scholarly journals The acid-labile subunit (ALS) of the 150 kDa IGF-binding protein complex: an important but forgotten component of the circulating IGF system

2001 ◽  
Vol 170 (1) ◽  
pp. 63-70 ◽  
Author(s):  
YR Boisclair ◽  
RP Rhoads ◽  
I Ueki ◽  
J Wang ◽  
GT Ooi
Keyword(s):  
Current Knowledge ◽  
Biological Fluids ◽  
Limited Attention ◽  
Igf Binding Proteins ◽  
Igf System ◽  
Binary Complexes ◽  
Igf I ◽  
Igf Binding ◽  
Acid Labile Subunit ◽  
Acid Labile

The insulin-like growth factors-I and -II (IGFs) are involved in a wide array of cellular processes such as proliferation, prevention of apoptosis, and differentiation. Most of these effects are mediated by the IGF-I receptor, although at higher IGF concentrations the insulin receptor can also be activated. As the expression of both the IGFs and their receptors is widespread, IGFs are thought to have autocrine/paracrine modes of actions also, particularly during foetal life. The endocrine component of the IGF system is recognised to be important after birth, with IGF-I mediating many of the effects of growth hormone (GH), and linking anabolic processes to nutrient availability. Consideration of ligands and receptors, however, is insufficient to provide a complete understanding of the biology of IGF. This is because IGFs are found in binary complexes of 40-50 kDa with members of a family of IGF-binding proteins (IGFBPs-1 to -6) in all biological fluids. In addition, in postnatal serum, most IGFs are sequestered into ternary complexes of 150 kDa consisting of one molecule each of IGF, IGFBP-3 or IGFBP-5, and acid-labile subunit (ALS). Despite evidence that ALS plays an important role in the biology of circulating IGFs, it has received only limited attention relative to the other components of the IGF system. This review provides an overview on the current knowledge of ALS protein and gene structure, organisation and regulation by hormones, and insights from novel animal models such as the ALS knockout mice.

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 Diagnostic interest of acid-labile subunit measurement in relationship to other components of the IGF system in pediatric patients with growth or eating disorders

2001 ◽  
pp. 245-250 ◽  
Author(s):  
V Barrios ◽  
J Argente ◽  
MT Munoz ◽  
J Pozo ◽  
JA Chowen ◽  
...  
Keyword(s):  
Anorexia Nervosa ◽  
Hormone Deficiency ◽  
Obese Patients ◽  
Igf System ◽  
Igf I ◽  
Igf Binding ◽  
Acid Labile Subunit ◽  
Acid Labile ◽  
Igfbp 3

OBJECTIVE: To analyze the possible utility of measuring acid-labile subunit (ALS) in some types of pathologies in which the IGF system is altered and to compare it with the clinical implications of measurements of other components of this axis. DESIGN AND METHODS: We studied serum ALS concentrations in 20 children with normal variants of short stature (NVSS) at diagnosis and 24 with growth hormone deficiency (GHD), 18 obese patients and 18 girls with anorexia nervosa at diagnosis and during a follow-up period. RESULTS: In patients with GHD and anorexia nervosa, mean ALS concentrations were significantly reduced, but there was a high percentage of overlap with control values. At diagnosis, ALS concentrations were normal in obese patients and children with NVSS. During follow-up, these values normalized in children with GHD who were treated with GH, tended to normalize in those with anorexia nervosa who showed weight gain, and did not change in obese children upon weight loss. However, ALS measurement was less accurate than that of IGF-I or IGF binding protein (IGFBP)-3 in diagnosis of GHD. The correlations found between ALS and some IGF system components at diagnosis either decreased or were non-significant during follow-up of these clinical conditions. CONCLUSION: ALS adds little information to that obtained with IGF-I and IGFBP-3 determinations.

Utility of circulating IGF-I as a biomarker for assessing body composition changes in men during periods of high physical activity superimposed upon energy and sleep restriction

2007 ◽  
Vol 103 (1) ◽  
pp. 340-346 ◽  
Author(s):  
Bradley C. Nindl ◽  
Joseph A. Alemany ◽  
Mark D. Kellogg ◽  
Jennifer Rood ◽  
Steven A. Allison ◽  
...  
Keyword(s):  
Body Composition ◽  
Body Mass ◽  
Binding Protein ◽  
Fat Free Mass ◽  
Retinol Binding Protein ◽  
Energy Deficit ◽  
Igf I ◽  
Igf Binding ◽  
Acid Labile Subunit ◽  
Acid Labile

