scholarly journals Isolation of the cDNA encoding the acid labile subunit (ALS) of the 150 kDa IGF-binding protein complex in cattle and ALS regulation during the transition from pregnancy to lactation

2006 ◽  
Vol 189 (3) ◽  
pp. 583-593 ◽  
Author(s):  
Jin W Kim ◽  
Robert P Rhoads ◽  
Nthabisheng Segoale ◽  
Niels B Kristensen ◽  
Dale E Bauman ◽  
...  
Keyword(s):  
Dairy Cows ◽  
Follicular Fluid ◽  
Binding Protein ◽  
Ribonuclease Protection Assay ◽  
Hepatic Expression ◽  
Igf I ◽  
Igf Binding ◽  
Acid Labile Subunit ◽  
Igf Binding Protein ◽  
Acid Labile

During the transition from pregnancy to lactation, dairy cows experience a 70% reduction in plasma IGF-I. This reduction has been attributed to decreased hepatic IGF-I production. IGF-I circulates predominantly in multi-protein complexes consisting of one molecule each of IGF-I, IGF binding protein-3 and the acid labile subunit (ALS). Recent studies in the mouse have shown that absence of ALS results in accelerated turnover and severely depressed concentration of plasma IGF-I. These observations suggest that reduced plasma ALS could be a second factor contributing to the fall of plasma IGF-I in peri-parturient cows. This possibility has not been studied due to the lack of bovine ALS reagents. To address this, we isolated the bovine ALS cDNA and used its sequence to develop a ribonuclease protection assay (RPA) and a bovine ALS antiserum. Using the RPA, ALS mRNA abundance was approximately fivefold higher in liver than in lung, small intestine, adipose tissue, kidney and heart, but was absent in muscle and brain. The antiserum detected the highest ALS levels in plasma followed by ovarian follicular fluid, lymph and colostrum. A portion of colostrum and follicular fluid ALS appears to be synthesized locally as ALS mRNA was found in mammary epithelial cells and ovarian follicular cells. Finally, we measured plasma ALS in dairy cows during the peri-parturient period (days −35 and +56 relative to parturition on day 0). Plasma ALS dropped by 50% between late pregnancy and the first day of lactation and returned to prepartum levels by day +56. To determine whether this reflected a change in hepatic expression, ALS mRNA was measured in liver biopsies collected on days −35, +3 and +56. ALS mRNA expression was significantly lower on day +3 than on day −35, but recovered completely by day +56. Finally, we examined the ability of GH to increase plasma ALS abundance at selected times before and after parturition (weeks −5, −2, +1 and +5). GH increased plasma ALS at weeks −5, −2 and +5, but not at week +1. Identical effects of GH were seen when the response considered was plasma IGF-I. We conclude that the decline in plasma ALS after parturition is a consequence of hepatic GH resistance and contributes to the associated reduction of plasma IGF-I.

scholarly journals Increased Insulin-Like Growth Factor (IGF)-II and IGF/IGF-Binding Protein Ratio in Prepubertal Constitutionally Tall Children

2002 ◽  
Vol 87 (12) ◽  
pp. 5455-5460 ◽  
Author(s):  
S. Garrone ◽  
G. Radetti ◽  
M. Sidoti ◽  
M. Bozzola ◽  
F. Minuto ◽  
...  
Keyword(s):  
Growth Velocity ◽  
Binding Protein ◽  
Molar Ratio ◽  
Igf System ◽  
Igf I ◽  
Igf Binding ◽  
Acid Labile Subunit ◽  
Igf Binding Protein ◽  
Acid Labile ◽  
Igfbp 3

