• Asian Pacific Journal of Cancer Prevention
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• v.17 no.12
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• pp.5315-5320
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• 2016

Purpose: Tumor cell growth and sensitivity to chemotherapy depend on many factors, among which insulin-like growth factors (IGFs) may play important roles. The aim of the present study was to evaluate the levels of insulin-like growth factors (IGFs) and IGF binding proteins (IGFBPs) in primary tumors and ascites as predictors of response to neoadjuvant chemotherapy in ovarian cancer (OC) patients. Materials and Methods: Tumor tissue samples and ascitic fluid were obtained from 59 patients with advanced OC. The levels of IGF-I, IGF-II, IGFBP-3, IGFBP-4 and PAPP-A were determined using ELISA kits. Taking into account the data on expression of these IGF-related proteins and outcome, logistic regression was performed to identify predictors of response to neoajuvant chemotherapy. Results: Human ovarian tumors expressed IGFs, IGFBP-3, IGFBP-4 and PAPP-A and these proteins were also present in ascites fluid and associated with its volume. IGFs and IGFBPs in ascites and soluble PAPP-A might play a key role in ovarian cancer progression. However, levels of proteins of the IGF system in tumors were not significant predictors of objective clinical response (oCR). Univariate analysis showed that the level of IGF-I in ascites was the only independent predictor for oCR. Conclusion: The level of IGF-I in ascites was shown to be an independent predictor of objective clinical response to chemotherapy for OC patients treated with neoadjuvant chemotherapy and debulking surgery.

• BMB Reports
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• v.32 no.3
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• pp.266-272
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• 1999

The insulin-like growth factor (IGF) system consisting of IGF-I, IGF-II, IGF-receptors, and IGF-binding proteins (IGFBP) regulates the proliferation of a variety of cancer cell types. To examine whether a decrease in endogenous IGFBP-3 stimulates proliferation or inhibits differentiation, Caco-2 cells, a human colon adenocarcinoma cell line, were stably transfected with an anti-sense IGFBP-3 expression construct or pcDNA3 vector as control. Accumulation of IGFBP-3 mRNA and secretion of IGFBP-3 into serum-free conditioned medium, 9 days after plating, were significantly lower in Caco-2 cell clones transfected with anti-sense IGFBP-3 cDNA compared to the controls. The anti-sense clones grew at a similar rate to the controls for 8 days after plating, but achieved a higher final density between days 10 and 12. The levels of sucrase-isomaltase mRNA, a marker of enterocyte differentiation of Caco-2 cells, were lower in the anti-sense clones examined on day 9. In conclusion, proliferation of Caco-2 cells can be stimulated by lowering endogenously-produced IGFBP-3.

• Clinical and Experimental Reproductive Medicine
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• v.21 no.3
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• pp.273-279
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• 1994

자궁내막이 생체내 insulin-like growth factor binding protein-1(IGFBP-1)의 혈중치를 유지하는데 얼마나 관여하는지를 평가해 보았다. Immunoreactive IGFBP-1의 혈중치의 측정을 위하여, 월경과다를 주소로 내원한 19명의 환자를 대상으로, gynecologic resectoscopy로 자궁내막 박리를 시행하였다. 자궁내막 박리를 시행한 환자의 혈중 IGFBP-1의 평균치는, 시행전과 비교할 때 감소된 소견을 보였으며, 월경주기와는 상관관계가 없었다. 이러한 소견으로 보아, 자궁내막이 혈중 IGFBP-1의 생성원의 하나로 사료되었다.

• Journal of Yeungnam Medical Science
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• v.12 no.2
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• pp.319-330
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• 1995

The influence of normal late pregnancy on insulin action and insulin secretion was studied in the Sprague-Dawley female rats. On 20th day after mating, intravenous glucose tolerance test(IVGTT) was performed in non pregnant control and pregnant rats. As results of IVGTT, glucose disappearance rate was not significantly different in both groups, but secretory response of insulin was significantly(p<0.05) increased in pregnant rat. And the ratio of insulin/glucose was significantly higher in pregnant rats, which means existence of insulin resistance. These insulin resistance was overcomed by increased secretory response of pancreatic insulin. Insulinogenic index(${\Delta}$ insulin/glucose - 5 min) was highly significantly (r=0.62, p<0.01) correlated with progesterone concentration. Glycogen level and amounts of $^{14}C$-glucose incorporated into glycogen after IVGTT were significantly(p<0.05) decreased in the liver, but were not changed significantly in soleus. Glycogen synthase activity of soleus and liver was not differ significantly in the both groups. Insulin binding at varying concentrations of insulin to crude membrane of pregnant liver was not significantly different from control. In conclusions, although these pregnant rats were normal glucose tolerance due to increased secretory response of insulin, that was correlated with progesterone concentration, pregnant rat had insulin resistance. The mechanisms of insulin resistance were not related to defect of insulin binding phase and glycogen synthase, but suggest pre-receptor and/or postreceptor phase.