Insulin-like growth factor (IGF)-I is a biomarker that may have greater utility than other conventional nutritional biomarkers in assessing nutritional, health, and fitness status. We hypothesized that the IGF-I system would directionally track a short-term energy deficit and would be more related to changes in body composition than other nutritional biomarkers. Thirty-five healthy men (24 ± 0.3 yr) underwent 8 days of exercise and energy imbalance. Total and free IGF-I, IGF binding proteins-1, -2, and -3, the acid labile subunit, transferrin, ferritin, retinol binding protein, prealbumin, testosterone, triiodothyronine, thyroxine, and leptin responses were measured. Dual-energy X-ray absorptiometry assessed changes in body mass and composition. Repeated-measures ANOVA, correlation analysis, and receiver operator characteristic curves were used for statistical analyses ( P ≤ 0.05). Body mass (−3.8%), fat-free mass (−2.2%), and fat mass (−12.9%) all decreased. Total and free IGF-I, IGF binding protein-3, and the acid labile subunit and prealbumin, but not transferrin, retinol-binding protein, and ferritin, directionally tracked the energy deficit and losses in body composition. The correlation ( r = 0.43) between changes in free IGF-I and body and fat-free mass was the only significant association observed. Receiver operator characteristic curve analysis revealed that a baseline value < 1.67 for the molar volume ratio of IGF-I to acid labile subunit had an area under the curve of 0.745 and was a significant discriminator for those subjects losing >5% body mass. The IGF-I system is an important adjunct in the overall assessment of adaptation to stress imposed by high levels of physical activity superimposed on energy and sleep restriction and is more closely associated with losses in body mass and fat-free mass than other conventional nutritional biomarkers.

scholarly journals The effects of recombinant human IGF-I administration on concentrations of acid labile subunit, IGF binding protein-3, IGF-I, IGF-II and proteolysis of IGF binding protein-3 in adolescents with insulin-dependent diabetes mellitus

1998 ◽  
Vol 157 (1) ◽  
pp. 81-87 ◽  
Author(s):  
TD Cheetham ◽  
JM Holly ◽  
RC Baxter ◽  
K Meadows ◽  
J Jones ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Insulin Dependent Diabetes Mellitus ◽  
Dependent Diabetes Mellitus ◽  
Igf I ◽  
Igf Binding ◽  
Acid Labile Subunit ◽  
Insulin Dependent ◽  
Igf Binding Protein ◽  
Acid Labile ◽  
Igfbp 3

The long term therapeutic potential of recombinant human (rh) IGF-I administration in insulin-dependent diabetes mellitus (IDDM) may be determined by changes in the IGF binding proteins (IGFBPs) and thus the bioavailability of IGF-I. We have therefore studied the effects of a single subcutaneous dose of rhIGF-I (40 micrograms/kg at 1800 h), when compared with an untreated control night, in 17 subjects with IDDM, on serum concentrations of IGF-I, IGF-II, IGFBP-3, acid labile subunit (ALS), and IGFBP-3 proteolysis. Mean (+/- S.E.M.) IGF-I levels increased from 242 +/- 30 ng/ml to 399 +/- 26 ng/ml (P = 0.01) after rhIGF-I whereas IGF-II levels declined from 600 +/- 45 ng/ml to 533 +/- 30 ng/ml. There was a small overnight reduction in baseline ALS levels from 48 +/- 2.8 to 44.5 +/- 3.2 micrograms/ml (P = 0.04) after rhIGF-I administration. An early fall in IGFBP-3 concentrations on the control night was not seen after rhIGF-I and overall mean levels were increased (5.2 +/- 0.2 micrograms/ml vs 4.9 +/- 0.2 micrograms/ml, P = 0.04, on the control night). On the baseline night, IGFBP-3 levels correlated with the sum of IGF-I and IGF-II (r = 0.73, P = 0.02) and with levels of the ALS (r = 0.7, P = 0.002). However after rhIGF-I, the sum of IGF-I and IGF-II no longer correlated with IGFBP-3, whereas the relationship with ALS was maintained. Immunoblot studies in six subjects indicated that 60%-70% of the IGFBP-3 was detected as a low molecular weight fragment at 1900 h on both study nights, but the amount of fragment declined to approximately 50% at 0100 h and 45% at 0700 h. In conclusion, despite a slight but significant fall in ALS, IGFBP-3 levels rise after rhIGF-I administration in IDDM. This cannot be explained by alterations in IGFBP-3 proteolysis, and may relate to the relative stability of ALS/IGFBP-3 when complexed principally with IGF-I rather than IGF-II.

