A systematic review of literature on Insulin-like growth factor-2-mediated hypoglycaemia in non-islet cell tumours.

INTRODUCTION: Insulin-like growth factor-2 (IGF-2)-mediated hypoglycemia is a rare yet clinically significant entity with considerable morbidity and mortality. Existing literature is limited and fails to offer a comprehensive understanding of its clinical trajectory, management and prognostication. METHODS: Systematic review of English-language articles reporting primary patient data on IMH was searched using electronic databases (PubMed, Scopus and Embase) from any date up to 21 December 2022. Data were analysed in STATA-16. RESULTS: The systematic review contains 172 studies, including 1 Randomised controlled trial, 1 prospective observational study, 5 retrospective observational studies, 150 case reports, 11 case series and 4 conference abstracts. A total of 233 patients were analysed, averaging 60.6 ± 17.1 years in age, with comparable proportions of males and females. The commonest tumours associated with Insulin-like Growth Factor-2-mediated hypoglycaemia were fibrous tumours (N = 124, 53.2%), followed by non-fibrous tumours originating from the liver (N = 21, 9%), hemangiopericytomas (N = 20, 8.5%) and mesotheliomas (N = 11, 4.7%). Hypoglycaemia was the presenting feature of NICT in 42% of cases. Predominant clinical features included loss of consciousness (26.7%) and confusion (21%). The mean IGF-2 and IGF-1 levels were 882.3 ± 630.6 ng/dL and 41.8 ± 47.8, respectively, with no significant correlation between these levels and patient outcomes. Surgical removal was the most employed treatment modality (47.2%), followed by medication therapy. The recovery rate was 77%, with chronic liver disease (CLD) significantly associated with a poor outcome (OR: 7.23, P: 0.03). Tumours originating from fibrous tissues were significantly associated with recovery (p < .001). In the logistic regression model, CLD remained a significant predictor of poor outcomes. CONCLUSION: This systematic review highlights that most non-islet-cell tumour-hypoglycaemia (NICTH) is due to fibrous tumours. NICTs demonstrate a variable prognosis, which is fair if originating from fibrous tissue. Management such as octreotide, corticosteroids, diazoxide, embolization, radiotherapy and surgical resection have disparate success rates.

Fetal macrosomia, fetal insulin, and insulin-like growth factor- 1 among neonates in Lagos, Nigeria: A case-control study.

PURPOSE: Fetal macrosomia is associated with perinatal injuries. The purpose of this study was to assess the relationship between fetal insulin, insulin-like Growth factor-1(IGF-1), and macrosomia in a resource-limited setting. METHOD: This was a case-control study at tertiary and secondary health facilities in Lagos, Nigeria. One hundred and fifty mother-neonate pairs were recruited, and their socio-demographic and obstetric history was recorded. Fetal cord venous blood was collected at birth, and neonatal anthropometry was measured within 24hrs of life. Insulin and IGF-1 assay were measured with Enzyme-Linked Immunosorbent Assay (ELISA). Pearson's Chi-square was used to assess the association between categorical variables and macrosomia. Spearman's rank correlation of insulin, IGF-1, and fetal anthropometry was performed. Multivariable logistic regression was used to evaluate the association of insulin and IGF-1 with fetal birth weight. A statistically significant level was set at P-value < 0.05. RESULTS: Macrosomic neonates had mean fetal weight, fetal length, and occipitofrontal circumference (OFC) of 4.15±0.26kg, 50.85±2.09cm and 36.35± 1.22cm respectively. The median Insulin (P = 0.023) and IGF-1 (P < 0.0001) were significantly higher among macrosomic neonates as compared to normal weight babies. Maternal BMI at birth (p = 0.003), neonate's gender (p < 0.001), fetal cord serum IGF-1 (p < 0.001) and insulin assay (P-value = 0.027) were significant predictors of fetal macrosomia. There was positive correlation between cord blood IGF-1 and birth weight (r = 0.47, P-value < 0.001), fetal length (r = 0.30, P-value = 0.0002) and OFC (r = 0.37, P-value < 0.001). CONCLUSION: Among participating mother-neonate dyad, maternal BMI at birth, neonate's gender, and fetal cord serum IGF-1 and serum insulin are significantly associated with fetal macrosomia.