• Animal cells and systems
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• v.13 no.1
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• pp.17-23
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• 2009

In previous studies, we found that Annexin I (Anx I) was co-secreted with insulin in response to glucose, and that extracellular Anx I stimulated the release of insulin via the Anx I binding site in rat pancreatic islets and the &-cell line. However, the role that Anx I plays in the insulin secretion was not established. Therefore, in this study, we evaluated the insulin secretion pattern in response to Anx I and the involvement of the cytoskeleton or PKC in Anx Istimulated insulin secretion in MIN6N8a cells. The peak time of insulin secretion in response to Anx I treatment corresponded with the second phase insulin secretion by glucose in the perifused pseudoislets. In addition, Anx I-stimulated insulin secretion was not affect by readily releasable pool depletion. Taken together, these findings indicate that Anx I treatment was associated with movement of the reserve pool of insulin. Furthermore, Anx I-stimulated insulin secretion was attenuated by treatment with a microfilament inhibitor, cytochalasin B, as well as by PKC down regulation. These results indicate that Anx I may be a regulator of second phase insulin secretion.

• Clinical and Experimental Pediatrics
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• v.59 no.5
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• pp.231-238
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• 2016

Purpose: Lipopolysaccharide-binding protein (LBP) is a 65-kDa acute phase protein, derived from the liver, which is present in high concentrations in plasma. Data regarding the association between circulating plasma LBP levels and obesity-related biomarkers in the pediatric population are scarce. We aimed to determine whether there was a difference in plasma LBP levels between overweight/obese and normal-weight adolescents and to assess the correlation of circulating LBP levels with anthropometric measures and obesity-related biomarkers, including insulin resistance, liver enzyme levels, and lipid profiles. Methods: The study included 87 adolescents aged 12-13 years; 44 were overweight/obese and 43 were of normal-weight. We assessed anthropometric and laboratory measures, including body mass index (BMI), blood pressure, insulin resistance, liver enzyme levels, and lipid profiles. Plasma LBP levels were measured using an enzyme-linked immunosorbent assay. Results: The mean age of the participants was $12.9{\pm}0.3$ years. Circulating plasma LBP levels were significantly increased in overweight/obese participants compared with those in normal-weight participants ($7.8{\pm}1.9{\mu}g/mL$ vs. $6.0{\pm}1.6{\mu}g/mL$, P<0.001). LBP levels were significantly and positively associated with BMI, systolic blood pressure, aspartate aminotransferase, alanine aminotransferase, total cholesterol, low density lipoprotein-cholesterol, fasting glucose and insulin, and insulin resistance as indicated by the homeostatic model assessment of insulin resistance (HOMA-IR) (all P<0.05). In multivariate linear regression analysis, BMI and HOMA-IR were independently and positively associated with plasma LBP levels. Conclusion: LBP is an inflammatory biomarker associated with BMI and obesity-related insulin resistance in adolescents. The positive correlation between these parameters suggests a potentially relevant pathophysiological mechanism linking LBP to obesity-related insulin resistance in adolescents.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.9
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• pp.3735-3740
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• 2015

Context: Insulin-like growth factor peptides play important roles in regulating cell growth, cell differentiation, and apoptosis, and have been demonstrated to promote the development of colorectal cancer (CRC). Objective: To examine the association of insulin-related biomarkers including insulin-like growth factor-1 (IGF-1), insulin-like growth factor binding protein-3 (IGFBP-3) and C-peptide with CRC risk and assess their relevance in predictive models. Materials and Methods: The odds ratios of colorectal cancer for serum levels of IGF-1, IGFBP-3 and C-peptide were estimated using unconditional logistic regression models in 100 colorectal cancer cases and 100 control subjects. Areas under the receiving curve (AUC) and integrated discrimination improvement (IDI) statistics were used to assess the discriminatory potential of the models. Results: Serum levels of IGF-1 and IGFBP-3 were negatively associated with colorectal cancer risk (OR=0.07, 95%CI: 0.03-0.16, P for trend <.01, OR=0.06, 95%CI: 0.03-0.15, P for trend <.01 respectively) and serum C-peptide was positively associated with risk of colorectal cancer (OR=4.38, 95%CI: 2.13-9.06, P for trend <.01). Compared to the risk model, prediction for the risk of colorectal cancer had substantially improved when all selected biomarkers IGF-1, IGFBP-3 and inverse value of C-peptide were simultaneously included inthe reference model [P for AUC improvement was 0.02 and the combined IDI reached 0.166% (95 % CI; 0.114-0.219)]. Conclusions: The results provide evidence for an association of insulin-related biomarkers with colorectal cancer risk and point to consideration as candidate predictor markers.

