Mechanism of secretion of plasma insulin-like growth factor-I into milk of lactating goats

1991 ◽  
Vol 131 (3) ◽  
pp. 459-466 ◽  
Author(s):  
C. G. Prosser ◽  
I. R. Fleet ◽  
A. J. Davis ◽  
R. B. Heap
Keyword(s):  
Growth Factor ◽  
Time Course ◽  
Specific Activity ◽  
Gel Filtration ◽  
Free Form ◽  
Insulin Like Growth Factor ◽  
Factor I ◽  
Lactating Goats ◽  
Igf I ◽  
Growth Factor I

ABSTRACT 125I-Labelled insulin-like growth factor-I (IGF-I) was infused as the free form directly into the pudic artery supplying one gland of lactating goats (n = 6). The infusion was for 60 min and 0·4±0·09% (s.e.m.) of the infusate was secreted into milk from the infused gland during its first passage through that gland. A large proportion of the 125I-labelled IGF-I escaped into the systematic circulation and was secreted into milk of both glands. A total of 5·2±0·4% of infused radioactivity was recovered in milk from both glands from 0 to 720 min. Radioactivity consisted of trichloroacetic acid (TCA)-precipitable and -soluble counts which were shown by gel filtration to be authentic IGF-I and degraded products of the peptide. The amount and time course of TCA-soluble radioactivity in milk from both glands was similar, suggesting degradation of 125I-labelled IGF-I at extramammary sites. Maximum specific activity for 125I-labelled IGF-I in milk from the infused gland was reached 80–120 min after the start of infusion and was 2·5-fold greater than milk from the non-infused gland. The time course of appearance of 125I-labelled IGF-I in milk suggests that transfer was via the transcellular pathway and this was further supported by comparing the pattern of transfer of [14C]sucrose and [14C]amino acids. When excess unlabelled IGF-I was included in the infusate, specific activity in milk from the infused gland was reduced to that of the non-infused gland, indicating a competitive and saturable mechanism of secretion for 125I-labelled IGF-I. Comparison of uptake and secretion of 125I-labelled IGF-I into milk from the non-infused gland with that of endogenous immunoreactive IGF-I suggests that vectorial transport of IGF-I across the mammary gland may be a significant contributor of IGF-I levels in milk. Journal of Endocrinology (1991) 131, 459–466

scholarly journals Recovery of Growth Hormone Release from Suppression by Exogenous Insulin-Like Growth Factor I (IGF-I): Evidence for a Suppressive Action of Free Rather Than Bound IGF-I1

1998 ◽  
Vol 83 (8) ◽  
pp. 2836-2842
Author(s):  
Ian M. Chapman ◽  
Mark L. Hartman ◽  
Karen S. Pieper ◽  
Emily H. Skiles ◽  
Suzan S. Pezzoli ◽  
...  
Keyword(s):  
Growth Factor ◽  
Time Course ◽  
Temporal Association ◽  
Saline Control ◽  
Insulin Like Growth Factor ◽  
Factor I ◽  
Igf I ◽  
Growth Factor I ◽  
Rebound Increase ◽  
Serum Gh

abstract To determine the time course of recovery of GH release from insulin-like growth factor I (IGF-I) suppression, 11 healthy adults (18–29 yr) received, in randomized order, 4-h iv infusions of recombinant human IGF-I (rhIGF-I; 3 μg/kg·h) or saline (control) from 25.5–29.5 h of a 47.5-h fast. Serum GH was maximally suppressed within 2 h and remained suppressed for 2 h after the rhIGF-I infusion; during this 4-h period, GH concentrations were approximately 25% of control day levels [median (interquartile range), 1.2 (0.4–4.0) vs. 4.8 (2.8–7.9) μg/L; P < 0.05]. A rebound increase in GH concentrations occurred 5–7 h after the end of rhIGF-I infusion [7.6 (4.6–11.7) vs. 4.3 (2.5–6.0) μg/L; P < 0.05]. Thereafter, serum GH concentrations were similar on both days. Total IGF-I concentrations peaked at the end of the rhIGF-I infusion (432 ± 43 vs. 263 ± 44 μg/L; P < 0.0001) and remained elevated 18 h after the rhIGF-I infusion (360 ± 36 vs. 202 ± 23 μg/L; P = 0.001). Free IGF-I concentrations were approximately 140% above control day values at the end of the infusion (2.1 ± 0.4 vs. 0.88 ± 0.3 μg/L; P = 0.001), but declined to baseline within 2 h after the infusion. The close temporal association between the resolution of GH suppression and the fall of free IGF-I concentrations, and the lack of any association with total IGF-I concentrations suggest that unbound (free), not protein-bound, IGF-I is the major IGF-I component responsible for this suppression. The rebound increase in GH concentrations after the end of rhIGF-I infusion is consistent with cessation of an inhibitory effect of free IGF-I on GH release.

