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 ...

Modern insulin analogue regimens, adjusted to PG targets, enable a majority of people with T2DM to reach HbA(1c)< or =7.0% after failure of OADs and OAD-basal insulin therapy. Insulin-treated patients may benefit more from transfer to analogue basal-bolus therapy, while insulin-naive individuals benefit equally well from the more convenient biphasic analogue regimen.

Atrophy of the thymus is one of the consequences of severe insulin deficiency. We describe here that the weight and the architecture of the thymus of diabetic rats is restored towards normal not only by insulin but also by insulin-like growth factor I (IGF-I) treatment. In contrast to insulin, this effect of IGF-I occurs despite persisting hyperglycemia and adrenal hyperplasia. We also investigated the in vivo effect of IGF-I on replication and differentiation of thymocytes from streptozotocin-induced diabetic rats. Thymocytes from diabetic rats incorporated less [3H]thymidine than did thymocytes from healthy rats. Insulin, as well as IGF-I treatment of diabetic rats increased [3H]thymidine incorporation by thymocytes. Flow cytometry of thymocytes labeled with monoclonal antibodies revealed a decreased expression of the Thy-i antigen in diabetic rats compared with control rats. In addition, a major deficiency of thymocytes expressing simultaneously the W3/25 and the Ox8 antigens (corresponding to immature human CD44/CD8+ thymocytes) was observed. These changes were restored towards normal by insulin as well as by IGF-I treatment. The antibody response to a T cell-dependent antigen (bovine serum albumin) was comparable in normal and diabetic rats. We conclude that IGF-I has important effects on the thymocyte number and the presence of CD4+/CD8+ immature cells in the thymus of diabetic rats despite persisting hyperglycemia. However, helper T-cell function for antibody production appears to be preserved even in the severely diabetic state.Insulin deficiency in humans is accompanied by an increased susceptibility to bacterial and mycotic infections. The reason for this is not clear, and results from different studies are inconsistent (for review, see ref. 1). Many of the immunological abnormalities are also observed in experimental diabetes in mice or rats. In streptozotocin-induced diabetic rats, the cellularity of lymphoid organs is diminished; T-cell responses (allograft reactivity and delayed T-cell hypersensitivity), B-cell responses (humoral antibodies), and phagocytic activities have been reported to be impaired (2-5). Insulin administration restores the immune response of diabetic rats toward normal. In hypophysectomized rats, depressed T-and B-cell functions as well as impaired nonspecific immune responses have been reported (6).Hypophysectomized and diabetic rats have decreased insulin-like growth factor I (IGF-I) levels in common and, therefore, may be used to study the effects of IGF-I in vivo.In both models, low levels of IGF-I are accompanied by growth arrest (7,8). The thymus and spleen are smaller and weigh less than in healthy rats of identical body weight (4, 6). IGF-I treatment of hypophysectomized rats and of diabetic rats leads to an increase in body weight and longitudinal bone growth and increases the cell number in primary and secondary lymphatic organs (9).In addition to insulin deficiency, untreated diabetic rats have decreased growth hormone (GH) serum levels and GH receptor number...

Hepatic mRNA levels of insulin-like growth factor I (IGF I) and of the fetal, nonglycosylated 32 kDa IGF-binding protein (BP) were analysed in diabetic, diabetic insulin-and IGF I-treated rats as well as in age-matched, healthy control animals. IGF I mRNA levels are reduced in diabetic rats and increased by insulin treatment. In contrast, the infusion of IGF I does not significantly upregulate IGF I mRNA levels. Fetal IGF BP mRNA expression is very low in healthy control animals, but high levels are found in diabetic rats. Insulin therapy lowers fetal IGF BP mRNA levels, whereas IGF I has no effect. We propose that insulin is a major regulator of the 32 kDa IGF BP levels in adult rats.Insulin-like growth factor I; mRNA, Protein, IGF-binding; (Streptozotocin-diabetic rat)

Glucocorticoid treatment causes osteoporosis and growth retardation in humans. Insulin-like growth factor I (IGF-I) stimulates differentiation and replication of cultured osteoblast-like cells and induces longitudinal bone growth in IGF-I-deficient rats. We investigated the influence of subcutaneously infused IGF-I on bone and mineral metabolism of male rats treated with a high dose of dexamethasone. Dexamethasone was added to the drinking water in a concentration of 1 mg/l. After 30 days of dexamethasone treatment, recombinant human IGF-I (300 micrograms/day) or solvent was infused sc by osmotic minipumps for 21 days while dexamethasone was continued. Age-matched untreated male rats served as healthy controls. Dexamethasone-treated rats lost weight. Their IGF-I levels were decreased to 36% of healthy controls. Infusion of IGF-I resulted in an increase in IGF-I serum levels (582% compared to healthy controls) and allowed some weight gain. Osteocalcin and calcitriol levels were markedly decreased in dexamethasone-treated rats and were not influenced significantly by IGF-I infusion. In contrast, IGF-I treatment restored the free calcitriol concentration (molar ratio of calcitriol to vitamin D-binding protein) towards normal. Furthermore, infusion of IGF-I partially corrected the dexamethasone-induced hyperinsulinemia. Histomorphometric analysis revealed no difference in vertebral trabecular bone density (i.e. growth-independent bone remodeling) between the three groups. In contrast, mean trabecular bone density in tibial metaphyses was increased markedly by dexamethasone, presumably due to osteoclast inhibition. Insulin-like growth factor I infusion did not significantly influence these structural metaphyseal bone parameters.(ABSTRACT TRUNCATED AT 250 WORDS)