• The Korean Journal of Nuclear Medicine
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• v.17 no.2
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• pp.35-40
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• 1983

To evaluated the usefulness of cultured human fibroblast for insulin receptor assay, the authors cultured fibroblast from biopsied normal adult female eyelid skin and assayed the insulin receptor with radioreceptor assay method. From the data obtained, percent of labeled insulin bound, numbers of insulin binding sites, affinity constants(Ka) and affinity of the empty sites(Ke) were calculated. The results were as follow; 1) The percent radioactivity bound of cultured fibroblast reached plateau at 4 hours $15^{\circ}C$ incubation. 2) The scatchard plot of insulin binding to cultured human fibroblast was curvilinear and the affinity to receptor was decreased with increased receptor occupancy. 3) The numbers of high affinity, low affinity and total insulin receptor of cultured fibroblasts were 852, 24,800 and 25,652 sites per cell. 4) High and low affinity constants of cultured fibroblasts were $3.4\times^{10}M^{-1},\;and\;1.08\times10^8M^{-1}$, and the affinity of empty site was $5.0\times10^8M^{-1}$.

• Molecules and Cells
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• v.20 no.2
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• pp.280-287
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• 2005

The insulin-mediated Ras/mitogen-activated protein (MAP) kinase cascade was examined in SK-N-BE(2) and PC12 cells, which can and cannot produce reactive oxygen species (ROS), respectively. Tyrosine phosphorylation of the insulin receptor and insulin receptor substrate 1 (IRS-1) was much lower in SK-N-BE(2) cells than in PC12 cells when the cells were treated with insulin. The insulin-mediated interaction of IRS-1 with Grb2 was observed in PC12 but not in SK-N-BE(2) cells. Moreover, the activity of extracellular-signal-related kinase (ERK) was much lower in SK-N-BE(2) than in PC12 cells when the cells were treated with insulin. Application of exogenous $H_2O_2$ caused increased tyrosine phosphorylation and Grb2 binding to IRS-1 in SK-N-BE(2) cells, while exposure to an $H_2O_2$ scavenger (N-acetylcysteine) or to a phophatidylinositol-3 kinase inhibitor (wortmannin), and expression of a dominant negative Rac1, decreased the activation of ERK in insulin-stimulated PC12 cells. These results indicate that the transient increase of ROS is needed to activate ERK in insulin-mediated signaling and that an inability to generate ROS is the reason for the insulin insensitivity of SK-N-BE(2) cells.

• Journal of the Korean Society of Food Science and Nutrition
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• v.26 no.2
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• pp.285-290
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• 1997

The insulin-like growth factors(IGFs) are bound to several binding proteins(IGFBPs) that appear to regulate IGF transport, receptor binding, and its action. The concentration of these peptides are altered by catabolic conditions. To determine IGF-I and IGFBP levels in noninsulin-dependent diabetes mellitus (NIDDM), sera was obtained from 5 patients and 7 controls. Serum levels of IGF-I in NIDDM were lower than those in either of the controls. By western immunoblot analysis, especially IGFBP-1 levels are increased, whereas IGFBP-3 levels decreased and their fragments was increased in NIDDM serum. IGFBP-3 proteolytic activity in NIDDM sera was inhibited by phenylmethylsulfonylfluoride (PMSF), aprotinin, and ethylenediaminetetraacetic acid(EDTA). This pattern of inhibition was consistent with a metal-dependent serine protease. By gelatin zymography, these proteolytic enzymes were identified as the size of 97 and 69 kDa. IGFBP-1, which is primarily insulin regulated, was increased in NIDDM and may modulate circulating IGF-I levels by regulating capillary passage of IGF-I. IGFBP-3 proteolysis markedly reduces its affinity for the IGFs, particularly for IGF-I. This accelerates their kinetics of dissociation, thereby increasing the proportions of IGF-I in free form and its availability to the cells.