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Background: Gestational diabetes mellitus (GDM) is characterized by disturbed glucose metabolism and activation of low-grade inflammation. We studied whether metformin treatment has favorable or unfavorable effects on inflammatory markers and insulin-like growth factor-binding protein 1 (IGFBP-1) in GDM patients compared with insulin, and whether these markers associate with major maternal or fetal clinical outcomes., Methods: This is a secondary analysis of a previous randomized controlled trial comparing metformin (n = 110) and insulin (n = 107) treatment of GDM. Fasting serum samples were collected at the time of diagnosis (baseline, mean 30 gestational weeks [gw]) and at 36 gw. Inflammatory markers serum high-sensitivity CRP (hsCRP), interleukin-6 (IL-6), matrix metalloproteinase-8 (MMP-8) and glycoprotein acetylation (GlycA) as well as three IGFBP-1 phosphoisoform concentrations were determined., Results: In the metformin and insulin groups combined, hsCRP decreased (p = 0.01), whereas IL-6 (p = 0.002), GlycA (p < 0.0001) and all IGFBP-1 phosphoisoforms (p < 0.0001) increased from baseline to 36 gw. GlycA (p = 0.02) and non-phosphorylated IGFBP-1 (p = 0.008) increased more in patients treated with metformin than those treated with insulin. Inflammatory markers did not clearly associate with pregnancy outcomes but non-phosphorylated IGFBP-1 was inversely associated with gestational weight gain., Conclusions: Metformin had beneficial effects on maternal serum IGFBP-1 concentrations compared to insulin, as increased IGFBP-1 related to lower total and late pregnancy maternal weight gain. GlycA increased more during metformin treatment compared to insulin. The significance of this observation needs to be more profoundly examined in further studies. There were no evident clinically relevant relations between inflammatory markers and pregnancy outcome measures., Trial Registration: The trial comparing metformin and insulin treatment was registered in ClinicalTrials.gov ( NCT01240785 ) November 3, 2010. Retrospectively registered.

Background: The reference change value (RCV) is an important parameter of biological variation used to assess the significance of differences between consecutive results obtained in a single individual. This study evaluated the RCV for insulin-like growth factor binding protein-1 (IGFBP-1) and fasting serum insulin (FSI) in individuals with different degrees of glucose tolerance., Methods: IGFBP-1 and FSI concentrations were measured in 33 fasting subjects who had two blood samples taken 10 days apart. Subjects were distributed in the following categories: Normal glucose tolerance (NGT), n = 15, impaired fasting glucose (IFG), n = 9 and impaired glucose tolerance (IGT), n = 9., Results: The RCV values for IGFBP-1 were 59.9%, 83.2% and 93.0% and for FSI were 68.5%, 79.0% and 93.4% for subjects with NGT, IFG and IGT respectively., Conclusions: The RCVs for IGFBP-1 and FSI increase with deteriorating glucose tolerance. When monitoring IGFBP-1 and FSI, changes in concentrations should be interpreted using glycaemic category-specific RCV values.

This non-randomized controlled trial aimed to compare the effect of the 5:2 diet on insulin levels as a primary outcome and markers of insulin secretion (connecting peptide (C-peptide) and insulin-like growth factor binding protein-1 (IGFBP-1)) and sensitivity (Homeostatic Model Assessment for Insulin Resistance (HOMA-IR)), as well as body composition as secondary outcomes in overweight/obese individuals with and without type 2 diabetes (T2D). Ninety-seven participants (62% women), 35 with T2D and 62 BMI- and waist-matched controls without T2D, followed the 5:2 diet (two days per week of fasting) for six months with a 12-month follow-up. At six months, there was no loss to follow-up in the T2D group, whereas four controls discontinued this study. Overall, 82% attended the 12-month follow-up. After the intervention, insulin levels decreased in the control group and glucose decreased in the T2D group, while C-peptide, HOMA-IR, waist circumference, BMI, trunk, and total fat% decreased in both groups. Furthermore, low IGFBP-1, indicating hyperinsulinemia, improved in the T2D group. The changes in fasting glucose and waist measurement were significantly more improved in the T2D group than in the controls. Persistent positive effects were observed at the 12-month follow-up. The 5:2 diet for six months was feasible and efficient to reduce markers of insulin secretion and resistance and therefore holds promise as management of overweight/obesity in subjects with and without T2D. [ABSTRACT FROM AUTHOR]

