Insulin-like growth factor axis in pregnancy and gestational diabetes mellitus.

The insulin-like growth factor (IGF) is involved in the regulation of growth and metabolism. The aim of this study was to determine selected parameters of IGF system at systemic and local levels [subcutaneous (SAT) and visceral adipose tissue (VAT)] to assess its possible role in gestational diabetes mellitus (GDM). 37 pregnant women (21 with GDM and 16 without GDM) and 15 age-matched non-pregnant females were included in the study. Blood samples were taken in 28-32 and 36-38 weeks of gestation and 6-12 months after delivery. SAT and VAT samples were obtained during delivery or surgery. Compared with non-pregnant women, serum IGF-1 and IGFBP-3 were increased in both groups of pregnant women. IGF-2 was elevated only in GDM women from 36 weeks of gestation culminating 6 months after delivery (p=0.003). Serum IGFBP-3 was increased and IGFBP-4 decreased in GDM women vs. pregnant women without GDM during the whole study (IGFBP-3: p?0.001 for GDM vs. non-GDM; IGFBP-4: p=0.004 for GDM vs. non-GDM). Pregnant women with GDM had decreased mRNA expression of IGF-1, IGF-1R and IGF-2R and IGFBP-4 in VAT and IGF-1R in SAT compared to pregnant women without GDM. Changes in local activity of IGF are associated with the development of GDM.

Expression of insulin-like growth factor-1 receptor in circulating tumor cells of patients with breast cancer is associated with patient outcomes.

In patients with breast cancer, markers of aggressiveness such as dysregulation of the insulin-like growth factor receptor (IGF1R) system and E-cadherin loss are commonly observed. Reduced IGF1R expression is correlated with decreased E-cadherin levels and increased cell motility. We assessed IGF1R and E-cadherin expression in circulating tumor cells (CTCs) in patients with breast cancer. Peripheral blood mononuclear cells of early (n = 87)- and metastatic (n = 126)-stage breast cancer patients (obtained prior to adjuvant and first-line chemotherapy) were evaluated using double immunofluorescence (IF) staining for cytokeratin (CK) and IGF1R. Triple IF using CK, IGF1R, and E-cadherin antibodies was performed in selected CTC(+) patients. IGF1R(+) CTCs were more frequently observed in early disease than in metastatic disease (86% vs 68% of CTCs, P = 0.04) stage, whereas IGF1R(-) CTCs were more common in metastatic than in early disease (32% vs 14% of CTCs, P = 0.002). 100% of CTC(+) patients with early disease, compared to 79% of those with metastatic disease, harbored IGF1R(+) CTCs (P = 0.007). Patients with early disease and exclusively IGF1R(+) CTCs had longer disease-free (P = 0.02) and overall survival (P = 0.001) compared to patients with both IGF1R(+) and IGF1R(-) CTC populations. 67% of early-stage CTC(+) patients evaluated had exclusively IGF1R(+)/E-cadherin(+) CTCs, 33% also had IGF1R(-)/E-cadherin(-) CTCs, and none had exclusively IGF1R(-)/E-cadherin(-) CTCs compared to 17%, 75%, and 8% of metastatic patients, respectively (P = 0.027). Similarly, in paired samples of patients with early disease that progressed to metastatic disease, the proportion of IGF1R(+)/E-cadherin(+) CTCs was reduced and IGF1R(-)/E-cadherin(-) CTCs were increased in the metastatic stage compared to early disease stage. IGF1R(+) CTCs are commonly detected in breast cancer, and their frequency decreases in the metastatic disease stage. IGF1R(+)/E-cadherin(+) CTCs also decrease in metastatic patients. IGF1R(+) CTCs are associated with favorable outcomes in early disease stage, suggesting that IGF1R expression is correlated with reduced metastatic potential in breast cancer.

Receptor-mediated selective impairment of insulin-like growth factor-1 activity in congenital disorders of glycosylation patients.