Improved estimates of clearance of 131I-labelled insulin-like growth factor-I carrier protein complexes from blood plasma of sheep

1989 ◽  
Vol 123 (3) ◽  
pp. 469-475 ◽  
Author(s):  
S. R. Davis ◽  
S. C. Hodgkinson ◽  
L. G. Moore ◽  
P. D. Gluckman
Keyword(s):  
Molecular Weight ◽  
Growth Factor ◽  
Half Life ◽  
Binding Protein ◽  
Free Form ◽  
High Molecular Weight Fraction ◽  
Insulin Like Growth Factor ◽  
Factor I ◽  
Igf I ◽  
Growth Factor I

ABSTRACT Clearance of protein-bound forms of insulin-like growth factor-I (IGF-I) from the circulation of sheep was determined using single injections of 131I-labelled ovine or [Thr59]-human IGF-I, in the 'free' form or prebound to 50 or 150 kDa plasma binding protein fractions. The half-life of circulating protein-bound forms of IGF-I was determined by size-exclusion chromatography of plasma samples taken over a 24-to 26-h experimental period. IGF-I bound to lower molecular weight binding protein(s) (approximately 50 kDa) showed a half-life of 26–40 min (mean 34 min; n = 6), while the half-life of a high molecular weight fraction (150 kDa) was considerably longer (range 398–603 min; mean 545 min; n =8). Metabolic clearance of IGF-I following administration of free tracer ranged from 3.0 to 5.3 ml/min in sheep (n = 4) weighing 26.0–28.5 kg. Tracer distribution volume was 59 ml/kg liveweight (n=4). Tracer degradation products were first detected in plasma 8 h after i.v. administration. No differences in stability of the purified ovine and recombinant human IGF-I tracer preparations were observed. However, a fraction of the [Thr59]-IGF-I tracer did not possess binding activity and this was associated with excretion of a greater proportion of administered radioactivity (over 22 h) in urine in animals receiving [Thr59]-IGF-I tracer (18.4–19.3%) compared with ovine IGF-I (7.1–11.0%). Following administration of free tracer or tracer bound to the 50 kDa protein, the proportion of radioactivity bound to the 150 kDa fraction increased over the first 20-30 min of observation. However, this was not apparent following administration of tracer bound to the 150 kDa protein, indicating that the more rapid turnover of IGF-I bound to the 50 kDa protein was associated, in part, with transfer of IGF-I to the 150 kDa binding protein fraction. The calculated secretion rates of the IGFs were two- to threefold and twentyfold higher, for IGF-I and -II respectively, relative to that of insulin. These data are evidence supporting roles for IGFs in the regulation of metabolism. Journal of Endocrinology (1989) 123, 469–475

Increase in milk secretion and mammary blood flow by intra-arterial infusion of insulin-like growth factor-I into the mammary gland of the goat

1990 ◽  
Vol 126 (3) ◽  
pp. 437-443 ◽  
Author(s):  
C. G. Prosser ◽  
I. R. Fleet ◽  
A. N. Corps ◽  
E. R. Froesch ◽  
R. B. Heap
Keyword(s):  
Blood Flow ◽  
Mammary Gland ◽  
Growth Factor ◽  
Insulin Like Growth Factor ◽  
Milk Secretion ◽  
Arterial Infusion ◽  
Factor I ◽  
Lactating Goats ◽  
Igf I ◽  
Growth Factor I

ABSTRACT The close-arterial infusion of free insulin-like growth factor-I (IGF-I; 1·1 nmol/min) for 6 h into the pudic artery supplying one mammary gland of lactating goats caused a 25±6% (mean ± s.e.m., n = 6) increase in the rate of milk secretion of that gland. The increase in the rate of milk secretion in the adjacent non-infused gland (14±4%) was not significantly different from that observed during saline infusion (4±5%). Blood flow to the infused gland was increased from 378±26 ml/min 1 h before to 487±56 ml/min approximately 5 h after the start of the infusion of IGF-I, declining to 420±44 ml/min approximately 2 h after the end of the infusion. The total concentration of IGF-I (free and bound) in milk of the infused gland was significantly higher than that of the non-infused gland. The concentrations of IGF-I in carotid arterial plasma samples increased during IGF-I infusion from a mean value of 32±2 nmol/l before to a maximum of 49±3 nmol/l 5 h after the infusion commenced. Circulating concentrations of total IGF-I declined slowly after the infusion with an estimated half-life of 5 h. Infusion of saline alone did not alter mammary blood flow or the concentration of total IGF-I in milk or plasma. The results indicate that the infusion of free IGF-I into the mammary arterial supply enhances milk secretion and mammary blood flow in intact, conscious goats. The more pronounced effect in the infused compared with the non-infused gland suggests that free IGF-I acts directly on the mammary gland. The response in the non-infused gland was attenuated presumably due to association of IGF-I with plasma binding proteins during recirculation. Journal of Endocrinology (1990) 126, 437–443