Abstract The height of subjects with constitutionally tall stature (CTS) is at least 2 sd above the mean of subjects of the same age and sex. Apart from a few discordant data on the role of GH and its direct mediator, IGF-I, no studies have been conducted on other components of the IGF system, which also condition the bioavailability and activity of IGF-I. We, therefore, investigated the possibility that other components of the IGF system might play a role in determining the increased growth velocity seen in CTS. To this end, we evaluated the behavior not only of IGF-I but also of IGF-II, IGF-binding protein (IGFBP)-3, and acid-labile subunit, the subunits that constitute the main IGF complex in circulation (150-kDa complex), as well as of IGFBP-1 and IGFBP-2, which are negatively regulated by GH and, like IGFBP-3, able to influence the bioavailability of the IGFs. The study was performed on 22 prepubertal subjects affected by CTS (16 males and 6 females), aged 2.8–13.3 yr (6.8 ± 0.5 yr, mean ± sem). Thirty-seven normal prepubertal subjects (16 males and 21 females) aged between 2.2 and 13.3 yr (6.7 ± 0.5 yr), who were comparable in socioeconomic and nutritional terms, served as controls. From the auxological point of view, subjects with CTS differed significantly from controls only in terms of growth velocity (HV-sd score; CTS, 1.8 ± 0.3; controls, 0.4 ± 0.2; P < 0.0001) and height (H-sd score; CTS, 3.1 ± 0.1; controls, 0.4 ± 0.2; P < 0.0001). The results demonstrated that the concentrations of IGF-I (27.3 ± 2.0 nmol/liter), IGFBP-3 (66.9 ± 3.8), and acid-labile subunit (216.8 ± 13.6) in CTS-affected subjects were not significantly different from those determined in controls (25.0 ± 2.9, 74.4 ± 4.1, and 241.0 ± 11.9, respectively). By contrast, IGF-II levels proved significantly higher in CTS subjects (IGF-II: 87.2 ± 3.4 vs. 52.4 ± 2.3, P < 0.0001). Chromatographic analysis, performed after acid treatment of pooled sera, showed only the presence of normal 7.5-kDa IGF-II in both CTS subjects and controls. In comparison with controls, CTS children showed a lower concentration of IGFBP-1 (1.6 ± 0.3 vs. 4.1 ± 0.7, P = 0.03) and a higher concentration of IGFBP-2 (14.3 ± 1.8 vs. 9.6 ± 1.1, P = 0.03). The IGFs (IGF-I and -II)/IGFBPs (−1 + −2 + −3) molar ratio was significantly higher (P < 0.0001) in CTS children than in controls. In particular, the IGF-II/IGFBP ratio (P < 0.0001) was responsible for the excess of the IGF peptide in relation to the concentrations of IGFBPs and, therefore, for the increase in the potentially bioactive free form of the IGFs. Moreover, the IGFBP-3/IGF molar ratio was significantly reduced, being less than 1 in CTS subjects (0.6 ± 0.1 vs. 1.1 ± 0.1), so that a quantity of IGF peptides lack sufficient IGFBP-3 to form the 150-kDa complex with which are normally sequestered in the vascular compartment. The data show that in CTS: 1) the most GH-dependent components of the IGF system are normal, consistent with the finding of a normal GH secretory state; 2) the less GH-dependent IGF-II is significantly increased, in agreement with the finding of a relationship between high levels of IGF-II and overgrowth in some syndromes; and 3) the IGF/IGFBP molar ratio is increased, and, therefore, a greater availability of free IGF for target tissues may be responsible for overgrowth in CTS.

scholarly journals Effects of Combined Recombinant Insulin-Like Growth Factor (IGF)-I and IGF Binding Protein-3 in Type 2 Diabetic Patients on Glycemic Control and Distribution of IGF-I and IGF-II among Serum Binding Protein Complexes

2007 ◽  
Vol 92 (7) ◽  
pp. 2652-2658 ◽  
Author(s):  
D. R. Clemmons ◽  
M. Sleevi ◽  
G. Allan ◽  
A. Sommer
Keyword(s):  
Blood Glucose ◽  
Binding Protein ◽  
Insulin Dosage ◽  
Igf I ◽  
Igf Binding ◽  
Acid Labile Subunit ◽  
Igf Binding Protein ◽  
Acid Labile ◽  
Igfbp 3