scholarly journals Synthesis of the acid-labile subunit of the growth-hormone-dependent insulin-like-growth-factor-binding protein complex by rat hepatocytes in culture

1991 ◽  
Vol 275 (2) ◽  
pp. 441-446 ◽  
Author(s):  
C D Scott ◽  
R C Baxter
Keyword(s):  
Growth Hormone ◽  
Binding Proteins ◽  
Rat Hepatocytes ◽  
Alpha Subunit ◽  
Igf Binding Proteins ◽  
Rat Serum ◽  
Igf I ◽  
Igf Binding ◽  
Acid Labile ◽  
Igfbp 3

Insulin-like growth factors (IGFs) circulate predominantly in a growth-hormone-dependent ternary complex of 125-150 kDa. This study investigates the production of the alpha-subunit of this complex, an acid-labile glycoprotein without intrinsic IGF-binding activity, which binds to the IGF-binding protein IGFBP-3 in the presence of IGFs. Medium conditioned by primary cultures of rat hepatocytes produced alpha-subunit with similar complex-forming activity to purified rat serum alpha-subunit. Bovine growth hormone stimulated hepatocyte production of both IGF-I and alpha-subunit. IGF-I tracer bound to pure rat IGFBP-3 was converted from approx. 60 kDa to 150 kDa by serum alpha-subunit, whole rat serum or rat hepatocyte culture medium; this converting activity was destroyed by transient acidification. In contrast, IGF-I bound to hepatocyte-medium IGF-binding proteins could not be converted into a high-molecular-mass from by purified rat serum alpha-subunit. Rat serum and hepatocyte-medium alpha-subunit appeared identical by electrophoretic analysis, since reaction of either with cross-linked IGF-I.IGFBP-3 tracer resulted in bands of molecular mass 130 kDa and 160 kDa, probably representing intact and partially deglycosylated complexes. However, IGF-binding proteins in rat serum and hepatocyte medium were different, in that affinity labelling of medium binding proteins, depleted of endogenous IGFs, showed no evidence of the 50-60 kDa cluster of bands characteristic of rat serum IGFBP-3. We conclude that rat hepatocytes in primary culture produce alpha-subunit similar to that in rat serum; however, alpha-subunit is unable to form ternary complexes with hepatocyte IGF-binding proteins, since cultured hepatocytes do not secrete IGFBP-3.

scholarly journals The growth hormone axis and insulin-like growth factors

2005 ◽  
Vol 58 (11-12) ◽  
pp. 558-562 ◽  
Author(s):  
Tatjana Radosavljevic ◽  
Vera Todorovic ◽  
Danijela Vucevic ◽  
Branka Sikic
Keyword(s):  
Growth Factors ◽  
Critical Role ◽  
The Body ◽  
Alternative View ◽  
Igf Binding Proteins ◽  
Peripheral Tissues ◽  
Igf System ◽  
Igf I ◽  
Igf Binding ◽  
Insulin Like Growth Factors

Introduction Growth is regulated by the interaction of environmental signals with endogenous neuroendocrine responses to the genetic programs that determine the body plan. The insulin-like growth factors (IGFs) are integral components of multiple systems controlling both growth and metabolism. The IGF system The IGF system is thought to be more complex than other endocrine systems, as genes for six IGF-binding proteins (IGFBPs) have been identified so far. The IGFs play a critical role in both cell cycle control and apoptosis, two functions involved in regulation of tumorigenesis. Insulin-like growth factor-I (IGF-I) is essential for normal growth. Confirmation of the significance of IGF-I in human physiology was obtained by the discovery of a patient with intrauterine growth retardation and postnatal growth failure associated with a mutation in the IGF-1 gene. Stages of evolution of the somatomedin hypothesis The original somatomedin hypothesis postulated that somatic growth was regulated by growth hormone's (GH's) stimulation of hepatic IGF-1 production, with IGF-1 acting in an endocrine fashion to promote growth. The dual effectors theory proposed an alternative view, involving direct effects by GH on peripheral tissues not mediated by IGF-1 and GH-stimulated local IGF-1 production for autocrine/paracrine action. It is now clear that G H stimulates the formation of ternary IGF binding complex, which stabilizes IGF-I in the serum.