A phase 1 trial of xentuzumab, an IGF-neutralizing antibody, in Japanese patients with advanced solid tumors.

Xentuzumab is an insulin-like growth factor (IGF) ligand-neutralizing antibody. This phase 1 trial assessed xentuzumab in Japanese patients with solid tumors. Patients aged ≥20 y old with solid tumors that were refractory or not amenable to standard therapy were enrolled. Patients received xentuzumab intravenously at a starting dose of 750 mg/wk. Dose escalation used a 3 + 3 design with dose de-escalation. The primary endpoint was to determine the maximum tolerated dose (MTD) of xentuzumab. Safety, pharmacokinetics, pharmacodynamics, and anti-tumor activity were also assessed. Fifteen patients received xentuzumab in the dose escalation part (750 mg/wk [n = 6]; 1000 mg/wk [n = 3]; 1400 mg/wk [n = 6]). There were no dose-limiting toxicities at any dose; the MTD of xentuzumab was not reached. Xentuzumab 1000 mg/wk was recommended as the relevant biological dose. Six further patients received xentuzumab 1000 mg/wk in an expansion cohort. Of 21 patients, 13 (61.9%) experienced a drug-related adverse event, most commonly fatigue (23.8%), neutropenia (19.0%), diarrhea, nausea, white blood cell count decrease, and muscle spasms (14.3% each). No relevant deviations from dose linearity of xentuzumab exposure were observed during dose escalation. Total IGF-1 and IGF-2 levels increased and bioactive IGF levels decreased from baseline to 24 h after the first infusion in cycle 1. Partial response was observed in 2 (9.5%) patients with desmoid-type fibromatosis. Disease control was achieved in 6 (28.6%) patients (median duration 42.4 mo). Xentuzumab monotherapy was well tolerated in Japanese patients and showed evidence of anti-tumor activity. This study was registered with www.clinicaltrials.gov (NCT02145741).

Concentrations of Insulin-like Growth Factors and Insulin-like Growth Factor-Binding Proteins and Respective Gene Expressions in Children before and after Hematopoietic Stem Cell Transplantation.

Insulin-like growth factors (IGF-1 and IGF-2) and insulin-like growth factor-binding proteins (IGFBP-1 to -7) are involved in the regulation of cell proliferation and differentiation and may be associated with various metabolic parameters. The aim of our study was to compare levels of IGFs and IGFBPs and the expressions of their genes in children before and after hematopoietic stem cell transplantation (HSCT) to assess their potential as markers of late metabolic complications of HSCT. We also conducted additional comparisons with healthy controls and of correlations of IGF and IGFBP levels with anthropometric and biochemical parameters. We analyzed 19 children treated with HSCT and 21 healthy controls. We found no significant differences in the levels of IGFs and IGFBPs and expressions of their genes before and after HSCT, while IGF and IGFBP levels were significantly lower in children treated with HSCT compared with controls. We conclude that our results did not reveal significant differences between the levels of IGFs and IGFBPs before and after HSCT, which would make them obvious candidates for markers of late complications of the procedure in children. However, due to the very low number of patients this conclusion must be taken with caution and may be altered by further research.

The Insight into Insulin-Like Growth Factors and Insulin-Like Growth-Factor-Binding Proteins and Metabolic Profile in Pediatric Obesity.

Insulin-like growth factors (IGFs) and insulin-like growth-factor-binding proteins (IGFBPs) regulate cell proliferation and differentiation and may be of importance in obesity development. The aim of the study was to analyze the expression of chosen IGF-axis genes and the concentration of their protein products in 28 obese children (OB) and 34 healthy control (HC), and their correlation with essential parameters associated with childhood obesity. The gene expression of IGFBP7 was higher, and the expression of IGF2 and IGFBP1 genes was lower in the OB. The expression of IGFBP6 tended to be lower in OB. IGFBP4 concentration was significantly higher, and IGFBP3 tended to be higher in the OB compared to the HC, while IGFBP1, IGFBP2, and IGFBP6 were significantly lower, and IGFBP7 tended to be lower in OB. We found numerous correlations between IGFs and IGFBP concentration and obesity metabolic parameters. IGFBP6 correlated positively with apelin, cholecystokinin, glucagone-like peptide-1, and leptin receptor. These peptides were also significantly lower in obese children in our study. The biological role of decreased levels of IGFBP6 in obese children needs further investigation.

