Supplementary Figure 2 from BMS-754807, a small molecule inhibitor of insulin-like growth factor-1R/IR
Joan M. CarboniMark D. WittmanZheng YangFrancis LeeAnn GreerWarren HurlburtStephen HillermanCarolyn CaoGlenn H. CantorJanet Dell-JohnCliff ChenLorell DiscenzaKrista MenardAixin LiGeorge L. TrainorDolatrai M. VyasRobert KrämerRicardo M. AttarMarco M. Gottardis
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Supplementary Figure 2 from BMS-754807, a small molecule inhibitor of insulin-like growth factor-1R/IRKeywords:
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This study examines the effect of experimental diabetes on the release of rat insulin-like growth factor I (rlGFI) and its binding protein (IGF-BP) by adult rat hepatocytes in primary culture. Rats treated with streptozotocin (75 mg/kg) had decreased serum rIGF-I values of 0.37 ± 0.04 U/ml compared to 1.06 ± 0.04 in age-matched untreated rats (1 U = 770 ng human IGF-I). Concomitant decreases in hepatocyte production rates for rIGF-I (15% of the rate in cells from normal rats) and IGF-BP (30% of normal) were also observed for hepatocytes isolated from diabetic rats. Insulin replacement therapy (1.2 U/ day) for 3–4 days normalized serum rIGF-I levels (0.92 ± 0.07 U/ml) and increased rIGF-I production by isolated hepatocytes to 67% the rate of normal cells and IGF-BP production to 70% normal. Treatment of streptozotocin-treated rats with rGH (150 μg/day) in vivo for 7 days failed to increase serum rIGF-I levels or hepatocyte production of rIGF-I. Insulin in vitro (3 × 10–7m) increased rIGF-I release by hepatocytes from nondiabetic rats, but had no effect on cells from diabetic animals, suggesting that factors other than insulin are required to maintain rIGF-I synthesis in diabetes. Serum rIGF-I levels showed a strong correlation with hepatocyte rIGF-I production in the animals used in this study. However, calculation of circulating rIGF-I half-life based on these values showed a 2-fold higher half-life in diabetic rats (7.91 ± 1.58 h) and rGH-treated diabetic rats (7.52 ± 1.25 h) than in nondiabetic (2.99 ± 0.35 h) and insulin-treated diabetic animals (3.85 ± 0.36 h). This suggests that the rate of clearance of circulating rIGF-I may be slower in diabetic animals. (Endocrinology119: 2346–2352, 1986)
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To investigate the ability of insulin-like growth factor-I (IGF-I), but not GH, to stimulate jejunal growth, we compared indices of IGF-I and insulin receptor expression in jejunal membranes from rats maintained with total parenteral nutrition (TPN) and treated with rhIGF-I and/or rhGH. TPN without growth factor treatment (TPN control) induced jejunal atrophy, reduced serum IGF-I, increased serum insulin concentrations, and increased IGF-I receptor number, IGF-I receptor messenger RNA, and insulin-specific binding to 133% to 170% of the orally fed reference values, P < 0.01. Compared with TPN control, IGF-I or IGF-I + GH stimulated jejunal mucosal hyperplasia; IGF-I treatment increased serum IGF-I by 2- to 3-fold and decreased serum insulin concentrations by 60%, decreased IGF-I receptor number by 50% (P < 0.001), and increased insulin receptor affinity and insulin receptor protein content. Treatment with GH alone increased serum IGF-I concentration, did not alter TPN-induced jejunal atrophy, and decreased insulin-specific binding and insulin receptor protein content (39% and 59%, respectively, of the TPN control values, P < 0.01). We conclude that: 1) jejunal IGF-I receptor content reflects circulating concentration of ligand and is not limiting for jejunal growth; and 2) increased circulating concentration of IGF-I may promote jejunal growth via interaction with jejunal insulin or IGF-I receptors.
Jejunum
Somatomedin
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Hybrid receptors (HRs), insulin receptor (IR)/insulin-like growth factor I receptor (IGF-I-R) heterodimers have been reported increased in skeletal muscle of obese and type 2 diabetic patients and to contribute to the patient insulin resistance. To investigate whether or not the increased expression of hybrid receptors is an early defect (probably genetic) of insulin resistance, we measured by specific enzyme-linked immunosorbent assays both IR, IGF-I-R, and HR content in skeletal muscle of healthy nonobese, nondiabetic subjects either insulin sensitive or insulin resistant, and also in patients with moderate obesity. IR content was significantly reduced in insulin-resistant subjects both nonobese and obese, compared with insulin-sensitive subjects (2.32± 0.26, 2.36 ± 0.18, and 3.45 ± 0.42 ng/mg protein, respectively, P = 0.002). In contrast, IGF-I-R content was similar in the three groups. Muscle HR content was not different in insulin-sensitive vs. insulin-resistant subjects (both nonobese and obese) (4.90 ± 0.46, 4.69 ± 0.29, and 4.91 ± 0.25 ng/mg protein, respectively, P = not significant). These studies indicate that, in insulin-resistant subjects without diabetes or severe obesity, muscle IR content but not IGF-I-R or HR content is reduced. They do not suggest, therefore, a primary (genetic) role of increased HR as a cause of IR decrease and insulin resistance.
