The role of insulin-like growth factor 1 and insulin-like growth factor binding protein 3 in human esophageal cancer.
Makoto SohdaHiroyuki KatoTatsuya MiyazakiMasanobu NakajimaMinoru FukuchiRyokuhei MandaYasuyuki FukaiNorihiro MasudaHiroyuki Kuwano
34
Citation
15
Reference
10
Related Paper
Citation Trend
Abstract:
Insulin-like growth factors (1GF-1) and insulin-like growth factor binding protein-3 (IGFBP-3) play important roles in cell growth and differentiation. The aim of this work was to investigate the roles of IGF-1 and IGFBP-3 in esophageal cancer.We examined the circulating IGF-1 and IGFBP-3 concentration in 18 healthy controls and 66 esophageal cancer patients by ELISA and a ligand capture immunoassay. Immunohistochemistry for IGF-1 was performed on surgical specimens obtained from 93 patients with esophageal cancer.The serum IGF-1 and IGFBP-3 levels were significantly elevated in patients compared with healthy subjects and there was a positive correlation between IGF-1 and IGFBP-3. There was a significant correlation between IGF-1 level and depth of invasion and pathological stage. Poor prognosis was significantly correlated with increasing IGF-1 levels. The survival rates of high IGF-1 expression immunohistochemical study patients were poorer than those of low expression patients.Elevated serum IGF-1 levels may be an important predictor of risk for esophageal cancer. IGF-1 related to the progression of esophageal cancer may depend on an autocrine function of IGF-1.Cite
Pubertal development has recently been evaluated from the standpoint of changes in insulin-like growth factor (IGF)-I and IGF-binding protein-3 (IGFBP-3) levels in healthy children. We studied puberty related changes in serum IGF-I and IGFBP-3 levels in 24 patients (11 prepubertal) with insulin dependent diabetes mellitus (IDDM) and 26 healthy subjects (14 prepubertal). Serum IGF-I and IGFBP-3 levels were assayed using immunoradiometric assays and radioimmunoassays, respectively. Serum IGF-I and IGFBP-3 levels in diabetics did not increase during puberty, as opposed to those in healthy children. Serum IGF-I and IGFBP-3 levels of diabetic patients were found to be lower than those of control subjects during puberty (p < 0.0001 and p < 0.05, respectively). Proteolysis is believed to be a general mechanism to increase IGF bioavailability in the presence of IGFBPs. Increased IGFBP-3 protease activity has been shown in sera of children with IDDM as well as a decrease in this activity in response to insulin therapy. Our data displaying low IGFBP-3 levels in diabetic children may be due to increased proteolysis, which also causes a shift in IGF-I to its lower molecular weight forms. Higher rate of clearance of the latter may be the reason for the low IGF-I levels we observed in children with IDDM. The moderate correlation between insulin dose and IGFBP-3 levels (r = 0.5, p < 0.01) may suggest insulin to be a contributing factor in the regulation of IGFBP-3 levels. We conclude that regulation of IGF-I and IGFBP-3 concentrations is disturbed in children with IDDM, in particular during adolescence.
Immunoradiometric assay
Proteolysis
Cite
Citations (15)
Somatomedin
Cite
Citations (18)
The insulin-like growth factors (IGF) are important anabolic hormones in the mammalian fetus; their anabolic actions are potentially modulated by alterations in the IGF-binding proteins (IGFBP). We have previously shown that the nutritional state of the fetus affects both IGF-I and the IGFBP concentrations. The present study was designed to determine the effect of alterations in insulin and IGF-I circulating concentrations on the IGFBPs. Because both insulin and IGF-I elicit decreases in glucose and amino acid concentrations, the concentrations of these substrates were clamped during the hormone infusions. Sixteen ovine fetuses were chronically catheterized at approximately 115 days of gestation, and experimental procedures performed at approximately 130 days of gestation. Insulin, IGF-I or both were infused for an 8-h period. Baseline concentrations of hormones and binding proteins were obtained, and concentrations were also obtained at the end of the infusion. Hepatic IGFBP-1 mRNA expression was also determined. Intravenous infusion of IGF-I significantly increased IGF-I concentrations in plasma in the ovine fetus. Intravenous infusion of insulin inhibited hepatic IGFBP-1 gene expression when amino acids and glucose were clamped. In contrast, intravenous infusion of recombinant human IGF-I (rhIGF-I) enhanced hepatic IGFBP-1 gene expression. Neither insulin nor rhIGF-I treatment had an effect on hepatic IGFBP-3 gene expression. Insulin did not alter plasma IGFBP-1 significantly, but it increased IGFBP-3 in plasma. rhIGF-I increased both IGFBP-1 and IGFBP-3 protein levels in plasma. The responses of IGFBP-1 and IGFBP-3 to increased plasma IGF-I and insulin may serve to protect the fetus from exaggerated anabolic effects and to blunt the hypoglycemic potential of circulating IGFs and insulin.