BACKGROUND: Congenital disorders of glycosylation (CDG) patients share a basic feature of protein hypoglycosylation. Activity of growth factors and their receptors, glycoproteins playing a pivotal role during child development, remains unexplored in CDG patients. METHODS: Peripheral blood lymphocytes (PBL) isolated from 9 CDG patients and 12 healthy controls were cultured in the presence of fetal bovine serum (FBS), platelet-derived growth factor (PDGF), basic fibroblast growth factor (bFGF), and insulin-like growth factor-1 (IGF-1), and BrdU incorporation was measured. Levels of plasma IGF-1 and PBL IGF-1 receptor (IGF-1R) and its glycosylation were detected using immunoassay and western blot. RESULTS: CDG patients showed significantly less (P < 0.01) serum-induced 5'-Bromo-2'-deoxyuridine (BrdU) incorporation in PBL than in controls. PDGF-/FGF-stimulated BrdU incorporation showed no difference in patients and controls, whereas IGF-1-induced DNA synthesis was significantly (P < 0.01) less in patients. Plasma IGF-1 levels and PBL IGF-1 receptor protein were significantly (P < 0.01) reduced in patients as compared to controls. IGF-1 receptor in PBL of all CDG patients had significantly (P < 0.01) reduced carbohydrate content when compared with control. CONCLUSIONS: These results show selective impairment of IGF-1-induced DNA synthesis in lymphocytes of CDG patients through decreased gene expression and hypoglycosylation of the IGF-1 receptor.

Increased insulin-like growth factor 1 receptor (IGF1R) expression in small cell lung cancer and the effect of inhibition of IGF1R expression by RNAi on growth of human small cell lung cancer NCI-H446 cell.

Insulin-like growth factor 1 receptor (IGF1R) is a tyrosine kinase receptor implicated in tumourigenesis that may be an attractive target for anti-cancer treatment. In this study, the expression and clinical significance of IGF1R were investigated in serum and lung cancer tissues from small cell lung cancinoma (SCLC). We also compared the effect of IGF1R up-regulation and IGF1R inhibition on viability and apoptosis of NCI-H446 cells. We found the concentration of IGF1R in blood serum was significantly increased and positive IGF1R protein in cancer tissue was more prevalent in SCLC. A statistically significant correlation among IGF1R-positve tumors, lymph node metastasis and local invasion was discussed. Furthermore, IGF1R overexpression lead to an increase of cell survival and suppressed cell apoptosis, IGF1R silencing mediated by RNAi abrogate this response of NCI-H446 cells. Our results further demonstrated that the effects of these treatments may be assigned to the effective inhibition of lung cancer cells from Akt/P27(Kip1) pathway in IGF-1R signaling. These features may have important implications for future anti-IGF1R therapeutic approaches.

Changes in circulating IGF1 receptor stimulating activity do not parallel changes in total IGF1 during GH treatment of GH-deficient adults.

CONTEXT: Previously we demonstrated that IGF1 receptor stimulating activity (IGF1RSA) offers advantages in diagnostic evaluation of adult GH deficiency (GHD). It is unknown whether IGF1RSA can be used to monitor GH therapy. OBJECTIVE: To investigate the value of circulating IGF1RSA for monitoring GH therapy. DESIGN/METHODS: 106 patients (54 m; 52 f) diagnosed with GHD were included; 22 were GH-naïve, 84 were already on GH treatment and discontinued therapy 4 weeks before baseline values were established. IGF1RSA was determined by the IGF1R kinase receptor activating assay, total IGF1 by immunoassay (Immulite). GH doses were titrated to achieve total IGF1 levels within the normal range. RESULTS: After 12 months, total IGF1 and IGF1RSA increased significantly (total IGF1 from 8.1 (95% CI 7.3-8.9) to 14.9 (95% CI 13.5-16.4) nmol/l and IGF1RSA from 115 (95% CI 104-127) to 181 (95% CI 162-202) pmol/l). After 12 months, total IGF1 normalized in 81% of patients, IGF1RSA in 51% and remained below normal in more than 40% of patients in whom total IGF1 had normalized. CONCLUSIONS: During 12 months of GH treatment, changes in IGF1RSA did not parallel changes in total IGF1. Despite normalization of total IGF1, IGF1RSA remained subnormal in a considerable proportion of patients. At present our results have no short-term consequences for GH therapy of GHD patients. However, based on our findings we propose future studies to examine whether titrating GH dose against IGF1RSA results in a better clinical outcome than titrating against total IGF1.

Endogenous LPS alters liver GH/IGF system gene expression and plasma lipoprotein lipase in goats.