Background: A major pathway through which obesity increases the risk of cardiometabolic diseases and cancer is by inducing hormonal and metabolic abnormalities, including hyperinsulinemia and altered insulin-like growth factor (IGF) signaling. However, little is known about the influence of lifetime adiposity on the relevant biomarkers. Objective: The aim of this study was to examine associations of trajectories of body fatness with plasma biomarker concentrations of the insulin-IGF system in 2 large prospective cohorts of US men and women. Design: Associations between trajectories of body fatness and concentrations of plasma C-peptide, IGF-I, IGF-binding protein (IGFBP) 1, IGFBP-3, and the IGF-I-to-IGFBP-3 molar ratio was examined in 9386 women of the Nurses' Health Study and 3941 men of the Health Professionals Follow-Up Study.Group-based trajectory modeling was used to create trajectory groups on the basis of self-reported somatotype data at ages 5, 10, 20, 30, and 40 y and body mass index (BMI) at ages 45, 50, 55, and 60 y. We used multivariate linear regression models to examine the associations of trajectories with biomarker concentrations. Results: Five trajectories of body fatness were identified: "leanstable," "lean-moderate increase," "lean-marked increase," "medium-stable/increase," and "medium-marked increase." Compared with the lean-stable group, the lean-marked increase and medium-marked increase groups had significantly higher concentrations of C-peptide (percentage difference-women: 44% and 73%; men: 27% and 51%) and lower concentrations of IGFBP-1 (women: -61% and -78%; men: -47% and -65%). Adjustment for current BMI attenuated the association to null for the medium- marked increase group, but the lean-marked increase group still had modestly higher concentrations of C-peptide (women: 10%; men: 6%) and lower concentrations of IGFBP-1 (women: -18%; men: -21%) than the lean-stable group. Conclusions: Adiposity across the life span was associated with higher C-peptide and lower IGFBP-1 concentrations in adulthood. The associations were largely driven by attained adiposity and, to a lesser extent, weight gain in early-middle adulthood. [ABSTRACT FROM AUTHOR]

Context Insulin-like growth factor (IGF)-I and IGF binding protein (IGFBP)-1 have been linked to cardiovascular disease (CVD) risk and pathophysiology in adults, but there are limited data in youth. Objective The aim of the study was to examine the relationship between IGF and IGFBP-1 with traditional and non-traditional CVD risk factors including inflammatory markers and body composition in an obese pediatric cohort. Design A cross-sectional study. Setting The study was carried out at a university children's hospital. Subjects Sixty-one obese non-diabetic adolescents. Outcomes Fasting IGF-I, IGFBP-1, lipoprotein profiles, high-sensitivity C-reactive protein (hsCRP), and total adiponectin as well as insulin sensitivity measures, blood pressure (BP), and anthropometrics. Results IGFBP-1 was negatively associated with insulin sensitivity measures, body mass index (BMI), and diastolic BP in males. IGF-I was negatively associated with hsCRP (r = -0.479, p < 0.0005), and IGFBP-1 was positively associated with adiponectin (r = 0.545, p < 0.0005). The IGF-I/CRP and IGFBP-1/adiponectin associations remained significant when controlling for both BMI and insulin sensitivity index (SI). Both IGF-I and IGFBP-1 were negatively associated with waist circumference (r = -0.327 and r = -0.275, respectively) and sagittal abdominal diameter (r = -0.333 and r = -0.371, respectively), while IGFBP-1 was negatively associated with fat mass (r = -0.347, p = 0.01) as well as neck circumference and fat-free mass in males. Controlling for BMI z-score and SI, IGFBP-1 remained negatively associated with diastolic blood pressure (r = 0.706, p = 0.001 and neck circumference (r = -0.548, p = 0.15) in males. Conclusions IGF-I and IGFBP-1 associate with CVD risk markers and may add to clinical assessments of cardiometabolic dysfunction in youth. [ABSTRACT FROM AUTHOR]

Insulin-like growth factor (IGF)−1 is associated with a higher risk of prostate cancer. IGF-binding protein (IGFBP)−1, a marker for insulin activity, also binds IGF-1 and inhibits its action. Data on IGFBP-1 and prostate cancer risk are sparse and whether the IGF and insulin axes interact to affect prostate cancer carcinogenesis is unknown. We evaluated the independent and joint influence of prediagnostic plasma levels of IGFBP-1 (fasting) and IGF-1 on risk of prostate cancer among 957 cases and 1,021 controls with fasting levels of IGFBP-1 and 1,709 cases and 1,778 controls with IGF-1 nested within the Health Professionals Follow-up Study. Unconditional logistic regression adjusting for matching factors was used to estimate the odds ratio (OR) and 95% confidence interval (CI). Higher prediagnostic fasting IGFBP-1 levels were associated with lower risk of prostate cancer (highest vs. lowest quartile OR = 0.67, 95% CI 0.52-0.86, ptrend = 0.003), which remained similar after adjusting for IGF-1. Prediagnostic IGF-1 was associated with increased risk of prostate cancer (highest vs. lowest quartile OR = 1.28, 95% CI = 1.05-1.56, ptrend = 0.01). The associations with each marker were primarily driven by lower-grade and non-advanced prostate cancer. Being low in IGFBP-1 and high in IGF-1 did not confer appreciable additional risk ( pinteraction = 0.42). In summary, prediagnostic fasting IGFBP-1 may influence prostate cancer carcinogenesis. Being low in IGFBP-1 or high in IGF-1 is sufficient to elevate the risk of prostate cancer. [ABSTRACT FROM AUTHOR]