Maternal Plasma Lipids During Pregnancy, Insulin-like Growth Factor-1, and Excess Fetal Growth.

CONTEXT: Maternal lipids during pregnancy and placental growth factors are associated with excess fetal growth. However, how these factors interact to increase the risk of delivering large-for-gestational-age (LGA) neonates remains unclear. In this study, we investigated the relationship between maternal plasma triglycerides (TGs) and free fatty acids (FFAs) during pregnancy, cord blood insulin-like growth factors (IGF), and LGA. OBJECTIVE: In a cell model, we studied the effect of different FAs on placental IGF-1 secretion. METHODS: This cohort study included pregnant women with term pregnancy and without diabetes or hypertensive disorders in pregnancy. Maternal fasting plasma TGs and FFAs were measured in the second trimester. Cord blood IGF-1, IGF-2, and IGF binding protein-1 and protein-3 were measured at the time of delivery. A human trophoblast cell line, 3A-sub-E, was used to evaluate the effect of different FFAs on placental IGF-1 secretion. RESULTS: We recruited 598 pregnant women-neonate pairs. Maternal plasma TG (180 mg/dL [152.5-185.5 mg/dL] vs 166 mg/dL [133-206 mg/dL], P = .04) and cord blood IGF-1 concentrations (72.7 ±â€…23.0 vs 54.1 ±â€…22.8 ng/mL, P < .001) were higher in the LGA group and were significantly associated with birth weight z score. Maternal plasma free palmitic acid (PA) and stearic acid (SA), but not oleic acid (OA) or linoleic acid (LA), were significantly associated with cord blood IGF-1 concentrations. In 3A-sub-E cells, treatment with PA, SA, and LA, but not OA, induced IGF-1 expression and secretion. CONCLUSION: Certain FFAs can induce placental IGF-1 secretion, which suggests a potential pathophysiology linking maternal plasma lipids and LGA.

Childhood trauma and insulin-like growth factors in amniotic fluid: An exploratory analysis of 79 women.

BACKGROUND: Perinatal stress has adverse effects on fetal outcome, yet the effect of early maternal trauma on fetal outcome has scarcely been studied. We investigated effects of maternal childhood trauma and current environment on important regulators of prenatal growth, fetal insulin-like growth factor (IGF)-1 and IGF-2 in amniotic fluid and assessed the impact of IGFs on newborn anthropometrics. METHODS: 79 pregnant women in their second trimester who underwent amniocentesis (15.9 ± 0.9 weeks of gestational age) and their newborns at birth were analyzed. Maternal childhood trauma was assessed using the childhood trauma questionnaire (CTQ) and current environment was operationalized by assessing maternal psychosocial, physical health and endocrine measurements in amniotic fluid. RESULTS: In this exploratory analysis of 79 pregnant women, maternal childhood trauma, defined as reporting at least low scores on any of the CTQ subscales, negatively correlated with fetal IGF-1 (Mln = 3.48 vs. 2.98; p = 0.012) and IGF-2 (Mdnln = 4.99 vs. 4.70; p = 0.002). Trauma severity, defined as the overall trauma score, negatively correlated with fetal IGF-2 (r = -0.24; p = 0.037). From trauma subscales, maternal sexual abuse correlated with fetal IGF-1 (r = -0.32; p = 0.006) and IGF-2 (r = -0.39; p = 0.001). Maternal BMI negatively correlated with fetal IGF-1 (r = -0.26; p = 0.023) and IGF-2 (r = -0.29; p = 0.011). Newborn anthropometrics were operationalized by length, weight, sex, gestational age, length/gestational age and weight/gestational age at birth. Fetal weight at birth associated with a trend with fetal IGF-1 when controlling for BMI. Maternal hypothalamus-pituitary-adrenal axis activity and maternal exercise did not contribute significantly to predicting fetal IGFs. Maternal childhood trauma (ß = -0.27; p = 0.011) and BMI (ß = -0.24; p = 0.026) remained significantly associated with fetal IGF-1. Maternal childhood trauma (ß = -0.32; p = 0.003), maternal BMI (ß = -0.30; p = 0.005) and maternal sexual abuse (ß = -0.22; p = 0.049) remained significantly associated with fetal IGF-2 and with a trend with fetal IGF-1 (ß = -0.21; p = 0.076) when excluding women with gestational diabetes. CONCLUSION: Maternal childhood trauma and BMI associate negatively with fetal IGF-1 and IGF-2 in amniotic fluid. Controlling for maternal BMI, fetal weight at birth remains associated with a trend with fetal IGF-1. The presented data suggests that childhood trauma can affect endocrine measurements of the developing next generation, providing a mechanism by which adverse maternal life events are transmitted to the next generation.

