest that the apparent GH resistance occurs at a postreceptor level.(ABSTRACT TRUNCATED AT 250 WORDS)

Insulin-like growth factor-1 (IGF-1) in mice reduces weight loss during starvation.

Plasma concentrations of IGF-1 decrease markedly during starvation secondary to a reduction in somatotropic receptors in the liver. We investigated whether IGF-1 administration during starvation in mice inhibits the catabolic state normally observed. Plasma concentrations of IGF-1 in starved mice receiving IGF-1 therapy were similar to values from non-starved mice, whereas bGH treatment failed to increase plasma IGF-1 levels. The degree of weight loss during 36 hours of starvation was reduced (p less than 0.01) by frequent treatment with subcutaneous IGF-1 but not by bGH therapy. The effect was restricted to the period 28 to 36 hours after commencement of the fast. These results suggest that a fall in circulating IGF-1 may play a role in the metabolic adaptation during malnutrition.

Similar hormonal changes in sera from scorbutic and fasted (vitamin C-supplemented) guinea pigs, including decreased IGF-I and appearance of an IGF-I reversible mitogenic inhibitor.

We previously proposed that the decreased rates of synthesis of collagen and proteoglycans in vitamin C-deficient guinea pigs were unrelated to the role of ascorbate in proline hydroxylation but might result from modulation of hormones known to change during fasting. In the present studies, we found that sera from guinea pigs on an ascorbate-free diet for 24-28 days or from those fasted for 4 days, with vitamin C supplementation, showed similar changes in the concentrations of several hormones. EGF and IGF-II concentrations were unchanged, but cortisol was increased 3-5 times and growth hormone was increased to approximately twice normal levels. Thyroxine and IGF-I concentrations were decreased to 40% and 25-33% of normal levels, respectively. The decrease in serum IGF-I must occur by a growth hormone-independent pathway. The extent of changes in hormone concentrations in sera from ascorbate-deficient guinea pigs was correlated with the extent of weight loss. Sera from scorbutic and fasted guinea pigs failed to stimulate DNA synthesis in quiescent BALB 3T3 cells in the presence of saturating concentrations of EGF and PDGF. Addition of experimental sera to normal serum showed that lack of mitogenic activity was due to the presence of an inhibitor. Inhibition was not related to IGF-I concentrations in the sera, although it was reversed by the addition of IGF-I to sera from scorbutic or fasted animals. These results support our proposed model and suggest that IGF-I, as well as an inhibitor of its activity, plays a role in the regulation of growth by vitamin C and other nutrients.