The article presents a study regarding the potentials of delta insulin-like growth factor binding protein-1 (ΔIGFBP-1) to be a biomarker for insulin resistance in hepatitis. The study has examined subjects with glucose tolerance test (GTT) and frequently sampled intravenous glucose tolerance test (FSIVGTT) to determine sensitivity index (Si) of insulin. It concludes that ΔIGFBP-1 is a suitable marker for insulin resistance in hepatitis.

Background: A marked reduction in serum levels of bioactive insulin-like growth factor-I (IGF-I) has been observed in fasting hemodialysis (HD) patients during a 4-h HD session. The aim of the present study was to investigate the beneficial effect of hyperinsulinemia during HD on bioactive IGF-I and inflammatory biomarkers. Methods: In a randomized cross-over study, 11 non-diabetic HD patients received a standardised HD session with either: 1) no treatment, 2) glucose infusion (10% glucose, 2.5 mL/kg/h), or 3) glucose-insulin infusion (10% glucose added 30 IU NovoRapid® per litre, 2.5 mL/kg/h). Each experiment consisted of three periods: pre-HD (-120 to 0 min), HD (0 to 240 min), and post-HD (240 to 360 min). A meal was served at baseline (-120 min); infusions were administered from baseline to 240 min. The primary outcome was change in bioactive IGF-I during the experiment. Secondary outcomes were changes in high-sensitivity C-reactive protein, interleukin-1β, interleukin-6, and tumor necrosis factor α. Comparisons were performed using mixed-model analysis of variance for repeated measures. Results: From baseline to the end of study, no significant differences were observed in the changes in either serum bioactive IGF-I or total IGF-I between study days. Overall, serum bioactive IGF-I levels rose above baseline at 120 to 300 min with a maximum increase of 20% at 120 min (95% confidence interval (CI), 9 to 31%; p < 0.001), whereas total IGF-I levels rose above baseline at 180 to 300 min with a maximum increase of 5% at 240 min (95% CI, 2 to 9%; p = 0.004). A significant difference was observed in the changes in serum IGF-binding protein-1 (IGFBP-1) between study days (p = 0.008), but differences were only significant in the post-HD period. From baseline to the end of HD, no significant difference was observed in the changes in serum IGFBP-1 levels between study days, and in this time period overall serum IGFBP-1 levels were below baseline at all time points with a maximum decrease of 51% at 180 min (95% CI, 45 to 57%; p < 0.001). None of the investigated inflammatory biomarkers showed any differences in the changes over time between study days. Conclusions: Postprandial insulin secretion stimulated the IGF-system during HD with no further effect of adding glucose or glucose-insulin infusion. Hyperinsulinemia during HD had no effect on biomarkers of inflammation. [ABSTRACT FROM AUTHOR]

Background. Insulin-like growth factor binding protein 1 (IGFBP-1) is a marker of insulin resistance. We hypothesized that IGFBP-1 is associated with the metabolic syndrome (MetS), which is related to insulin resistance. Methods. We examined 51 obese Caucasian children (mean age 12.1 ±± 2.3, 55% male, mean body mass index [BMI] 31.8 ±± 4.8 kg/m2). Anthropometrical markers, pubertal stage, hepatic ultrasound, waist circumference, blood pressure, fasting serum IGFBP-1, IGFBP-3, IGF-I, adiponectin, leptin, transaminases, glucose, insulin, triglycerides, and HDL-cholesterol concentrations were determined at onset and the end of the one-year lifestyle intervention. Results. In contrast to IGF-I and IGFBP-3, IGFBP-1 correlated significantly to most parameters of the MetS in cross-sectional (waist circumference: r == −−0.45, triglycerides: r == −−0.29; insulin: r == −−0.31; HOMA: r == --0.30) and longitudinal analyses (ΔΔ triglycerides: r == −−0.22; ΔΔ Insulin: r == −−0.25; ΔΔ HOMA: r == −−0.62). The association between changes of HOMA and changes of IGFBP-1 was stronger than the associations between changes of leptin or adiponectin, and changes of HOMA. The risk for the MetS was inversely related to IGFBP-1 levels (odds ratio: −−0.05 per additional IGFBP-1 unit; 95% confidence interval: −−0.08 up to −−0.02; p == 0.019) in a multiple logistic regression analyses adjusted to BMI, pubertal stage, age, and gender. The nine obese children with the MetS had significantly lower IGFBP-1 levels (1.6 ±± 1.3 ngm/l) than the 42 obese children without the MetS (4.0 ±± 3.8 ng/ml). The eleven obese children with fatty liver assessed by ultrasound had significantly lower IGFBP-1 levels (1.5 ±± 1.3 ngm/l) than the 40 obese children without fatty liver (4.2 ±± 4.1 ng/ml). Conclusion. The strong relationships between IGFBP-1, insulin resistance, and the MetS suggest that IGFBP-1 might be a promising marker for these entities in obesity. This study is registered at clinicaltrials.gov (NCT00435734). [ABSTRACT FROM AUTHOR]