Somatomedin
Cite
Citations (10)
Insulin-like growth factors (1GF-1) and insulin-like growth factor binding protein-3 (IGFBP-3) play important roles in cell growth and differentiation. The aim of this work was to investigate the roles of IGF-1 and IGFBP-3 in esophageal cancer.We examined the circulating IGF-1 and IGFBP-3 concentration in 18 healthy controls and 66 esophageal cancer patients by ELISA and a ligand capture immunoassay. Immunohistochemistry for IGF-1 was performed on surgical specimens obtained from 93 patients with esophageal cancer.The serum IGF-1 and IGFBP-3 levels were significantly elevated in patients compared with healthy subjects and there was a positive correlation between IGF-1 and IGFBP-3. There was a significant correlation between IGF-1 level and depth of invasion and pathological stage. Poor prognosis was significantly correlated with increasing IGF-1 levels. The survival rates of high IGF-1 expression immunohistochemical study patients were poorer than those of low expression patients.Elevated serum IGF-1 levels may be an important predictor of risk for esophageal cancer. IGF-1 related to the progression of esophageal cancer may depend on an autocrine function of IGF-1.
Cite
Citations (34)
It has been demonstrated that healthy centenarians have more favorable anthropometric characteristics and insulin-mediated glucose uptake than aged subjects. The plasma insulin-like-growth factor I (IGF-I) concentration may account for such differences. Three groups of subjects were studied: 1) adults (<50 yr; n = 30), 2) aged subjects (75–99 yr; n = 30), 3) centenarians (>100 yr; n = 19). In all subjects, fasting plasma IGF-I, IGF-binding protein-3 (IGFBP-3), leptin, and lipid concentrations were determined; body composition was assessed by bioimpedance analysis; and insulin-mediated glucose uptake was evaluated by euglycemic hyperinsulinemic glucose clamp. IGF-I declined with advancing age, but no differences between aged subjects and centenarians were found. IGFBP-3 showed a trend similar to IGF-I, but lower values were present in centenarians than in aged subjects. Nevertheless, centenarians had a plasma IGF-I/IGFBP-3 molar ratio greater than that in aged subjects. Centenarians had also a whole body glucose disposal (WBGD) greater than that in aged subjects, but similar to that in adults. Mini Mental State Examination (27± 2.1 vs. 18.3 ± 3.1; P < 0.02) and Instrumental Activities Daily Living (26 ± 2.6 vs. 8.4 ± 4.1; P < 0.001) scores were significantly different in aged subjects and centenarians, respectively. In centenarians, the plasma IGF-I/IGFBP-3 molar ratio correlated with the body mass index (r = −0.55; P < 0.009); the amount of body fat (r =− 0.62; P < 0.003); fat-free mass (r = 0.56; P < 0.008); fasting plasma leptin (r =− 0.63; P < 0.004), triglycerides (r =− 0.58; P < 0.01), free fatty acid (r =− 0.64; P < 0.005), and low density lipoprotein cholesterol (r = −0.59; P < 0.009) concentrations; Mini Mental State Examination (r = 0.53; P < 0.0.03); and WBGD (r = 0.64; P < 0.005). All correlations were independent of daily fat and carbohydrate intake and WBGD (P < 0.05 for all). No significant correlations between the plasma IGF-I/IGFBP-3 molar ratio and plasma total (r = 0.31; P = NS) and high density lipoprotein cholesterol (r = 0.34; P = NS) concentrations were present. The correlation between the plasma IGF-I/IGFBP-3 molar ratio and WBGD persisted after adjustment for body fat, fasting plasma insulin concentration, daily carbohydrate and fat intake, and daily physical activity (r = 0.55; P < 0.009), but not after further adjustment for plasma free fatty acid concentration (r = 0.30; P = 0.17). In conclusion, healthy centenarians have plasma IGF-I/IGFBP-3 molar ratios greater than aged subjects. A more elevated plasma IGF-I/IGFBP-3 molar ratio might improve insulin action and plasma lipid concentration in centenarians.