The galactopoietic effect of bovine growth hormone in goats is associated with increased concentrations of insulin-like growth factor-I in milk and mammary tissue

1991 ◽  
Vol 128 (3) ◽  
pp. 457-463 ◽  
Author(s):  
C. G. Prosser ◽  
C. Royle ◽  
I. R. Fleet ◽  
T. B. Mepham
Keyword(s):  
Growth Factor ◽  
Mammary Tissue ◽  
Insulin Like Growth Factor ◽  
Factor I ◽  
Lactating Goats ◽  
Significant Difference ◽  
Igf I ◽  
Growth Factor I ◽  
Group 2 ◽  
Group 1

ABSTRACT Lactating goats exhibiting widely divergent responses to short-term (4 days) treatment with bovine GH (bGH) were retrospectively divided into two groups based on the magnitude of this response. There was no difference between groups in terms of the pretreatment milk yield, but by day 4 of treatment milk secretion had increased by 4·99±2·5 (s.e.m.) ml/h (P > 0·05 compared with pretreatment) for group 1 and 22·9±2·4 ml/h (P< 0·001) for group 2. Plasma GH increased in both groups, but concentrations were significantly higher both before and during treatment in group 1 compared with group 2. Plasma concentrations of insulin-like growth factor-I (IGF-I) increased significantly during bGH treatment for both groups and there was no significant difference between the two until day 4 of treatment when levels of IGF-I in group 1 began to decline, whereas those from group 2 were maintained. Concentrations of IGF-I in milk from goats in group 1 were not significantly altered by GH administration, whereas those in goats in group 2 were increased by 40% (P < 0·01 compared with pretreatment). Levels of IGF-I in mammary secretory tissue from four animals from group 1 were not altered by bGH (2·8±0·2 and 2·77 ±0·08 nmol/kg tissue before and after treatment respectively), but were significantly (P < 0·05) increased in four animals from group 2 (2·80±0·2 and 9·9±1·1 nmol/kg tissue). Thus, it appears that the galactopoietic response in goats was associated with significantly lower levels of GH in plasma after 3 days of treatment and, more strikingly, greater amounts of IGF-I in milk and mammary tissue. This latter observation is consistent with the hypothesis that the effects of bGH on the mammary gland itself are mediated by IGF-I and that the availability of IGF-I to mammary tissue is an important component of the overall galactopoietic response to bGH. Journal of Endocrinology (1991) 128, 457–463

The effects of the insulin-like growth factor-I aptamer, NBI-31772, on glucose homeostasis in the mouse

2005 ◽  
Vol 83 (7) ◽  
pp. 557-563 ◽  
Author(s):  
Josef V Silha ◽  
Liam J Murphy
Keyword(s):  
Growth Factor ◽  
Specific Activity ◽  
Insulin Like Growth Factor ◽  
Igf Binding Proteins ◽  
Duration Of Action ◽  
Intravenous Glucose ◽  
Factor I ◽  
Key Words Insulin ◽  
Igf I ◽  
Growth Factor I

The majority of insulin-like growth factor-I (IGF-I) in the adult rodent circulation is bound to high affinity IGF binding proteins. We investigated the changes in IGF-I clearance, blood glucose and plasma insulin levels, and tissue 2-deoxyglucose uptake after intravenous administration of the IGF aptamer, NBI-31772, which selectively competes with IGF-I for binding to the IGFBPs, but has no effect at the IGF-I receptor. Clearance of 125I-IGF-I was significantly increased in NBI-31772-treated mice compared with vehicle-treated mice (t1/2 = 45.0 ± 1.9 vs. 56.3 ± 3.9 min, respectively; p = 0.021). However, NBI-31772 had no significant effect on glucose levels, and no insulin sparing effect was apparent neither under basal conditions nor during an intravenous glucose challenge. The decline in the specific activity after 3H-2-deoxyglucose administration was significantly less rapid in NBI-31772-treated mice compared with controls, suggesting that the IGF-I aptamer had an inhibitory effect on hepatic gluconeogenesis. In contrast, no insulin-like effect was apparent in other tissues examined. 3H-2-deoxyglucose accumulation was similar in all tissues analyzed, including skeletal muscle, which is thought to be particularly sensitive to IGF-I. These data suggest that the IGF-I aptamer affects clearance of radiolabeled IGF-I from the circulation, but has no marked effects on glucose nor insulin homeostasis. The search for hydrophilic IGF aptamers with longer duration of action that could be used in the treatment of diabetes may be rewarding. Key words: insulin resistance, gluconeogenesis, 2-deoxyglucose uptake, glucose clearance.

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