Insulin-like growth factor I (IGF I) is structurally similar to insulin and shares many of its biologic properties. We compared the short-term metabolic effects of recombinant IGF I (100 micrograms [13.3 nmol] per kilogram of body weight) and insulin (0.15 IU [1 nmol] per kilogram) in eight healthy volunteers (four men and four women). The hypoglycemic responses to both hormones were nearly identical in the doses used. The lowest blood glucose levels were reached after 30 minutes: 1.98 +/- 0.44 mmol per liter after IGF I and 1.78 +/- 0.29 after insulin. On a molar basis, IGF I was only 6 percent as potent as insulin in the production of hypoglycemia. Insulin also inhibited lipolysis more effectively than IGF I. Levels of epinephrine, norepinephrine, growth hormone, glucagon, and cortisol responded similarly to both agents. The hypoglycemia produced by IGF I is probably due to the supraphysiologic concentrations of the free peptide that result from its rapid intravenous injection. Fifteen minutes after injection, the serum level of IGF I increased from 144 +/- 38 ng per milliliter at base line to 424 +/- 56, of which 80 percent was free in the plasma (not bound to IGF carrier proteins). The determination of whether any of the short-term metabolic effects of IGF I have any clinical application will require further investigation.

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Isolated livers of normal and hypophysectomized (hypox) rats with or without GH replacement therapy were perfused in an erythrocyte-free recirculating perfusion system for 4 h in the presence of [35S]cysteine. Albumin secretion and synthesis increased in a parallel and linear fashion over 4 h. The albumin secretion rates were 0.53 and 0.21 mg/g liver h-1 in normal and hypox animals, respectively. Insulin-like growth factor (IGF) secretion, measured as insulin equivalents in the fat cell assay as well as in a competitive protein binding assay, and IGF synthesis, as determined from [35S]cysteine incorporation into immunoprecipitable IGF, likewise increased linearly and in parallel throughout the perfusion time. The IGF secretion rate was 50 microU/g liver h-1. The secreted IGF had a molecular weight of approximately 7700 daltons. Secretion and synthesis of IGF were reduced to 11% in hypox rats and were largely restored by human GH replacement therapy (to 86% of normal). A single specific binding protein with an approximate molecular weight of 35,000 was detected in the perfusate. The binding protein was measured by covalent cross-linkage to [125I]IGF I by dimethylsuberimidate. The secretion of this binding protein was 62% of normal in hypox animals and 79% in GH-treated hypox rats. The data suggest that IGF is continuously synthesized and released by the liver. Assuming a half-life for IGF of 3 h in the normal rat, a plasma volume of 8 ml, and a liver weight of 8.5 g, the rate of IGF production by the perfused normal rat liver (50 microU/g liver h-1) would be sufficient to maintain serum IGF at the concentration determined in normal rat serum (approximately 130 microU/ml). This suggests that the liver is the major site of IGF production in the rat.

Insulin-like growth factor I (IGF-I) is an important mediator of growth hormone (GH) action and it appeared tempting to evaluate possible clinical applications. Recombinant IGF-I was infused s.c. at a dose of 20 jug/kg of body weight per hour during 6 days in two healthy adult subjects. Blood glucose and fasting insulin levels remained within normal limits and IGF-H levels were suppressed. In contrast to insulin, fasting C peptide levels were decreased. GH secretion was also suppressed by IGF-I. Our preliminary data allow us to distinguish between the effects of GH per se and those of IGF-I: GH causes hyperinsulinism, whereas IGF-I leads to decreased insulin secretion. Glomerular filtration rate, as estimated by creatinine clearance, increased to 130% of preinfusion values during the IGF-I infusion. Total creatinine and urea excretion remained unchanged. We conclude that IGF-I influences kidney function and, in contrast to GH, exerts an insulin-sparing effect. It may be speculated that the therapeutic spectrum of IGF-I is quite different from that of GH.