Abstract Context: Administration of recombinant human IGF-I (rhIGF-I)/recombinant human IGF binding protein-3 (rhIGFBP-3) to patients with type 2 diabetes improves blood glucose and enhances insulin sensitivity. The changes in various components of the IGF system that occur in response to rhIGF-I/rhIGFBP-3 as well as the minimum effective dose have not been determined. Objectives: The aim was to determine the dose of rhIGF-I/rh-IGFBP-3 necessary to achieve a significant decrease in glucose and to determine the changes that occur in the IGF-II and acid labile subunit in response to treatment. Design: A total of 39 insulin-requiring type 2 diabetics were randomized to placebo or one of six groups that received different dosages of rhIGF-I/rhIGFBP-3. After 3 d in which insulin doses were adjusted to improve glucose control, a variable insulin dosage regimen was continued, and either placebo or one of six dosages (0.125–2.0 mg/kg·d) of rhIGF-I/rhIGFBP-3 was administered for 7 d. All subjects were hospitalized, and dietary intake as well as insulin dosage were controlled with instructions to treat to normal range targets. Results: Fasting glucose was reduced in the groups that received either 1 (32 ± 5% reduction) or 2 mg/kg·d (40 ± 6% reduction) of the complex. Mean daily glucose (four determinations) was reduced by 26 ± 4% in the 1 mg/kg group and by 33 ± 5% in the 2 mg/kg group compared with 18 ± 4% in the placebo group. Total serum IGF-I increased between 2.0 ± 0.3- and 5.7 ± 1.3-fold by d 8. IGFBP-3 concentrations increased significantly only in the 2 mg/kg group. IGF-II concentrations declined to values that were between 27 ± 4% and 64 ± 7% below baseline. Acid labile subunit concentrations declined significantly in the three highest dose groups. The sum of the IGF-I + IGF-II concentrations was significantly increased at the two highest dosages. There were very few drug-associated adverse events reported in this study with the exception of hypoglycemia, which occurred in 15 subjects who had received rhIGF-I/rhIGFBP-3 treatment. Conclusions: Administration of rhIGF-I/rhIGFBP-3 resulted in a redistribution of the amount of IGF-I and IGF-II that bound to IGFBP-3. Fasting and mean daily blood glucose were reduced significantly in the two highest dosage groups. The results suggest that both the total concentration of IGF-I as well as its distribution in blood may determine the extent to which insulin sensitivity is enhanced.

Long-term effects of insulin-like growth factor (IGF)-I on serum IGF-I, IGF-binding protein-3 and acid labile subunit in Laron syndrome patients with normal growth hormone binding protein

1997 ◽  
pp. 626-630 ◽  
Author(s):  
H Kanety ◽  
A Silbergeld ◽  
B Klinger ◽  
A Karasik ◽  
RC Baxter ◽  
...  
Keyword(s):  
Binding Protein ◽  
Long Term Effects ◽  
Laron Syndrome ◽  
Igf I ◽  
Igf Binding ◽  
Acid Labile Subunit ◽  
Igf Binding Protein ◽  
Acid Labile ◽  
Igfbp 3

A minority of patients with Laron syndrome have normal serum GH binding protein (GHBP), indicating that the defect is elsewhere than in the extracellular domain of the GH receptor. We have evaluated the effect of long-term IGF-I treatment on serum IGF-binding protein (IGFBP)-3 and the acid-labile subunit (ALS) in three sibling with Laron syndrome caused by a GH post-receptor defect and with normal GHBP. The children (a boy aged 3 years, a girl aged 4 years and a boy aged 10 years) were treated by daily s.c. injection of IGF-I in a dose of 150 micrograms/kg. IGFBP-3 was measured by RIA and Western ligand blotting, ALS by RIA. Based values of IGFBP-3 and ALS were low. During IGF-I treatment, the IGFBP-3 concentrations in the girl gradually increased, whereas in the boys there was a 60% decrease during the first week, followed by gradual increase towards baseline. The ALS concentrations followed a similar pattern. We conclude that IGF-I treatment induces and initial suppression and then an increase in the IGFBP-3 and ALS concentrations, confirming data from animal experiments that IGFBP-3 synthesis is not solely under GH control. The differences in responsiveness between the female and male siblings may reflect genetic differences, or lower circulating concentrations of IGF-I in the boys compared with the girl.

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