Abstract: Objective: Hemodialysis is associated with catabolism and one contributing factor could be decreased bioavailable IGF-I. The aim of this investigation was to study the response of IGF-I and IGFBP-1 to a euglycemic hyperinsulinemic clamp before hemodialysis in type 2 diabetes (T2D) with chronic kidney disease on hemodialysis (CKD5D). Stage 5 (Stages 0–5 according to renal function) indicates a GFR less than 15mL/min/1.73m2, D indicates hemodialysis. The response was compared with that in type 1 diabetes (T1D) with normal renal function. Design: Five overnight fasted patients with T2D with CKD5D were subjected to an insulin infusion (1.6mU/kg/h) for 4 h after which they had lunch followed by a four hour hemodialysis session. The results were compared with results from a previous study in seven T1D patients with normal renal function who had received a similar clamp the same insulin dose with the addition of an initial bolus dose. Blood samples were drawn at 15 to 30min intervals for analysis of IGFBP-1, IGF-I and insulin and at 5min intervals to determine blood glucose. Results: There was no significant change between pre- and postdialysis values of IGF-I but there was a significant 29% increase (p <0.05) at the end of hemodialysis compared with the basal levels before insulin infusion in the T2D patients with CKD5D. The fasting mean levels of IGFBP-1 were increased in both T1D with normal renal function (geometric mean: 216 μg/l, range 169–275 μg/l) and in T2D with CKD5D (geometric mean: 112 μg/l , range 78–162 μg/l, p =0.15 compared with T1D patients) in spite of a high mean insulin level (32±5mU/l). Insulin caused a similar decrease (p <0.05 all groups) in IGFBP-1 mean levels for the first 90min in the T2D patients with CKD5D (73±7% of basal IGFBP-1 values) and the T1D patients (69±6%) with normal renal function. After 90min there was a blunted response in the T2D patients with CKD5D whereas IGFBP-1 in the T1D patients with normal renal function continued to decline. After hemodialysis the IGFBP-1 serum levels increased compared with the levels at the end of insulin infusion but the predialysis values remained significantly lower than before the insulin infusion. Conclusion: Type 2 diabetes patients with chronic kidney disease requiring hemodialysis (CKD5D) have a high mean basal level of IGFBP-1 in spite of increased insulin levels. The first 90min response of IGFBP-1 to insulin infusion is similar in T2D patients with CKD5D and T1D patients with normal renal function. After 90min of insulin infusion a blunted decrease in IGFBP-1 was seen in T2D patients with CKD5D compared with type \1 diabetes with normal renal function. Insulin infusion before hemodialysis reduced the earlier reported increase in IGFBP-1 and increased IGF-I levels. Insulin infusion before dialysis in patients with CKD5D should be further studied since it could contribute to an anabolic effect with more bioavaialable IGF-I thus reducing the catabolic effect of hemodialysis. [Copyright &y& Elsevier]

Insulin-like growth factor-binding protein 1 (IGFBP-1) is a member of a family of six homologous proteins that regulate the action of the insulin-like growth factors. IGFBP-1 is a 25 kDa protein that beside its native form, may exist in several phosphoforms (30 kDa), which are predominant in the circulation of humans. Phosphorylation of IGFBP-1 is a post-translational modification that has a great influence on the IGF-I action. IGFBP-1 forms multimers and complexes with α2-macroglobulin (α2M). Polymerisation of IGFBP-1 was also reported. In order to analyse and separate these IGFBP-1 molecular species, affinity chromatography methods were used in this study. The results demonstrated that most of the IGFBP-1 circulates in complexes with α2M, which can be isolated by affinity chromatography using immobilised anti-α2M antibodies. IGFBP- 1/α2M complexes may be differentiated from IGFBP-1 dimer and multimers using lectin-affinity chromatography, since the latter do not interact with lectins. It seems that the complexes contain not only monomeric IGFBP-1, but also its multimers. Dimer and multimers are stable under reducing conditions, suggesting covalent linkage between units. Free IGFBP-1 monomer can be separated from multimers using Con A-affinity chromatography. The concentration of free IGFBP-1 is relatively low in the circulation. [ABSTRACT FROM AUTHOR]

