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Cell migration is a pivotal step in metastatic process, which requires cancer cells to navigate a complex spatially‐confined environment, including tracks within blood vessels and in the vasculature of target organs. Here it is shown that during spatially‐confined migration, the expression of insulin‐like growth factor‐binding protein 1 (IGFBP1) is upregulated in tumor cells. Secreted IGFBP1 inhibits AKT1‐mediated phosphorylation of mitochondrial superoxide dismutase (SOD2) serine (S) 27 and enhances SOD2 activity. Enhanced SOD2 attenuates mitochondrial reactive oxygen species (ROS) accumulation in confined cells, which supports tumor cell survival in blood vessels of lung tissues, thereby accelerating tumor metastasis in mice. The levels of blood IGFBP1 correlate with metastatic recurrence of lung cancer patients. This finding reveals a unique mechanism by which IGFBP1 sustains cell survival during confined migration by enhancing mitochondrial ROS detoxification, thereby promoting tumor metastasis. [ABSTRACT FROM AUTHOR]

Stearoyl-CoA desaturase-1 (SCD1) catalyzes the rate-liming step of monounsaturated fatty acid biosynthesis and is a key regulator of systemic glucose metabolism. Mice harboring either a global (GKO) or liver-specific deletion (LKO) of Scd1 display enhanced insulin signaling and whole-body glucose uptake. Additionally, GKO and LKO mice are protected from high-carbohydrate diet-induced obesity. Given that high-carbohydrate diets can lead to chronic metabolic diseases such as obesity, diabetes, and hepatic steatosis, it is critical to understand how Scd1 deficiency confers metabolically beneficial phenotypes. Here we show that insulin-like growth factor-binding protein 1 (IGFBP1), a hepatokine that has been reported to enhance insulin signaling, is significantly elevated in the liver and plasma of GKO and LKO mice fed a low-fat high-carbohydrate diet. We also observed that the expression of hepatic Igfbp1 is regulated by oleic acid (18:1n9), a product of SCD1, through the mTORC1-FGF21 axis both in vivo and in vitro. [ABSTRACT FROM AUTHOR]

Purpose: Subendometrial myometrium exerts wave‐like activity throughout the menstrual cycle, and uterine peristalsis is markedly reduced during the implantation phase. We hypothesized that abnormal uterine peristalsis has an adverse effect on the endometrial decidualization process. We conducted an in vitro culture experiment to investigate the effect of cyclic stretch on the morphological and biological endometrial decidual process. Methods: Primary human endometrial stromal cells (HESCs) were isolated from hysterectomy specimens and incubated with or without 8‐bromo‐cyclic adenosine monophosphate (8‐br‐cAMP) and medroxyprogesterone acetate (MPA) for 3 days. After decidualization, cultures were continued for 24 hours with or without cyclic stretch using a computer‐operated cell tension system. Results: Cyclic stretch significantly repressed expression of decidual markers including insulin‐like growth factor‐binding protein 1 (IGFBP1), prolactin (PRL), forkhead box O1 (FOXO1), and WNT4 on decidualized HESCs. In addition, cyclic stretch of decidualized HESCs affected the decidual morphological phenotype to an elongated shape. The alternation of F‐actin localization in decidualized HESCs was not observed in response to cyclic stretch. Conclusions: These data suggest that cyclic stretch inhibits the morphological and biological decidual process of HESCs. Our findings imply that uterine abnormal contractions during the implantation period impair endometrial decidualization and contribute to infertility. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