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FOXO1
Calorie Restriction
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The effects and binding of insulin-like growth factor-I (IGF-I) in skeletal muscle were investigated in the isolated mouse soleus muscle from normal lean and goldthioglucose- obese mice. In muscles from lean mice, IGF-I stimulated 2-deoxyglucose uptake, glycolysis, and glycogen synthesis and activated glycogen synthase. The latter effect occurred in the absence of glucose in the incubation medium, as was also observed with insulin. The maximal effects of IGF-I and insulin on 2-deoxyglucose uptake were not additive. IGF-I was about 4–9% as potent as insulin (half-maximal effects occurred with 5-14 nM IGF-I) and nearly as effective as insulin. A specific binding of [125I]iodo-IGF-I was observed, which was not inhibited by unlabeled insulin or proinsulin. IGF-I was less than 1% (on a molar basis) as potent as insulin in competing with [125I]iodoinsulin binding. Unlike [125I]iodoinsulin binding, [125I]iodo-IGF-l binding was similar in muscles from lean and goldthioglucose-obese mice. As observed with insulin, however, the effects of IGF-I on 2- deoxyglucose uptake and glycogen synthase were markedly depressed in muscles from obese mice compared to lean controls. These findings indicate that, in skeletal muscle, IGF-I exerts insulin-like effects with an intermediate potency between that observed in fat cells and heart muscle. The data also suggest that, in skeletal muscle, IGF-I exerts insulin-like effects through its own specific receptors, whereas IGF-I and insulin appear to stimulate the same glucose transport system and activate glycogen synthase through a common pathway.
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Knip M, Tapanainen P, Pekonen F, Blum WF. Insulin-like growth factor binding proteins in prepubertal children with insulin-dependent diabetes mellitus. Eur J Endocrinol 1995:133:440–4. ISSN 0804–4643 To study the possible role of insulin-like growth factor binding proteins (IGFBPs) in the discrepancy between normal or only slightly retarded growth and substantially reduced concentrations of insulin-like growth factor I (IGF-I) in prepubertal children with insulin-dependent diabetes mellitus (IDDM), we measured the plasma concentrations of IGF-I, IGFBP-1, IGFBP-2 and IGFBP-3 and free insulin in 24 prepubertal diabetic subjects and 12 control children. In addition, the growth hormone response to exercise was evaluated. The diabetic children had significantly decreased peripheral IGF-I levels (8.2 + 1.1 ( sem ) vs 16.7 + 2.5 nmol/l; p < 0.001), whereas the concentrations of free insulin were increased (217 + 14 vs 103 + 21 pmol/l; p < 0.001). The concentrations of IGFBP-1 and IGFBP-3 were of the same magnitude in both groups. The diabetic children had significantly increased levels of IGFBP-2 (465 + 13 vs 416 + 14 μg/l; p = 0.029), which were inversely related to the circulating IGF-I levels (r = −0.35; p = 0.034). The diabetic and control children had comparable growth hormone responses to exercise. Diabetic children with poor glucose control had even lower IGF-I levels than those with moderate metabolic control (6.0 + 0.8 vs 10.3 + 1.7 nmol/l; p = 0.037). No differences could be observed in the plasma concentrations of various IGFBPs between these two groups of diabetic subjects. The absence in prepubertal diabetic children of increased IGFBP-1 levels observed in adolescent and adult patients with IDDM may contribute to their maintained linear growth, despite definitely decreased IGF-I concentrations. The role of increased IGFBP-2 levels in prepubertal children with IDDM remains open, but the inverse relationship between IGF-I levels and IGFBP-2 concentrations suggests that IGF-I may be involved in the regulation of IGFBP-2. Mikael Knip, Department of Pediatrics, University of Oulu, FIN-90220 Oulu, Finland
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Human physiology
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ABSTRACT The possible roles of insulin-like growth factor-I (IGF-I) and insulin in regulating cartilage growth were studied in the teleost Anguilla japonica . Significant sulphation activity was found in the extracts of pancreas, liver and muscle, but not in those of kidney, intestine or spleen. The hepatic sulphation activity was significantly decreased by hypophysectomy or by fasting for 14 days, suggesting that this activity is regulated by pituitary function and nutritional status. Northern blot analysis revealed that the hepatic IGF-I mRNA in the eel consists of a major 4·0 kb band. This mRNA was GH-dependent and was significantly decreased by fasting for 14 days. On the other hand, fasting for 14 days had no significant effect on pancreatic sulphation activity. Pancreatic extracts from both intact and hypophysectomized eels exhibited equally significant stimulating activity. Addition of bovine or human insulin (1–250 ng/ml) to the culture medium significantly stimulated sulphate uptake in a dose-dependent manner. Teleost (coho salmon) insulin was as effective as bovine insulin. Bovine insulin was more effective than IGF-I at lower concentrations (1–4 ng/ml) but less effective at higher concentrations (10–250 ng/ml). These results indicate that not only IGF-I but also insulin are likely to be involved in the regulation of cartilage growth in the eel. Journal of Endocrinology (1992) 133, 211–219
Somatomedin
Hypophysectomy
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Hybrid receptors (HRs), insulin receptor (IR)/insulin-like growth factor I receptor (IGF-I-R) heterodimers have been reported increased in skeletal muscle of obese and type 2 diabetic patients and to contribute to the patient insulin resistance. To investigate whether or not the increased expression of hybrid receptors is an early defect (probably genetic) of insulin resistance, we measured by specific enzyme-linked immunosorbent assays both IR, IGF-I-R, and HR content in skeletal muscle of healthy nonobese, nondiabetic subjects either insulin sensitive or insulin resistant, and also in patients with moderate obesity.
Insulin receptor substrate
GRB10
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