Aims: To compare the responses of GIP, GLP-1, ghrelin and IGFBP-1 between meals with different fat and energy content in adolescents with type 1 diabetes (T1DM) and to relate them to gastric emptying and glycaemia. Methods: On different days and in a random order, 7 adolescents with T1DM ingested a high- and low-fat meal (fat content: 38 and 2 g, energy content: 640 and 320 kcal, respectively). At normoglycaemia, the same prandial insulin dose was given at both meals and to all subjects. Postprandial blood samples were taken repeatedly over 4 hours. Gastric emptying was estimated by the paracetamol absorption method. Results: The area under the curve (AUC) for GIP0-240 min and for GLP-10-120 min was larger, but smaller for relative ghrelin0-240 min, after the high-fat meal (p = 0.002, 0.030 and 0.043, respectively). IGFBP-1 decreased significantly, but not differently, after the meals. Larger GLP-1 secretion correlated with slower gastric emptying (p = 0.029) and higher fasting ghrelin levels correlated with lower postprandial glycaemia (p = 0.007). Conclusion: In adolescents with T1DM, the postprandial responses of GIP, GLP-1 and ghrelin, but not that of IGFBP-1, depend more on meal size than on insulin. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Modern intensive care techniques have led to higher survival rates of extremely low birth weight infants (ELBW, birth weight <1,000 g). Previous studies have suggested a link between abnormal birth parameters and subsequent endocrine disturbances, but a possible impact on bone maturation during childhood has not been studied. ELBW children were studied (mean chronological age (CA), 6.01 years; range, 4.5-8.2). Skeletal maturation was assessed according to Greulich and Pyle (8). Bone age (BA) was defined as retarded when DeltaBA-CA was < -1 SD and accelerated when DeltaBA-CA was >+1 SD. BA was either retarded or accelerated in 15 patients (24.6%). Twenty-one of 61 radiograms (34.4%) showed a discordant BA with a marked gender difference (14/24 boys; 7/37 girls). DeltaBA-CA correlated significantly with BMI (r = 0.36; p = 0.005) and height SDS (r = 0.35; p = 0.006). We found significant correlations between BA and androgens. Insulin-like growth factor binding protein-1 (IGFBP-1), which decreases in insulin-resistant individuals, correlated negatively with BA. In conclusion, bone maturation in ELBW children is correlative with height and weight. It is modulated by a variety of metabolic factors, including IGFBP-1 and androgens. Bone age, together with height and weight catch-up, can thus possibly serve as early indicators of insulin resistance later in life. [ABSTRACT FROM AUTHOR]

This article investigates the effects of ethanol on Insulin-like growth factor (IGF)-I secretion, p42/44 mitogen-activated protein kinase (MAPK) activity, and IGF binding protein (IGFBP-1 secretion) in primary cultured rat hepatocytes. The p42/44 MAPK activity increased with the ethanol concentration compared to control after ethanol treatment. The secretion of IGF-I significantly increased compared to control, but IGFBP-1 secretion was inhibited. Treatment with 4-methylpyrazole blocked the IGF-I and IGFBP-1 secretion and p42/44 MAPK activity. Increased IGF-I secretion and inhibited IGFBP-1 secretion due to ethanol-induced p42/44 MAPK activity (at 30 min) was blocked by treatment with PD98059. Taken together, these results suggest that ethanol is involved in the modulation of the secretion of IGF-I and IGFBP-1 by p42/44 MAPK in primary cultured rat hepatocytes. In addition, inhibition of p42/44 MAPK activity by ethanol occurs via the activity of ADH. [ABSTRACT FROM AUTHOR]

