Insulinlike growth factors (IGF) act qualitatively like insulin on insulin target tissues in vitro. In the circulation in vivo they are bound to specific carrier proteins. In this form or when continuously infused into hypophysectomized (hypox) rats they do not exert acute insulinlike effects on glucose homeostasis. This study definitively shows that intravenous bolus injections of pure IGF I or II act acutely on glucose homeostasis: they lower the blood sugar, enhance the disappearance of U-['4qglucose from serum and increase its incorporation into diaphragm glycogen in normal and hypox rats in the presence of antiinsulin serum. The same effects were obtained with recombinant human IGF I iqjected intravenously either with or without antiinsulin serum into normal rats.Free fatty acid levels decreased transiently only in normal animals. Lipid synthesis from glucose in adipose tissue was not stimulated in hypox and barely stimulated in normal rats.The half-life of injected IGF I or II in normal rats (-4 h) is strikingly different from that in hypophysectomized rats (20-30 min) and appears to depend on the growth hormone-induced 150,000-200,000-mol wt IGF carrier protein that is lacking in hypophysectomized rats.15 min after the bolus serum IGF I and II concentrations were similar to steady state levels during long-term infusion in hypox rats. Free IGF was barely detectable, however, in the infused animals, whereas 40-100% was found free 15 min after the bolus. These observations for the first time confirm the hypothesis that only free IGF, but not the IGF carrier protein complex, is bioavailable to insulin target tissues.

The physiology of the specific serum binding proteins which constitute the main storage pool for insulin-like growth factors (IGFs) in mammals is still incompletely understood. We have, therefore, investigated the regulation of these proteins in (i) hypophysectomized (hypox) rats infused with recombinant human growth hormone (rhGH) or recombinant human IGF I (rhIGF I) and (ii) streptozotocin-diabetic rats infused with insulin or rhIGF I. The main carrier protein, a GH-dependent complex of apparent molecular mass 200 kDa, contains N-glycosylated IGF-binding subunits (42, 45, and 49 kDa) that differ in their glycosyl but not in their protein moiety. These subunits are lacking in hypox and diabetic rats. They are induced by GH and insulin, respectively, and appear in the 200-kDa complex. Infusion of rhIGF I induces the subunits in both states; however, only in diabetic, not in hypox, rats do they form the 200-kDa complex. Glycosylated carrier protein subunits do not appear before 8 hr of rhIGF I infusion. During that period, hypox rats may become severely hypoglycemic. After 16 hr, glycosylated subunits are clearly induced, and blood sugar values are normal. We conclude: (i) The Nglycosylated subunits of the 200-kDa complex reflect the IGF I status.(ii) IGF I may mediate the induction of these subunits by GH. (iii) Significant association to the 200-kDa complex occurs only in the presence of GH. It is likely that GH, but not IGF I, induces a component, which itself does not bind IGF, but associates with the glycosylated IGF-binding subunits. (iv) The glycosylated subunits protect against IGF-induced hypoglycemia and may be involved in tissue-specific targeting of IGFs.In mammalian blood, insulin-like growth factors (IGFs) circulate in tight association with specific high-affinity carrier proteins (1-3). Although they constitute the main reservoir of IGFs in the organism, the significance of this storage pool is still under debate. Experimental evidence suggests three possible functions of IGF carrier proteins: (i) protection of the organism against acute insulin-like effects of the large quantities of IGFs in blood by decreased availability to tissue receptors (4-8), (ii) prolongation of the half-life of IGFs in the circulation (6,9), and (iii) potentiation of the growthpromoting effects of IGFs (10).Native serum from normal rats contains at least two IGF carrier protein complexes: upon neutral gel filtration on Sephadex G-200 one of them elutes with an apparent molecular mass of 150-200 kDa, the other with 40-50 kDa [in this paper termed 200-and 40-kDa complexes, respectively, according to our Sephadex G-200 elution profiles (see Fig. 1)]. The 200-kDa complex carries most of the endogenous rat IGF (11) and has been shown to be growth hormone (GH)-dependent (12-15): hypophysectomized (hypox) and diabetic rats, both of which are GH deficient and have low IGF I serum levels, lack the 200-kDa complex. It reappears after GH or insulin treatment, respectively, together with the rise of endogenous IGF. On the ...

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Trypsin-treatment of isolated rat adipocytes abolishes the metabolic effects not only of insulin, but also of the insulin-like growth factors : in trypsin-treated cells, concentrations of these hormones that are otherwise maximally effective no longer stimulate 3-0-methylglucose transport and lipogenesis or inhibit epinephrineinduced lipolysis. Concomitantly, the trypsin-treated adipocytes no longer display specific insulin binding. In contrast, the characteristics of the binding of the insulin-like growth factors are not grossly affected by prior trypsinization of the adipocytes.These findings add further support to the concept that the insulin-like growth factors act on glucose metabolism and antilipolysis via the insulin receptor of the adipocyte.Insulin-like growth factors I and I1 purified from human serum [1,2] exert the same biological effects as insulin on adipose tissue and adipocytes : they stimulate glucose transport and net gas exchange, CO2 production and lipogenesis from glucose, and they inhibit lipolysis [3]. When compared on a molar basis, the biological potency of the two factors is z 35-times and 2 125-times less than that of insulin [3]. Adipocytes contain specific membrane binding sites for the insulin-like growth factors [3 -51. However, the latter have been shown to compete also with insulin for binding to the insulin receptor of the adipocyte [3 -61. Therefore, the question arises whethcr the acute insulin-like actions of the insulin-like growth factors are mediated via the insulin receptor or via their own specific acceptor sites. The correlation between the biological potencies of the three polypeptides and their competitive potencies at their respective membrane binding sites suggests that the insulin-like growth factors do exert their insulin-like effects on the adipocyte through the insulin receptor [3]. The present work was undertaken in order to obtain further evidence in favour or against this concept.

Insulin-like growth factors (IGFs) in blood form two complexes with specific binding proteins (BPs): a large, growth hormone (GH)-dependent complex with restricted capillary permeability, and a smaller complex, inversely related to GH, with high turnover of its IGF pool and free capillary permeability. The distribution of BPs and of IGFs I and II between these complexes was studied in sera from healthy adults treated with IGF I or/and GH and from patients with extrapancreatic tumor hypoglycemia. Like GH, IGF I administration raises IGF I and two glycosylation variants of IGFBP-3 in the large complex, but unlike GH drastically reduces IGF II. During IGF I infusion, IGFBP-3 appears in the small complex whose IGFBP-2 and IGF I increase three-to fivefold and fivefold, respectively. GH treatment, associated with elevated insulin levels, suppresses IGFBP-2 and inhibits its increase owing to infused IGF I. The small complex of tumor sera contains increased amounts of IGFBP-2 and -3, and two-to threefold elevated IGF IL Conclusions: low GH and/or insulin during IGF I infusion and in extrapancreatic tumor hypoglycemia enhance expression of IGFBP-2 and favor partition of IGFBP-3 into the small complex. Free capillary passage and high turnover of its increased IGF I or II pools may contribute to compensate for suppressed insulin secretion during IGF I infusion or to development of tumor hypoglycemia. (J. Clin. Invest. 1990. 86:952-961.) Key words: IGF binding proteins-IGF I treatment * extrapancreatic tumor hypoglycemia Introduction Insulin-like growth factors (IGFs)' are synthesized and released by many tissues and cell types (1, 2). The liver contributes most of the IGFs in the circulation (1, 3). IGFs are always found in association with specific high-affinity binding proteins (2). As is true for IGFs, the highest concentrations of IGF