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 pathogenesis of extrapancreatic tumor hypoglycemia has been related to the secretion of big insulin-like growth factor (IGF) II by the tumor. In 25 of 28 patients with this type of hypoglycemia we found 1.5-8-fold elevated serum levels of immunoreactive big (15-25 kD), but decreased levels of normal IGF II. After removal of the tumor, big IGF II disappeared and normal IGF II increased. Tumors contained elevated levels of IGF II, 65-80% in the big form. The insulin-like bioactivity of big IGF II and its affinity towards IGF-binding proteins (IGFBP)-2 and -3 are similar to those of normal IGF II, but two-to threefold higher on a molar basis. Big IGF II is mainly bound to the 50-kD IGFBP complex. The latter contains -10 times more of this peptide than in normal serum and displays three-to fourfold increased insulin-like bioactivity. The formation of the 150-kD IGFBP complex with "25I-recombinant human IGFBP-3 is impaired in tumor serum. This results in sequestration of IGFBP-3 and predominant association of big IGF II with IGFBP-2 and -3 in the 50-kD complex. Increased bioavailability of big IGF II in this complex due to unrestricted capillary passage and enhanced insulin bioactivity of this big IGF II pool provide a continuous increased insulin-like potential available to insulin and type 1 IGF receptors of insulin-sensitive tissues and thus may lead to sustained hypoglycemia. (J.

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 ...

The insulin-like growth factors I and 11, two purified constituents of nonsuppressible insulinlike activity of human serum, have been compared with regard to some biological actions in vitvo and some receptor-binding characteristics.1. In the presence of an excess of insulin-antibodies the insulin-like growth factors I and I1 (a) stimulate the net gas exchange in rat adipose tissue (fat pad assay) to a similar extent; (b) enhance 3-0-methylglucose transport, glucose oxidation and lipogenesis from glucose in rat adipocytes, with slight but significant differences in potency; (c) inhibit lipolysis in adipose tissue from fastedrefed rats, again with slight potency differences.2. In adipose tissue and adipocytes the biological activity of insulin-like growth factors I and I1 is between 1/35 and 1/125 of that of insulin on a molar basis.3. Insulin-like growth factors I and I1 are equally potent mitogens (stimulation of DNAsynthesis and cell multiplication in cultured chick embryo fibroblasts).4. Insulin-like growth factors I and I1 stimulate 35S02-incorporation into rat costal cartilage with minor differences in potency.5. In rat adipocytes, insulin-like growth factors I and I1 compete with insulin for binding to the insulin receptor. However, their potencies in 'displacing' '251-labeled insulin are between 75 (for factor 11) and 290 times (for factor I) lower than that of insulin. In addition, the factors I and 11 bind to binding sites specific for the factors and for which insulin does not compete. Considerable differences between factors I and I1 exist regarding their specific binding and their potencies in competing for binding of labeled factors I and 11.6. In chick embryo fibroblasts and isolated chick embryo chondrocytes the insulin-like growth factors I and I1 compete more or less equally for binding to a binding site specific for the factors and which appears to mediate their effects on cell growth and sulfation.7. Insulin-like growth factors I and I1 bind specifically to a partially purified carrier protein of human serum. Pronounced differences in specific binding and in their potencies of competition are observed.Thus, the insulin-like growth factors I and 11, two structurally closely related polypeptides, display more or less similar activities in various biological systems in vitro. In all of these, their biological potency can be reasonably correlated with their potency of competition either for the insulin receptor (fat cells) or for a specific binding site (fibroblasts and chondrocytes). In some of the radioactive ligand systems, where the biological function of binding sites for insulin-like growth factor is still unknown (such bindings sites are found in fat cells and on the serum carrier protein), clear cut differences between factors I and I1 are apparent.Nonsuppressible insulin-like activity is obtained by acid-ethanol extraction of a human plasma fraction which consists mainly of ct and fi globulins [l].Nonsuppressible insulin-like activity (NSILA-S) (for review see [ 2 ] ) of human serum has r...