Low levels of IGF-I are associated with increased risk of cardiovascular disease and type 2 diabetes. The aim of this study was to investigate the IGF-I system in patients with acute myocardial infarction (AMI) without previously known diabetes. One hundred and sixty-eight AMI patients were classified before hospital discharge by means of an OGTT as having NGT, IGT or newly detected type 2 diabetes. Age- and sex-matched subjects from the background population ( n=185) served as the control group. The associations between fasting levels of IGF-I and IGF binding proteins 1 and 3 (IGFBP-1, IGFBP-3) and glucose metabolism during a follow-up period of 12 months were studied. At hospital discharge, age-adjusted IGF-I (IGF-I SD) was significantly lower in patients with abnormal glucose tolerance (AGT=IGT or type 2 diabetes) compared with patients with NGT ( p=0.014) and control subjects ( p<0.001). IGF-I was strongly correlated with IGFBP-3 ( r=0.730, p<0.001), which was significantly lower in patients with AGT compared with patients with NGT ( p=0.009) and control subjects ( p<0.001). Fasting levels of IGFBP-1 did not differ significantly between patients with NGT and AGT or between patients and control subjects. In a multiple logistic regression analysis in patients, IGF-I at hospital discharge was a significant predictor of AGT at discharge and after 12 months (adjusted odds ratio 0.29, p=0.022, and adjusted odds ratio 0.29, p=0.034, respectively). Low levels of IGF-I may be a useful predictor of abnormal glucose metabolism in patients with AMI. [ABSTRACT FROM AUTHOR]

Objective. Catabolism and growth impairment are well-known complications of inflammatory bowel disease (IBD). This may be caused by the disease activity itself and/or the medical treatment, and both may lead to changes in the growth hormone (GH)/insulin-like growth factor I (IGF-I) axis. The aim of the present study was to examine the effects of enteral nutrition, Impact Powder®, as adjuvant therapy to corticosteroid treatment on changes in the GH/IGF-I axis in patients with Crohn's disease (CD). Material and methods. The patients were randomized to 3-IP (ω-3-fatty acid (FA), 3&ThickSpace;g/day) or 6-IP (ω-6-FA, 9&ThickSpace;g/day). Changes in total IGF-I (tIGF-I) and total IGF-II (tIGF-II), free IGF-I (fIGF-I), IGF binding proteins (IGFBP-1 and IGFBP-3), IGFBP-3 protease activity and insulin levels were examined in 31 patients with active CD (CDAI: 186–603) during treatment with prednisolone (40&ThickSpace;mg for 1 week) and tapering the dose by 5&ThickSpace;mg/week. Clinical and biochemical markers of inflammation were studied at day 0, and after 5 and 9 weeks. Results. There were no differences at baseline between the two groups. During the treatment period, tIGF-I, fIGF-I and IGFBP-3 increased significantly in both groups compared to baseline ( p [ABSTRACT FROM AUTHOR]

Abstract: Proteolytic modification of insulin-like growth factor binding proteins (IGFBPs) plays an important physiological role in regulating insulin-like growth factor (IGF) bioavailability. Recently, we demonstrated that matrix metalloproteinase-7 (MMP-7)/Matrilysin produced by various cancer cells catalyzes the proteolysis of IGFBP-3 in vitro and regulates IGF bioavailability, resulting in an anti-apoptotic effect against anchorage-independent culture. In the present study, we investigated whether MMP-7 contributes to proteolysis of the other five IGFBPs, IGFBP-1, IGFBP-2, IGFBP-4, IGFBP-5, and IGFBP-6, and whether this results in phosphorylation of the IGF type 1 receptor (IGF-1R). MMP-7 cleaved all six IGFBPs, resulting in IGF-mediated IGF-1R phosphorylation, which was inhibited by EDTA treatment. These results suggest that MMP-7 derived from cancer cells can regulate IGF bioavailability in the microenvironment surrounding the tumor, where various kinds of IGF/IGFBP complexes are found, thereby favoring cancer cell growth and survival during the processes of invasion and metastasis. [Copyright &y& Elsevier]

Abstract: Introduction: Alcohol induces disturbances in insulin-like growth factor-I (IGF-I) and IGF binding protein-1 (IGFBP-1) levels. The aim of the present study was to compare pure ethanol and alcopop effects on total and free IGF-I, IGFBP-1, IGF-I:IGFBP-1 complex, insulin and plasma glucose levels in healthy subjects. Methods: Five males and seven females (21–51 years) consumed pure ethanol and alcopops with identical alcohol content in a cross-over design after 6h fasting. Blood samples were obtained for determination of serum ethanol and plasma glucose at 0, 30, 60, 90, 120 and 180min. Serum total and free IGF-I, IGFBP-1, IGF-I:IGFBP-1 complex, and insulin were measured at 0, 60 and 180min. Results: Area under the curve for serum ethanol concentration was significantly less following alcopop compared to pure ethanol (1124±201 vs. 1691±359mmol/Lh, P <0.01). Serum insulin and glucose levels were unchanged by ethanol while alcopop intake was followed by a transient increase in glucose and insulin levels (P <0.05). Pure ethanol and alcopop reduced free IGF-I levels by the end of the study period (P =0.05). IGFBP-1 and the IGF-I:IGFBP-1 complex increased following ethanol intake (P <0.05) while only a small transient IGFBP-1 increase was observed following alcopop intake. No change in total IGF-I was observed. Conclusion: Both drinks resulted in reduced free IGF-I levels, however, only pure ethanol increased IGFBP-1 and the IGF-I:IGFBP-1 complex. Alcopop intake was associated with a transient increase in IGFBP-1 and unchanged IGF-I:IGFBP-1 complex levels probably due to marked changes in insulin and glucose levels. [Copyright &y& Elsevier]