Evaluation of GLUT1, IGF-2, VEGF, FGF 1, and angiopoietin 2 in infantile hemangioma.

INTRODUCTION: Infantile hemangioma (IH) is a common vascular tumor in children. It is reported that IHs are associated with immunochemical markers such as vascular endothelial growth factor (VEGF)-A, glucose transporter isoform 1 (GLUT1), and insulin-like growth factor-2 (IGF-2). MATERIAL AND METHODS: This cross-sectional study focused on pediatric patients with IH. A total of 46 patients (mean age 14.2±21.9 months) with IH and 45 healthy controls (mean age 21.8±15.08 months) were enrolled. Demographic data, clinical findings, and laboratory parameters were recorded. Blood samples were collected. Serum GLUT1, IGF-2, VEGF-A, fibroblast growth factor 1 (FGF1), and angiopoietin 2 levels were assessed by enzyme-linked immunosorbent assay. RESULTS: Serum GLUT1, IGF-2, and VEGF-A levels were significantly higher in patients with IH than in healthy controls (8.80±4.07pg/mL vs. 5.66±4.34pg/mL, 281.10±84.12pg/mL vs. 234.19±75.38pg/mL, 1196.99±389.34pg/mL vs. 996.99±349.16pg/mL, respectively, p=0.026, p=0.030, and p=0.036). Serum GLUT1, IGF-2, and VEGF-A levels in patients with complicated hemangioma were significantly higher than in healthy controls (9.69±3.94pg/mL vs. 5.66±4.34pg/mL, 289.94±83.18pg/mL vs. 234.19±75.38pg/mL, 1276.22±388.24pg/mL vs. 996.99±349.16pg/mL, respectively, p=0.017, p=0.022, and p=0.011). Serum GLUT1, IGF-2, and VEGF-A levels in patients with hemangioma receiving propranolol treatment were significantly higher than in healthy controls. Serum FGF1 levels were higher in patients with IH, complicated hemangioma, and hemangioma receiving propranolol treatment than in healthy controls but the difference was not statistically significantly. CONCLUSION: Serum GLUT1, IGF-2, and VEGF-A levels were positively correlated with disease severity in patients with hemangioma, for example, in complicated hemangioma and hemangioma requiring propranolol treatment. However, further research on larger and different age subgroups is warranted to assess these markers.

Investigating the Relationship Between IGF-I, IGF-II, and IGFBP-3 Concentrations and Later-Life Cognition and Brain Volume.

BACKGROUND: The insulin/insulin-like signaling (IIS) pathways, including insulin-like growth factors (IGFs), vary with age. However, their association with late-life cognition and neuroimaging parameters is not well characterized. METHODS: Using data from the British 1946 birth cohort, we investigated associations of IGF-I, IGF-II and IGF binding protein 3 (IGFBP-3; measured at 53 and 60-64 years of age) with cognitive performance [word-learning test (WLT) and visual letter search (VLS) at 60-64 years and 69 years of age] and cognitive state [Addenbrooke's Cognitive Exam III (ACE-III) at 69-71 years of age], and in a proportion, quantified neuroimaging measures [whole brain volume (WBV), white matter hyperintensity volume (WMHV), hippocampal volume (HV)]. Regression models included adjustments for demographic, lifestyle, and health factors. RESULTS: Higher IGF-I and IGF-II at 53 years of age was associated with higher ACE-III scores [ß 0.07 95% confidence interval (CI) (0.02, 0.12); scoreACE-III 89.48 (88.86, 90.1), respectively). IGF-II at 53 years of age was additionally associated with higher WLT scores [scoreWLT 20 (19.35, 20.65)]. IGFBP-3 at 60 to 64 years of age was associated with favorable VLS score at 60 to 64 and 69 years of age [ß 0.07 (0.01, 0.12); ß 0.07 (0.02, 0.12), respectively], higher memory and cognitive state at 69 years of age [ß 0.07 (0.01, 0.12); ß 0.07 (0.01, 0.13), respectively], and reduced WMHV [ß -0.1 (-0.21, -0.00)]. IGF-I/IGFBP-3 at 60 to 64 years of was associated with lower VLS scores at 69 years of age [ß -0.08 (-0.15, -0.02)]. CONCLUSIONS: Increased measure in IIS parameters (IGF-I, IGF-II, and IGFBP-3) relate to better cognitive state in later life. There were apparent associations with specific cognitive domains (IGF-II relating to memory; IGFBP-3 relating to memory, processing speed, and WMHV; and IGF-I/IGFBP-3 molar ratio related to slower processing speed). IGFs and IGFBP-3 are associated with favorable cognitive function outcomes.