O-GlcNAcylation on serine/threonine is a post-translational modification that controls the activity of nucleocytoplasmic proteins according to glucose availability. We previously showed that O-GlcNAcylation of FoxO1 in liver cells increases its transcriptional activity. In the present study, we evaluated the potential involvement of FoxO1 O-GlcNAcylation in the context of pancreatic β-cell glucotoxicity. FoxO1 was O-GlcNAcylated in INS-1 832/13 P cells and isolated rat pancreatic islets. O-GlcNAcylation of FoxO1 resulted in a 2-fold increase in its transcriptional activity toward a FoxO1 reporter gene and a 3-fold increase in the expression of the insulin-like growth factor-binding protein 1 (Igfbp1) gene at the mRNA level, resulting in IGFBP1 protein oversecretion by the cells. Of note, increased IGFBP1 in the culture medium inhibited the activity of the insulin-like growth factor 1 receptor (IGF1R)/phosphatidyl inositol 3 kinase (PI3K)/Akt pathway. We reveal in this report a novel mechanism by which O-GlcNAcy-lation inhibits Akt activity through an autocrine mechanism. However, although inhibition of IGFBP1 expression using siRNA restored the PI3 kinase/Akt pathway, it did not rescue INS-1 832/13 cells from high-glucose- or O-GlcNAcylation-induced cell death. In contrast, FoxO1 down-regulation by siRNA led to 30 to 60% protection of INS-1 832/13 cells from death mediated by glucotoxic conditions. Therefore, whereas FoxO1 O-GlcNAcylation inhibits Akt through an IGFBPl-mediated autocrine pathway, the deleterious effects of FoxO1 O-GlcNAcylation on cell survival appeared to be independent of this pathway [ABSTRACT FROM AUTHOR]

BACKGROUND ‘Pregnancies of unknown location’ (PULs) include viable and failing intrauterine and extrauterine pregnancies. The aim of this study was to evaluate the role of novel biochemical markers in the prediction of spontaneous resolution of PULs. METHODS Serum samples were taken at the first visit to the pregnancy unit for measuring the traditional markers β-hCG and progesterone, and for inhibin A, inhibin pro-αC-related immunoreactivity (inhibin pro-αC-RI) and insulin-like growth factor-binding protein 1 (IGFBP-1). Follow-up was continued until the pregnancy had resolved, the location of the pregnancy and viability was determined or treatment was required. Outcomes were dichotomized into ‘spontaneous resolution’ and ‘other outcome’ categories. RESULTS One-hundred and nine cases of PUL were included in the data analysis. Spontaneous resolution occurred in 70% and a further scan was required in 30% to reach a diagnosis. Levels of progesterone and inhibin A were significantly lower (both P < 0.001) and levels of IGFBP-1 significantly higher (P = 0.02) in the pregnancies that spontaneously resolved than in those pregnancies that required further intervention. In decision tree analysis, the novel markers were less useful than progesterone and β-hCG in predicting spontaneously resolving PULs. Inhibin pro-αC-RI and IGFBP-1 were not useful in the prediction of spontaneously resolving PULs. Inhibin A is more predictive than β-hCG alone, but serum progesterone is the best single marker and progesterone and hCG together continues to be the best way of predicting spontaneously resolving PULs. CONCLUSIONS These novel biochemical markers are not clinically useful in predicting spontaneously resolving PULs. [ABSTRACT FROM AUTHOR]

Subcutaneous microdialysis has been used for continuous glucose monitoring in patients with diabetes mellitus (DM) to facilitate tight regulation of blood glucose levels. The aims of this study were therefore to investigate (i) the relationship between capillary and interstitial glucose in patients with type 1 or 2 DM and healthy subjects and (ii) the feasibility of using microdialysis to assess local insulin sensitivity in adipose tissue. Using subcutaneous microdialysis, interstitial glucose, lactate, pyruvate and glycerol were determined as measures of glucose and lipid metabolism in adipose tissue, before and after an oral glucose tolerance test (OGTT) in 14 patients and seven controls. The results were correlated to whole-body insulin sensitivity and insulin sensitivity in liver estimated from the levels of insulin-like growth factor-binding protein 1 (IGFBP-1). Capillary and interstitial glucose correlated before and after OGTT in healthy subjects and in type 1 DM but not in type 2 DM. In fasting state, the glycerol levels were higher in both type 1 and type 2 DM compared with controls. After the OGTT, the insulin levels were sufficient to suppress lipolysis in type 1 but not in type 2 DM. The glucose/lactate ratio was higher at fasting in type 1 DM and after OGTT in type 1 and 2 DM. In type 1 DM, basal interstitial glycerol levels correlated to whole-body glucose utilization. In type 2 DM, correlations were found between the basal glycerol levels and whole-body insulin sensitivity and between glucose/lactate and per cent decrease in IGFBP-1 levels 120 min after OGTT. Capillary and interstitial glucose correlated before and after OGTT in healthy subjects and patients with type 1 DM. Correlations were also found between insulin sensitivity in whole body and in adipose tissue in both type 1 and type 2 DM and between insulin sensitivity in subcutaneous adipose tissue and liver in type 2 DM. This study shows that microdialysis technique can be used to study in vivo insulin sensitivity in adipose tissue over time and may be useful in the evaluation of, for example, the effects of new drugs on insulin sensitivity. [ABSTRACT FROM AUTHOR]