Background: Components of the insulin-like growth factor (IGF) system have been associated with several cancers, but very few studies are available for ovarian cancer. Methods: A case-control study conducted between 1999 and 2003 in Italy, including a total of 59 women with incident, histologically confirmed ovarian cancer and 108 controls admitted to the same hospital network as cases, for acute non-neoplastic diseases. All subjects were interviewed using a validated questionnaire. Results: After adjustment for potential confounders, the multivariate odds ratios for the highest versus the lowest tertile of various IGF components were 0.6 (95% confidence interval, CI: 0.2–1.4) for free IGF-I, 0.4 (CI: 0.1–1.5) for total IGF-I, 2.6 (CI: 0.9–6.9) for IGF-binding protein (IGFBP)-1, and 0.2 (CI: 0.0–0.6) for IGFBP-3. Conclusions: This study suggests a protective role of IGFBP-3 and a positive association of IGFBP-1 with ovarian cancer. The complex role of the IGF system in ovarian carcinogenesis deserves further clarification. Copyright © 2004 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

: ObjectiveTo evaluate the effects of rosiglitazone on insulin resistance, growth factors, and reproductive disturbances in women with polycystic ovary syndrome (PCOS).: DesignProspective study.: SettingWomen with PCOS attending as outpatients of the Endocrine Division, Hospital Durand, Buenos Aires.: Patient(s)Twenty-four insulin-resistant women with PCOS.: Intervention(s)Hormonal evaluations and a standardized oral glucose tolerance test before and after a 3-month trial of 4 mg of rosiglitazone daily.: Main outcome measure(s)Serum LH, FSH, T, IGF-1, IGFBP-1, IGFBP-3, leptin, 17α-hydroxyprogesterone, insulin, and glucose concentrations. The area under insulin curve (AUC-insulin), the HOMA index (insulin resistance), the QUICKI index (insulin sensitivity), and the β-cell function were calculated. Body mass index (BMI) and the waist/hip ratio were evaluated.: Result(s)A significant decrease was observed in serum fasting insulin, AUC insulin, HOMA index, β-cell function, IGF-1, LH, and waist/hip ratio. The QUICKI index and IGFBP-1 increased significantly. Serum sex hormone–binding globulin, androgens, leptin, IGFBP-3, and BMI remained unchanged. Twenty-two of 23 females had their menses restored, and three patients became pregnant. One patient was excluded because she became pregnant at the second month.: Conclusion(s)Associated with the decrease in LH, rosiglitazone improved insulin-resistance parameters and normalized the menstrual cycle, which suggests that this drug could improve the endocrine-reproductive condition in insulin-resistant women with PCOS. [Copyright &y& Elsevier]

Insulin rapidly and completely inhibits expression of the hepatic insulin-like growth factor binding protein-1 (IGFBP-1), phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) genes. This inhibition is mediated through a phosphatidyl inositol 3-kinase-dependent regulation of a DNA element, termed the thymine-rich insulin response element, found within the promoters of each of these genes. This has led to the conclusion that these three promoters are regulated by insulin using the same molecular mechanism. However, we recently found that the regulation of the IGFBP1 but not the PEPCK or G6Pase genes by insulin was sensitive to rapamycin, an inhibitor of mTOR. Here, we present further evidence that different regulatory pathways mediate the insulin regulation of these promoters. Importantly, we identify a protein phosphatase activity in the pathway connecting mTOR to the IGFBP-1 promoter. These data have major implications for the development of molecular therapeutics for the treatment of insulin-resistant states such as diabetes and hypertension. [Copyright &y& Elsevier]