An antibody-free LC-MS/MS method for the quantification of intact insulin-like growth factors 1 and 2 in human plasma.

Insulin-like growth factors 1 and 2 (IGF-1 and IGF-2) are important biomarkers in research and diagnosis of growth disorders. Quantitative analysis is performed using various ligand-binding assays or enzymatic digestion LC-MS/MS methods, whose widespread adoption is hampered by time-consuming sample preparation procedures. We present a simple and fast antibody-free LC-MS/MS method for the quantification of intact IGF-1 and IGF-2 in human plasma. The method requires 50 µL of plasma and uses fully 15N-labelled IGF-1 as internal standard. It features trifluoroethanol (TFE)-based IGF/IGF-binding protein complex dissociation and a two-step selective protein precipitation workflow, using 5% acetic acid in 80/20 acetone/acetonitrile (precipitation 1) and ice-cold ethanol (precipitation 2). Detection of intact IGF-1 and IGF-2 is performed by means of a Waters XEVO TQ-S triple quadrupole mass spectrometer in positive electrospray ionisation (ESI+) mode. Lower limits of quantification were 5.9 ng/mL for IGF-1 and 8.4 ng/mL for IGF-2. Intra-assay imprecision was below 4.5% and inter-assay imprecision was below 5.8% for both analytes. An excellent correlation was found between nominal and measured concentrations of the WHO reference standard for IGF-1. Comparison with the IDS-iSYS IGF-1 immunoassay showed good correlation (R2 > 0.97), although a significant bias was observed with the immunoassay giving substantially higher concentrations. The LC-MS/MS method described here allows for reliable and simultaneous quantification of IGF-1 and IGF-2 in plasma, without the need for enzymatic digestion. The method can be readily implemented in clinical mass spectrometry laboratories and has the potential to be adapted for the analysis of different similarly sized peptide hormones.

Investigating IGF-II and IGF2R serum markers as predictors of body weight loss following an 8-week acute weight loss intervention: PREVIEW sub-study.

BACKGROUND: Weight reduction is effective in preventing T2D however, weight reduction and maintenance is difficult to achieve on a population scale. Serum insulin-like growth factor II (IGF-II) and IGF-II receptor (IGF2R) have been associated with diabetic status and body weight in prior studies and, in addition, IGF-II has been indicated as predictive of future weight change. We measured these serum markers in participants with obesity/overweight and prediabetes from the New Zealand arm of the PREVIEW lifestyle intervention randomised trial before and after an 8-week low energy diet (LED). METHODS: Total IGF-II (n = 223) and soluble IGF2R (n = 151) were measured using commercial ELISA kits on fasted serum samples taken prior to an 8-week LED and also from participants completing the LED. RESULTS: IGF-II levels were not correlated with baseline body weight although mean levels did significantly decrease following the LED. Change in IGF-II serum level was correlated to fasting glucose change (p = 0.04) but not to weight change. Baseline serum IGF2R was correlated with BMI (p = 0.007) and was significantly higher in Maori compared to European Caucasian participants independent of body weight (p = 0.0016). Following LED, IGF2R change was positively associated with weight change (p = 0.02) when corrected for ethnicity. Pre-LED levels of these serum markers were not predictive of the magnitude of weight loss over the 8 weeks. CONCLUSION: Neither marker was useful in predicting magnitude of short-term weight loss. IGF2R is positively associated with BMI and is higher in Maori compared to European Caucasian individuals.

