Bioavailability of insulin-like growth factors (IGFs) in rats determined by the molecular distribution of human IGF-binding protein-3.
Insulin-like growth factor-binding protein-3 (IGFBP-3) forms a 140-kilodalton (kDa) complex with an acid-labile glycoprotein after complexing with IGF-I or IGF-II. To investigate the bioavailability of circulating IGFs in the rat, we determined the molecular distribution and disappearance of an iv bolus of human IGFBP-3 (130 micrograms/kg). Serum fractions were assayed after size-separation chromatography for human (h) and rat (r) IGFBP-3 with specific RIAs. Within 2 min of injection, 52.9 +/- 1.6% of the hIGFBP-3 appeared in a 140-kDa complex. This form remained in the circulation for hours, whereas hIGFBP-3 in 50- and 30-kDa forms disappeared within 30-60 min. The rapid complexing of hIGFBP-3 to the 140-kDa form did not occur in vitro. Measurement of endogenous rIGFBP-2 indicated that there was minimal exchange of hIGFBP-3 with rIGFBP-3 in the 140-kDa complex within the 60 min of the in vivo study. To determine the importance of IGF-I in regulating the molecular distribution of hIGFBP-3 in serum, the experiment was repeated in streptozotocin-diabetic rats, with total IGF-I levels 50% lower than control values. In these animals, 40.1 +/- 5.2% of the hIGFBP-3 appeared in the 140-kDa complex 2 min after injection, significantly less than that in controls (P < 0.05), and hIGFBP-3 disappeared more quickly from the circulation than in controls (P < 0.05). After coinjection of recombinant human IGF-I, the retention of hIGFBP-3 in the circulation was prolonged in both control and diabetic animals. Because IGFBP-3 must bind IGF before it can associate with the acid-labile subunit, these findings indicate a much greater availability of IGFs to the circulation than previously estimated.
Lewitt
M S
MS
Department of Endocrinology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia.
Saunders
H
H
Baxter
R C
RC
D000818:Animals; D001682:Biological Availability; D002352:Carrier Proteins / Q000737:chemistry / Q000493:pharmacokinetics*; D002845:Chromatography; D006801:Humans; D018969:Insulin-Like Growth Factor Binding Proteins; D008297:Male; D008970:Molecular Weight; D051381:Rats; D017208:Rats, Wistar; D013002:Somatomedins / Q000378:metabolism*; D014018:Tissue Distribution
D002352:Carrier Proteins; D018969:Insulin-Like Growth Factor Binding Proteins; D013002:Somatomedins