Hyperinsulinaemia and reduced insulin sensitivity are common features in patients with cirrhosis. Octreotide, a long-acting somatostatin analogue, is used in cirrhotic patients in the treatment of bleeding oesophageal varices. Octreotide has potent effects on the growth hormone (GH)/insulin-like growth factor I (IGF-I) axis in healthy subjects. but the effects on the GH/IGF-I axis in patients with cirrhosis have been described only briefly. The effects of a 12 h infusion of octreotide (bolus 0.75 microg/kg followed by 0.75 microg/kg/h) in 25 subjects (normals n=9, compensated cirrhotics n=8, decompensated cirrhotics n=8) were compared with those in placebo-treated controls (n=19) during fasting conditions. IGF-I, free IGF-I, IGF binding proteins (IGFBPs), insulin, C-peptide, GH and glucose were measured. Insulin resistance was calculated using the HOMA method. Octreotide reduced levels of total IGF-I in patients with compensated cirrhosis (p=0.03) and free IGF-I in decompensated cirrhosis (p<0.01). Insulin resistance was significantly reduced in normal subjects. whereas the reduction in insulin resistance did not reach statistical significance in patients with cirrhosis. In normal subjects, octreotide increased the IGFBP-1 area under curve threefold (p<0.01) and decreased IGFBP-3 levels (p<0.01), but these effects were blunted in the cirrhotic patients. Similarly, the reduction of insulin and C-peptide was blunted in the cirrhotic patients, whereas a significant reduction in GH was demonstrated in all groups. The effects of octreotide on the GH/IGF-I axis are mitigated in patients with cirrhosis and this may be a reflection of relative hyperinsulinaemia during octreotide treatment in these patients. [ABSTRACT FROM AUTHOR]

SummaryAims To study whether changes in endogenous insulin secretion at the same glycaemic control affect the plasma concentrations of lipoproteins in patients with Type 2 diabetes mellitus. Methods Fifteen patients, age 59 ± 2 years (mean ± sem), body weight 86.3 ± 3.0 kg, body mass index 29.6 ± 0.9 kg/m2 were treated with sulphonylurea and insulin in combination or with insulin alone in a randomized, double-blind, crossover study. All patients were treated with a multiple daily injection regimen with the addition of glibenclamide 10.5 mg daily or placebo tablets. Results During combination therapy, the dose of insulin was 25% less (P < 0.002) and there was a 29% increase in plasma C-peptide concentration (P = 0.01). Plasma levels of free insulin were not changed. Plasma levels of sex hormone-binding globulin (SHBG) and insulin-like growth factor-binding protein (IGFBP)-1 were lowered. There were no differences in the 24-h blood glucose profiles or HbA1c (6.0 ± 0.2 vs. 6.3 ± 0.2%; P = 0.16). Body weight was similar. There was a significant decrease in plasma LDL cholesterol (3.04 ± 0.24 vs. 3.41 ± 0.21 mmol/l; P = 0.04), apolipoprotein A1 and of lipoprotein(a) but an increase in VLDL-triglycerides (1.36 ± 0.31 vs. 0.96 ± 0.16 mmol/l; P = 0.02) during combination therapy. The ratio between LDL cholesterol and apolipoprotein B concentrations was significantly lower during combination therapy (P < 0.01). Conclusions Combination therapy with insulin and sulphonylureas increases portal insulin supply and thereby alters liver lipoprotein metabolism when compared with insulin therapy alone. [ABSTRACT FROM AUTHOR]

Objective:To establish the relation of insulin-like growth factor-I (IGF-I) and IGF-binding protein-1 (IGFBP-1) with 24-hour metabolic excursions in normal healthy women and in response to acute interruption of metabolic homeostasis by hypoinsulinemia.Methods:Hourly blood samples during the 24-hour metabolic clock were obtained from seven normally cyclin women. Uniform dietary composition (50% carbohydrate, 35% fat, and 15% protein) and timing of meals (8 AM, 12 PM, and 6 PM) were prescribed. Daytime hypoinsulinemia was induced by omitting meals and by Sandostain (100 μg) administration. Changes in serum levels of glucose, insulin, cortisol, IGF-I, and IGFBP-1 were measured.Results:The diurnal pattern of serum IGFBP-1 levels during the 24-hour metabolic clock was characterized by a rapid fall during the feeding phase of the day and a progressive 3.5-fold rise during nocturnal fasting; IGF-I levels were unchanged. Changes in IGFBP-1 levels were in parallel to those of cortisol and were inversely related to increases in glucose (80%) and insulin (tenfold) levels after each meal and to their decline during nocturnal fasting. Daytime fasting and administration of Sandostatin were accompanied by rapid and sustained increases in IGFBP-1 when insulin levels declined to 54 ± 20 pmol/L.Conclusions:With constant levels of IGF-I, the diurnal rhythm of IGFBP-1 may subserve a physiologic function by coordinating insulin and IGF-I action with substrate availability. Fluctuations of insulin levels during the 24-hour metabolic clock in normal women appear to sere as a signal, with an inhibitory effect on IGFBP-1 production when levels are above 70 pmol/L and a stimulatory effect at levels below 70 pmol/L. These findings provide a basis for future investigations in woman with nutritionally related reproductive disorders. [ABSTRACT FROM PUBLISHER]