Endotoxin lipopolysaccharide (LPS) affects the ruminant health and animal performance. The main purposes of this study were to investigate the potential effects of GH/IGF system and lipoprotein lipase (LPL) concentration on resistance the circulating LPS concentration increased in liver with high concentrate diet treatment. Non-lactating goats were randomly allocated to two groups: a high-concentrate diet (HCD) or a low-concentrate diet (LCD) in cross over design and the blood collection at different time points after feeding at the end of the experiment. The average rumen pH was significantly reduced (P<0.05), but the duration with pH was not more than 120 min in the HCD group. The plasma LPL concentration was significantly raised (P<0.05). However, from 2 h onwards, LPS concentration was significantly reduced (P<0.01) in the HCD group compared with LCD group. In addition, the plasma IGF1 concentration and the hepatic insulin-like growth factor-1 receptor (IGF1R) mRNA expression were markedly reduced (P<0.05). However, growth hormone (GH) secretion at 15, 30, and 45 min after feeding and growth hormone receptor (GHR) mRNA expression in the liver was significantly increased (P<0.05) in HCD group. The correlation analysis showed that the plasma LPL concentration was positively correlated with hepatic GHR mRNA expression (P<0.05). Conversely, the plasma LPS concentration was negatively correlated with LPL concentration (P<0.05). These findings reveal that alterations in GH/IGF system function in response to a high-concentrate diet are accompanied by corresponding changes in systemic LPL in non-lactating goats' liver in presence of endogenous LPS stress.

Serum insulin-like growth factors and insulin-like growth factor-binding proteins: clinical implications.

The last decade has been characterized by a major investigative thrust into the physiology of two unique but ubiquitous peptides, insulin-like growth factor (IGF)-I and IGF-II. The regulatory systems that control the tissue bioactivity of the IGFs have been delineated, and subcellular signaling mechanisms have been clarified. Clearly, both tissue and circulating growth factor concentrations are important in defining the relationship between IGF-I and cell activity. Bone, liver, and circulatory IGF-I have received the most attention by investigators, in part because of the ease of measurement and the interaction with disease states such as osteoporosis. More recently, attention has focused on the role IGF-I plays in neoplastic transformation and growth. Two large prospective observational studies have demonstrated greater risk for prostate and breast cancer associated with high circulating concentrations of IGF-I. Animal models and in vitro studies confirm that there is a close, albeit complex, interaction between IGF-I signaling and bone turnover. This report will focus on: (a) IGF physiology, including IGF ligands, binding proteins, and proteases; (b) the relationship between IGF-I and bone mass in respect to risk for osteoporosis; (c) the heritable regulation of the IGF-I phenotype; and (d) the association between serum IGF-I and cancer risk. The IGFs remain a major area for basic and clinical investigations; future studies may define both diagnostic and therapeutic roles for these peptides or their related proteins in several disease states.

Insulin-like growth factors (IGF-I, free IGF-I and IGF-II) and insulin-like growth factor binding proteins (IGFBP-2, IGFBP-3, IGFBP-6, and ALS) in blood circulation.

Insulin-like growth factors (IGFs) and IGF binding proteins (IGFBPs) play an important role in cell growth and differentiation. Clinical and epidemiological studies have indicated that measuring IGFs and IGFBPs in blood has potential implications in assessing growth-related abnormalities and risks of certain types of cancer. To facilitate the application, we reported a large collection of reference ranges of IGFs and IGFBPs in normal population and evaluations of these molecules in serum and plasma as well as the impact of freeze-thaw cycles on the measurement. IGF-I, IGFBP-3 andALS showed a similar pattern of change associated with age. Levels of these molecules were low at birth and increased with age through puberty. After puberty the levels declined slowly with age. Overall, IGF-I, IGFBP-3 and ALS were slightly higher in females than in males. Free IGF-I accounted for about 1% of the total IGF-I and its variation with age was similar to total IGF-I. IGF-II levels were also increased with age from birth to puberty, but became stable after puberty. There was little difference in IGF-II levels between genders. IGFBP-2 levels declined with age from birth to puberty. Levels of IGFBP-6 in contrast were increased with age. These IGF binding proteins were higher in males than in females. IGFs, IGFBP-3 and ALS were 5-10% higher in serum than in plasma. IGFBP-2 and IGFBP-6 differed substantially between serum and plasma. Freeze-thaw treatment up to five cycles had little impact on plasma levels of IGFs and IGFBP-3. Our observations suggest that levels of IGFs and their binding proteins are varied with age, gender, and types of specimen and that these variations need to be taken into consideration when IGFs and their binding proteins are utilized in clinic and research.