Fibroblast Growth Factor 19 in Gestational Diabetes Mellitus and Fetal Growth.

Fibroblast growth factor 19 (FGF19) has been implicated in glucose homeostasis. Gestational diabetes mellitus (GDM) enhances fetal insulin secretion and fetal growth. Girls weigh less and are more insulin resistant than boys at birth. We sought to assess whether FGF19 is associated with GDM and fetal growth and explore potential sex dimorphic associations. This was a nested case-control study in the Shanghai Birth Cohort, including 153 pairs of newborns of GDM versus euglycemic mothers matched by infant's sex and gestational age at birth. Cord plasma FGF19, insulin, C-peptide, proinsulin, IGF-I and IGF-II concentrations were measured. Cord plasma FGF19 concentrations were similar in GDM versus euglycemic pregnancies (mean ± SD: 43.5 ± 28.2 versus 44.5 ± 30.2 pg/mL, P=0.38). FGF19 was not correlated with IGF-I or IGF-II. FGF19 concentrations were positively correlated with birth weight (r=0.23, P=0.01) and length (r=0.21, P=0.02) z scores, C-peptide (r=0.27, P=0.002) and proinsulin (r=0.27, P=0.002) concentrations in females. Each SD increment in cord plasma FGF19 was associated with a 0.25 (0.07-0.43) increase in birth weight z score in females. In contrast, FGF19 was not correlated with birth weight or length in males. These sex dimorphic associations remained after adjusting for maternal and neonatal characteristics. The study is the first to demonstrate that GDM does not matter for cord blood FGF19 concentrations. The female specific positive correlation between FGF19 and birth weight is suggestive of a sex-dimorphic role of FGF19 in fetal growth. The observations call for more studies to validate the novel findings and elucidate the underlying mechanisms.

Sex Differences in Metabolic Recuperation After Weight Loss in High Fat Diet-Induced Obese Mice.

Dietary intervention is a common tactic employed to curtail the current obesity epidemic. Changes in nutritional status alter metabolic hormones such as insulin or leptin, as well as the insulin-like growth factor (IGF) system, but little is known about restoration of these parameters after weight loss in obese subjects and if this differs between the sexes, especially regarding the IGF system. Here male and female mice received a high fat diet (HFD) or chow for 8 weeks, then half of the HFD mice were changed to chow (HFDCH) for 4 weeks. Both sexes gained weight (p < 0.001) and increased their energy intake (p < 0.001) and basal glycemia (p < 0.5) on the HFD, with these parameters normalizing after switching to chow but at different rates in males and females. In both sexes HFD decreased hypothalamic NPY and AgRP (p < 0.001) and increased POMC (p < 0.001) mRNA levels, with all normalizing in HFDCH mice, whereas the HFD-induced decrease in ObR did not normalize (p < 0.05). All HFD mice had abnormal glucose tolerance tests (p < 0.001), with males clearly more affected, that normalized when returned to chow. HFD increased insulin levels and HOMA index (p < 0.01) in both sexes, but only HFDCH males normalized this parameter. Returning to chow normalized the HFD-induced increase in circulating leptin (p < 0.001), total IGF1 (p < 0.001), IGF2 (p < 0.001, only in females) and IGFBP3 (p < 0.001), whereas free IGF1 levels remained elevated (p < 0.01). In males IGFBP2 decreased with HFD and normalized with chow (p < 0.001), with no changes in females. Although returning to a healthy diet improved of most metabolic parameters analyzed, fIGF1 levels remained elevated and hypothalamic ObR decreased in both sexes. Moreover, there was sex differences in both the response to HFD and the switch to chow including circulating levels of IGF2 and IGFBP2, factors previously reported to be involved in glucose metabolism. Indeed, glucose metabolism was also differentially modified in males and females, suggesting that these observations could be related.

