I don't agree,or disagree....so where are these so called studies????...feel free to post a link.
The following clearly support the notion that longR3 and other analogs of IGF-1 that bind poorly or not at all to IGF-1 binding proteins are cleared from the body quicker than regular IGF-1
If you have studies that indicate the contrary please share. I am open minded
Am J Physiol. 1999 Apr;276(4 Pt 1):E663-71. Links
Clearance of IGFs and insulin from wounds: effect of IGF-binding protein interactions.Robertson JG, Belford DA, Ballard FJ.
Child Health Research Institute, North Adelaide, South Australia 5006.
We have examined the role binding proteins have in regulating the clearance of exogenous growth factors from wounds. Hunt-Schilling chambers were subcutaneously implanted in rats, and the clearance of insulin-like growth factor (IGF) I from the chamber wound fluid was compared with IGF-II, LR3-IGF-I, which binds poorly to IGF-binding proteins (IGFBP), or insulin. Elimination rate constants of the slow phase of the decay curves did not differ between IGF-I and IGF-II. However, LR3-IGF-I and insulin were cleared more rapidly from wound fluid than IGF-I so that the half-lives for IGF-I, IGF-II, LR3-IGF-I, and insulin were 872, 861, 563, and 324 min, respectively. In wound fluid, minimal degradation of the IGFs occurred, whereas insulin was degraded considerably. The increased clearance of LR3-IGF-I and insulin equated with a reduced association with wound fluid IGFBPs, and increased amounts of radioactivity of these peptides were detected in the circulation and urine. These results show that this model of wound repair may be of use in examining the kinetics of growth factors and other bioactive molecules in extravascular spaces and support the hypothesis that IGFBPs can be significant regulators of IGF bioavailability in vivo.
PMID: 10198302 [PubMed - indexed for MEDLINE]
J Endocrinol. 1993 Aug;138(2):327-36. Links
Plasma clearance and tissue distribution of labelled insulin-like growth factor-I (IGF-I) and an analogue LR3IGF-I in pregnant rats.Bastian SE, Walton PE, Wallace JC, Ballard FJ.
Department of Biochemistry, University of Adelaide, South Australia.
To determine whether the changes in insulin-like growth factor-binding proteins (IGFBPs) and IGF-I levels during pregnancy in rats affect the clearance of IGFs from the circulation, we have measured pharmacokinetic parameters and the tissue distribution of radiolabelled IGF-I and LR3IGF-I, a potent analogue which has a markedly reduced affinity of binding to the IGFBPs. Intravenous boluses of radiolabelled growth factors were administered to catheterized virgin and age-matched pregnant rats on day 18 of gestation when plasma IGFBPs, in particular IGFBP-3, are dramatically reduced. IGF-I was cleared more rapidly from plasma in pregnant rats compared with the virgins; metabolic clearance rate (MCR) = 2.88 +/- 0.12 (S.E.M.) and 0.90 +/- 0.05 ml/min per kg respectively. Although LR3IGF-I was cleared more rapidly than IGF-I from plasma, similar clearance rates for the analogue were obtained in both pregnant and virgin animals, MCR = 9.19 +/- 0.15 and 9.84 +/- 0.28 ml/min per kg respectively. In virgin rat plasma, labelled IGF-I was mainly associated with the 150 kDa complex, whereas in pregnant rat plasma IGF-I was predominantly associated with lower M(r) IGFBPs (approximately 30-50 kDa). The majority of LR3IGF-I was detected as free peptide. A larger proportion of the tracer was detected as small M(r) breakdown products in plasma from rats under conditions of reduced binding to IGFBPs, e.g. during pregnancy or when LR3IGF-I was the labelled tracer, suggesting greater rates of IGF degradation. More LR3IGF-I tracer was detected in kidneys, ovaries and adrenals of virgin rats and in the ovaries and adrenals of pregnant rats, compared with IGF-I tracer. IGF-I radioactivity was greater than LR3IGF-I in caecum, brain, liver and heart in virgin rats and in kidneys, caecum, brain, liver, heart, placenta, fetus and fetal plasma of the pregnant rats. These results show that the reduction in IGFBP during pregnancy dramatically increased the clearance of IGF-I from the circulation towards that obtained with LR3IGF-I. The observation that less LR3IGF-I was detected in placenta, fetus and fetal plasma compared with IGF-I raises the possibility that the ability to bind IGFBPs during pregnancy may enhance IGF uptake by the conceptus.
PMID: 7693845 [PubMed - indexed for MEDLINE]
J Endocrinol. 1997 Nov;155(2):377-86. Links
IGF-I variants which bind poorly to IGF-binding proteins show more potent and prolonged hypoglycaemic action than native IGF-I in pigs and marmoset monkeys.Tomas FM, Walton PE, Dunshea FR, Ballard FJ.
Cooperative Research Centre for Tissue Growth and Repair, Adelaide, South Australia, Australia.
The relative acute hypoglycaemic potencies of IGF-I and several variants of IGF-I which bind poorly to the IGF-I binding proteins (IGFBPs) have been examined in marmosets (Callithrix jacchus) and the pig. In the marmoset study, IGF-I and des(1-3)IGF-I were compared in anaesthetised and conscious animals in a range of bolus doses from 42 to 270 micrograms/kg body weight. In the pig study, IGF-I was compared with four variants, des(1-3)IGF-I long-IGF-I, R3IGF-I and long-R3IGF-I (LR3IGF-I), which show reduced affinity for the IGFBPs as well as with insulin. Doses in the pig were 20 and 50 micrograms/kg body weight for the IGFs and 3 micrograms/kg for insulin. In each study serial blood samples were taken from 30 min before to 4 h after the bolus injection. Plasma glucose levels were decreased in a dose-responsive manner with the pig more sensitive than either the conscious or anaesthetised marmoset (maximum lowering 4.8, 3.7 and 2.5 mmol/l respectively). The IGF variants were consistently 2- to 3-fold more potent than IGF-I in each animal for lowering of plasma glucose to the nadir, with the potency reflecting the relative affinities for binding to the IGFBPs and the IGF-I receptors. Thus, hypoglycaemic potency was in the order IGF-I < long-IGF-I < R3IGF-I approximately LR3IGF-I < des (1-3)IGF-I. Notably the variants suppressed plasma glucose levels over a much longer period than did IGF-I, the cumulative suppression over four hours showing an approximately 4- to 8-fold increase in the extent of hypoglycaemia. The prolonged suppression was not simply proportional to the hypoglycaemic nadir; at doses equipotent for glucose lowering, the cumulative hypoglycaemic effect for the variants in either species was about 2-fold that for IGF-I. The differential effect of the variants in the marmoset could not be accounted for by correlated changes in plasma insulin, IGF-I or IGFBP levels in plasma. Indirect effects via inhibition of glucagon, or direct effects via hepatic insulin receptors are postulated to account for the results. There was a dose-related reduction in plasma amino acids in the pig but, unlike the case for plasma glucose, only one analogue, LR3IGF-I was more potent than IGF-I. The response to LR3IGF-I was accentuated at the high dosage but on the basis of the other variants tested this effect could not be ascribed to either of the incorporated molecular variations. Despite their more rapid clearance from the circulation, variants of IGF-I which show lower affinity for binding to IGFBPs show proportionately superior potency for sustained hypoglycaemic action. Since our data were obtained in animal models of accepted relevance to humans these results point to the possible superior efficacy of the variants, especially des(1-3)IGF-I, over IGF-I for use as an adjunct to insulin treatment of hyperglycaemic conditions.
PMID: 9415072 [PubMed - indexed for MEDLINE]