Acute response of IGF-I and IGF binding proteins induced by thermal injury

2000 ◽  
Vol 278 (6) ◽  
pp. E1087-E1096 ◽  
Author(s):  
Charles H. Lang ◽  
Xiaoli Liu ◽  
Gerald J. Nystrom ◽  
Robert A. Frost
Keyword(s):  
Plasma Concentration ◽  
Binding Proteins ◽  
Thermal Injury ◽  
Igf Binding Proteins ◽  
Igf System ◽  
Significant Difference ◽  
Mrna Transcripts ◽  
Igf I ◽  
Igf Binding ◽  
Igfbp 3

Previous studies demonstrate that thermal injury decreases circulating levels of insulin growth factor I (IGF-I) and alters the plasma concentration of several IGF binding proteins (IGFBP), but the mechanisms for these alterations have not been elucidated. In the current study, a 30% total body surface area full-thickness scald burn was produced in anesthetized rats, and animals were studied 24 h later. The plasma concentration of both total and free IGF-I was decreased (38 and 65%, respectively) in burn rats compared with values from time-matched control animals. Thermal injury decreased the IGF-I peptide content in liver ∼40%, as well as in fast-twitch skeletal muscle (56–69%) and heart (28%). In contrast, IGF-I content in kidney was elevated by 36% in burn rats. Northern blot analysis of liver indicated that burn decreased the expression of small (1.7- and 0.9- to 1.2-kb) IGF-I mRNA transcripts but increased the expression of the 7.5-kb transcript. In contrast, there was a coordinate decrease in all IGF-I mRNA transcripts in muscle and kidney of ∼30%. For liver, muscle, and kidney, there was no significant difference in the expression of growth hormone receptor mRNA between control and burn rats. Thermal injury increased plasma IGFBP-1 levels, and this change was associated with increased IGFBP-1 mRNA in both liver and kidney. IGFBP-3 levels in plasma were concomitantly decreased by burn injury. This change was associated with a reduction in IGFBP-3 mRNA in liver but an increased expression of IGFBP-3 in kidney and muscle. Thermal injury also decreased the concentration of the acid-labile subunit (ALS) in plasma and ALS mRNA expression in liver. Finally, hepatic expression of IGFBP-related peptide-1 was increased twofold in liver but was unchanged in kidney or muscle of burn rats. These results characterize burn-induced changes in various components of the IGF system in select tissues and thereby provide potential mechanisms for alterations in the circulating IGF system and for changes in tissue metabolism.

scholarly journals Effects of short-term caloric restriction on circulating free IGF-I, acid-labile subunit, IGF-binding proteins (IGFBPs)-1–4, and IGFBPs-1–3 protease activity in obese subjects

2006 ◽  
Vol 155 (4) ◽  
pp. 575-581 ◽  
Author(s):  
Michael Højby Rasmussen ◽  
Anders Juul ◽  
Lise Lund Kjems ◽  
Jannik Hilsted
Keyword(s):  
Weight Loss ◽  
Protease Activity ◽  
Biologically Active ◽  
Hypocaloric Diet ◽  
Short Term ◽  
Igf I ◽  
Igf Binding ◽  
Acid Labile Subunit ◽  
Obese Subjects ◽  
Acid Labile

Objective: Decreased levels of GH and total IGF-I have been reported in obesity. It has been hypothesized that increased free (biologically active) IGF-I levels generated from IGF-binding protein (IGFBP) protease activity could be the mechanism for the low GH release in dieting obese subjects. However, no published data exist on free IGF-I levels, acid labile subunit (ALS), or IGFBP protease activity in relation to GH release during a hypocaloric diet. The main purpose of this study was to determine free IGF-I, ALS, IGFBPs-1–4, and IGFBPs-1–3 protease activity in relation to 24-h GH release before and after a short-term very low-calorie diet (VLCD). Design: Six obese subjects before weight loss, five after an average weight loss of 36.1 kg, and five age-and sex-matched lean controls underwent a 4-day VLCD. All subjects were studied on two occasions, once during normal basic diet and again during the last day of the VLCD (1.6 MJ). Methods: Free IGF-I was determined by a non-competitive immunoradiometric assay. Results: Free IGF-I levels decreased in concert with increased ALS and unchanged blunted GH release after a VLCD in the obese subjects. IGFBPs-1–3 proteolytic activity was found to be unchanged by hypocaloric diet in all groups. Conclusions: We conclude that free IGF-I decreases after a short-term hypocaloric diet in obese subjects with no concomitant change in 24-h GH release. Circulating free IGF-I per se cannot be the main mechanism of the attenuated GH release in dieting obese subjects.

Sign in / Sign up

Export Citation Format

Share Document