Modifications of IGF2 and EGFR plasma protein concentrations in NAFLD patients after bariatric surgery.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is strictly associated with the epidemic of obesity and is becoming the most prevalent liver disease worldwide. In severe obesity, bariatric surgery (BS) is the most effective treatment not only for obesity but also for the associated metabolic co-morbidities, NAFLD, among others. To date, noninvasive diagnostic/prognostic methods cannot evaluate hepatic improvements following surgery. OBJECTIVES: We aimed to measure plasma level of insulin-growth factor-2 protein (IGF2) and epithermal growth factor receptor (EGFR), and to assess their relationship with clinical and biochemical parameters during the 12 months follow-up. METHODS: Demographic, clinical-biochemical data, and plasma IGF2 and EGFR were measured in 69 patients preoperatively (T0) and 6 and 12 months (T6M and T12M, respectively) after BS. Liver biopsy was performed at T0. Relationships between IGF2, EGFR, and several biochemical parameters were performed using Pearson or Spearman correlation analysis. RESULTS: IGF2 plasma level increases during follow-up, passing from 2.5 (1.8-15.5) at baseline to 13.3 (8.6-19.1) at T12M, p < 0.001. Conversely, EGFR showed a not significant reduction. At T12M, the plasma level of both markers was comparable to those of lean subjects. The clinical-biochemical parameters (BMI, glycated hemoglobin, HOMA-IR) also return to the normal range at T12M. Correlation analysis demonstrated that IGF2 was significantly associated with total bilirubin, direct bilirubin, and albumin at T0 while with blood glucose, ALT, GGT, and AST/ALT ratio at T6M and T12M. CONCLUSIONS: IGF2 plasma levels increase after bariatric surgery, and these changes are associated with the modification of hepatic biochemical parameters, even if other clinic or metabolic improvements cannot be excluded.

Epigenetic characterization of the H19/IGF2 locus in calf clones placenta / Caracterização epigenética do locus H19/IGF2 na placenta de bezerros clones

Somatic Cell Nuclear Transfer (SCNT-Cloning) is a promising technique in many areas and is based on genetically identical individuals. However, its efficiency is low. Studies suggest that the leading cause is inadequate epigenetic reprogramming. This study aimed to characterize the methylation pattern of the exon 10 regions of the IGF2 gene and the Imprinting Control Region (ICR) of the H19 gene in the placenta of cloned calves. For this study, female and male cloned calves presenting different phenotypes were used. Genomic DNA from these animals' placenta was isolated, then treated with sodium bisulfite and amplified to the ICR/H19 and IGF2 loci. PCR products were cloned into competent bacteria and finally sequenced. A significant difference was found between controls and clones with healthy phenotypes for the ICR/H19 region. In this region, controls showed a hemimethylated pattern, as predicted in the literature due to this region has an imprinted control, while clones were showed less methylated. For the IGF2, no significant differences were found between controls and clones. These results suggest that different genomic regions in the genome may be independently reprogrammed and that failures in reprogramming the DNA methylation patterns of imprinted genes may be one of the causes of the low efficiency of SCNT.(AU)

A Transferência Nuclear de Células Somáticas (TNCS-Clonagem) é uma técnica promissora em várias áreas, e se baseia na produção de indivíduos geneticamente idênticos. No entanto, sua eficiência é baixa. Estudos sugerem que a principal causa seja uma reprogramação epigenética inadequada. O objetivo desse trabalho é caracterizar o padrão de metilação da região éxon 10 do gene IGF2 e da Região Controladora de Imprinting (ICR) do gene H19 na placenta de bezerros clonados. Para a execução do trabalho foram selecionados clones bovinos fêmeas e machos, apresentando diferentes fenótipos. O DNA da placenta desses animais foi extraído, e em seguida foi tratado com bissulfito de sódio e amplificado para os loci ICR/H19 e IGF2. Os produtos da PCR foram clonados em bactérias competentes e, por fim, sequenciados. Foi encontrada uma diferença significativa entre os controles e os clones com fenótipos saudáveis para a região da ICR/H19. Nesta região, os controles tiveram um padrão hemimetilado, como previsto pela literatura, devido essa região ser imprinted. Enquanto os clones encontravam-se menos metilados. Para a região do éxon 10 do IGF2, não foi encontrada diferença significativa entre controles e clones. Estes resultados sugerem que as diferentes regiões do genoma podem se reprogramar independente umas das outras e que falhas na reprogramação do padrão de metilação do DNA de genes imprinted podem ser uma das causas da baixa eficiência da TNCS.(AU)

Serum minerals (Ca, P, Co, Mn, Ni, Cd) and growth hormone (IGF-1 and IGF-2) levels in postmenopausal Saudi women with osteoporosis.