BACKGROUND Clinical criteria and the presence of auto-antibodies might not be sufficient to discriminate type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) in children with new onset of disease. OBJECTIVE To determine whether biochemical markers can be used to distinguish T1DM from T2DM. DESIGN AND INTERVENTION This was a single-center, US-based, prospective study of children with newly diagnosed primary diabetes. Children with secondary diabetes as a result of medication, cystic fibrosis, or other medical conditions were excluded. Eligible participants were enrolled between July 1999 and July 2000. T1DM was presumptively diagnosed in nonobese children who were dependent on insulin to maintain glycemic control. T2DM was presumptively diagnosed in children with a BMI >85% for age and sex and a family history of T2DM, who were insulin-independent and glutamic acid decarboxylase autoantibody-negative. Glucose, CO2, urinary ketones, and HbA1c levels were measured at diagnosis. A fasting blood sample was collected on the morning of diagnosis or on the morning after diagnosis to determine the levels of C-peptide and insulin-like-growth-factor-binding protein 1 (IGFBP-1). C-peptide was assessed by immuno-chemiluminescent assay and IGFBP-1 was assessed by radioimmunoassay. OUTCOME MEASURES The main outcome measures were the receiver operator characteristic (ROC), area under the curve (AUC), sensitivity, specificity, and cut-off value of each biochemical marker. RESULTS The study enrolled a total of 175 children, 149 of whom were presumptively diagnosed with T1DM. The mean age of children with T1DM was 8.7 years, compared with a mean age of 14.2 years for children with T2DM (P<0.001). Children with T1DM were most likely be non- Hispanic whites (78%, P<0.001). By contrast, children with T2DM were most likely to be non- Hispanic blacks (58%, P<0.001). Markers of insulin resistance demonstrated a significant difference between T1DM and T2DM. The mean fasting C-peptide level was 0.13 nmol/l in T1DM and 0.88nmol/l in T2DM (P<0.001). The ROC curve for fasting C-peptide determined a cut-off value of 0.28nmol/l, with a sensitivity of 83%, a specificity of 89%, and an AUC of 0.94. The mean fasting IGFBP-1 level was 38.1 ng/ml in T1DM and 3.6ng/ml in T2DM (P<0.001). The ROC curve for fasting IGFBP-1 determined a cut-off value of 3.6ng/ml, with a sensitivity of 93%, a specificity of 79%, and an AUC of 0.92. The CO2 level for children with TIDM was 17.9mmol/l, versus 22.7mmol/l for children with T2DM (P= 0.016). The ROC curve for CO2 determined a cut-off value of 21.5 mmol/l, with a sensitivity of 83%, a specificity of 64%, and an AUC of 0.76. Urinary ketones were present in 79% and 56% of children with T1DM and T2DM, respectively. A cut-off value of 10 mg/dl was associated with a sensitivity of 74%, a specificity of 52%, and an AUC of 0.73. CONCLUSION Children with new-onset T1DM and T2DM can be distinguished by a combination of biochemical markers. [ABSTRACT FROM AUTHOR]