Cite
Citations (175)
We previously demonstrated that supraphysiological insulin concentrations reducedthe plasma 34K insulinlike growth factor-binding protein (IGF-BP) concentrations in humans. Inthis study we examined whether physiological changes in plasma insulin concentrations regulateIGF-BP and, if so, whether the regulation is influenced by race, glucose tolerance, or rate of glucose metabolism. For these purposes we 1) analyzed the relationship between fasting plasma insulin and IGF-BP concentrations in 2 racial groups (23 Caucasians and 35 southwestern American Indians), 2) measured the response of plasma IGF-BP to oral glucose in 20 normal subjects, and 3) determined the dose-response characteristics of plasma IGF-BP to glucose and insulin in23 normal subjects at 4 different insulin and glucose concentrations. The fasting plasma insulin concentration was inversely related to the plasma IGF-BP concentration in both the Caucasian and Indian groups (P < 0.0001). In the Caucasian group the mean plasma IGF-BP concentrationwas higher [15 ± 4 (±se) μg/L] than in the Indian group (8 ± 2 μg/L; P < 0.05). This difference was independent of race and glucose tolerance, and it could be explained by lower plasma insulin concentrations in the Caucasian (387 ± 50 pmol/L) than in the Indian group (215 ± 43 pmol/L; P < 0.001). After oralglucose administration, the insulin concentration (423 ± 72 pmol/L) was maximal 30 min after glucose treatment, and significant suppression of the IGF-BP concentration occurred at 90 min. Analysis of the dose-response curves revealed maximal suppression of IGF-BP at about 1150 pmol/L insulin, and halfmaximal suppression at about 290 pmol/L. The plasma glucose concentration or the rate of glucose metabolism had no effect on the IGF-BP concentration. These data suggest that insulin is a major regulator of plasma IGF-BP concentrations under physiological conditions.
Insulin response
Glucose tolerance test
Cite
Citations (196)
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
Cite
Citations (17)
Cite
Citations (152)
Gallaher BW, Oliver MH, Eichhorn K, Kessler U, Kiess W, Harding JE, Gluckman PD, Breier BH. Circulating insulin-like growth factor II/mannose-6-phosphate receptor and insulin-like growth factor binding proteins in fetal sheep plasma are regulated by glucose and insulin. Eur J Endocrinol 1994; 131:398–404. ISSN 0804–4643 We have reported previously that levels of insulin-like growth factor I (IGF-I) and IGF-II in fetal sheep plasma decrease with maternal starvation and increase following an infusion of glucose to the starved fetus, while a fetal infusion of insulin elevates UGF-I alone. We now report the changes in the circulating IGF-II/M6P receptor and plasma IGF binding proteins (IGFBPs), as measured by western blotting and ligand blotting, respectively, in fetus and mother during this study. In fetal plasma, the circulating IGF-II/mannose-6-phosphate (M6P) receptor, IGFBP-3 and IGFBP-4 were reduced during starvation. While circulating IGF-II/M6P receptor and IGFBP-4 levels were increased following the fetal insulin or glucose infusion, IGFBP-3 was unchanged and increased only after 48 h of maternal refeeding. Both IGFBP-1 and IGFBP-2 increased with starvation but while IGFBP-1 levels returned to control values following both insulin and glucose infusion, levels of IGFBP-2 were not reduced significantly by either infusion or by refeeding. In maternal plasma, levels of IGFBP-3 and IGFBP-4 decreased while IGFBP-1 and IGFBP-2 increased after 48 h of starvation. Levels of each IGFBP were unaltered following the fetal infusions but returned to values obtained during the control period after refeeding. These data show that each of the IGF carrier proteins is sensitive of changes in nutrition, either acutely, such as IGFBP-1, or chronically, as for IGFBP-3. This suggests that the circulating IGFII/M6P receptor and the IGFBP's may modulate IGF activity in the fetus during different nutritional states. BH Breier, Research Centre for Developmental Medicine and Biology, Department of Paediatrics, School of Medicine, University of Auckland, Private Bag 92019, Auckland, New Zealand
Cite
Citations (31)
In simple obesity, spontaneous and stimulated growth hormone (GH) secretions are diminished. However, this diminished GH secretion does not result in decreased somatic growth in obese children. Although the increased insulin level, low insulin-like growth factor binding protein (IGFBP)-1 and the resulting increase of bioavailability of insulin-like growth factor I (IGF-I) have been suggested as being involved, the exact mechanism has not yet been established. We investigated serum IGF-I, free IGF-I, IGFBP-1, IGFBP-3 and insulin levels in 36 obese and 39 non-obese healthy children. Insulin and IGFBP-3 were significantly higher in the obese group than in the control group (p < 0.05, p = 0.001, respectively). IGF-I, free IGF-I, free IGF-I/IGF-I and IGFBP-1 levels in the obese children were not significantly different from those in the control group. A positive correlation was found between body mass index (BMI) and IGF-I in the obese children (r = 0.30, p = 0.05). IGFBP-3 levels correlated positively with IGF-I (r = 0.44, p < 0.005), and free IGF-I levels (r = 0.37, p = 0.05) in the obese children. A negative correlation was found between IGFBP-1 and insulin levels (r = -0.30, p = 0.05) in the obese children. We concluded that normal growth in obese children might be maintained through normal IGF-I and increased IGFBP-3 levels, which are stimulated by increased insulin levels or nutritional factors or by increased responsiveness to GH.
Cite
Citations (47)