Osteoporosis is reported to be common among Saudi women. Several minerals appear to be important determinants of insulin-like growth factor (IGF), the bioactivity of which regulates bone and mineral metabolism. Here we proposed that mineral status may alter the IGF system among individuals with osteoporosis. This study aims to evaluate the relationships between essential elements and IGF levels among postmenopausal Saudi women with osteoporosis. A total of 128 postmenopausal Saudi women aged ≥50 years old were recruited in this study. Diagnosis of osteoporosis was done by using dual-energy x-ray absorptiometry to determine the bone minerals density (BMD). Serum calcium and phosphate were determined using routine chemical analyzer. Serum Co, Mn, Ni, Cd were measured using inductively coupled plasma mass spectrometry. Serum IGF-1 and IGF-2 were determined using Luminex xMAP. Using stepwise linear regression analysis, only Cd was identified to be significantly associated with IGF1 in osteoporosis, explaining 3% (confidence interval 0.01-0.05; P = 0001) of the variance perceived. Our results suggest that Cd exposure indirectly affects BMD which may increase the risk of osteoporosis in postmenopausal women. Further longitudinal study using a larger sample size is recommended to determine causality of Cd levels and IGF-1.

Altered insulin-like growth factor-2 signaling is associated with psychopathology and cognitive deficits in patients with schizophrenia.

BACKGROUND: Schizophrenia is linked with abnormal brain neurodevelopment, on which IGF-2 (insulin-like growth factor-2) has a great impact. The purpose of this study was to assess the levels of serum IGF-2 and its binding proteins IGFBP-3 and IGFBP-7 in schizophrenia patients and the associations of these proteins with schizophrenia psychopathology and cognitive deficits. METHODS: Thirty-two schizophrenia patients and 30 healthy controls were recruited. The PANSS and a neurocognitive test battery were used to assess schizophrenic symptomatology and cognition, respectively. Serum IGF-2, IGFBP-3 and IGFBP-7 levels were determined using ELISA. RESULTS: The schizophrenia patients had a much lower content of serum IGF-2, IGFBP-3 and IGFBP-7 than controls. For the patients, IGF-2 levels were negatively correlated with the PANSS negative scores and positively associated with working memory, attention, and executive function. The correlations between IGF-2 and the PANSS negative scores, working memory or executive function were still significant after controlling for age, sex, education level, BMI, illness history and age of onset. No significant associations of IGFBP-3 or IGFBP-7 with the PANSS scores and cognitive function were observed in the patients. CONCLUSIONS: Our study demonstrates that serum IGF-2 was significantly correlated with negative and cognitive symptoms in patients with schizophrenia, suggesting that altered IGF-2 signaling may be implicated in the psychopathology and cognitive deficits in schizophrenia.

Fetuin-A and fetal growth in gestational diabetes mellitus.

OBJECTIVE: Fetuin-A is a glycoprotein produced by hepatocytes and has been associated with insulin resistance and bone growth in postnatal life. Gestational diabetes mellitus (GDM) is a condition characterized by insulin resistance. It is unclear whether GDM may affect cord blood fetuin-A levels and whether fetuin-A is associated with fetal growth. RESEARCH DESIGN AND METHODS: In a nested case-control study of 153 matched pairs of neonates of mothers with GDM and euglycemic pregnancies in the Shanghai Birth Cohort, we evaluated cord blood fetuin-A in association with GDM and fetal growth. RESULTS: Comparing the newborns of GDM versus euglycemic mothers, cord blood fetuin-A concentrations were similar (mean±SD: 783.6±320.0 vs 754.8±281.9 µg/mL, p=0.53), while insulin-like growth factor (IGF)-I (76.6±27.8 ng/mL vs 68.1±25.1 ng/mL, p=0.008) and IGF-II (195.3±32.5 ng/mL vs 187.5±30.8 ng/mL, p=0.042) concentrations were higher. Cord blood fetuin-A was not correlated with insulin, IGF-I or IGF-II. Cord blood fetuin-A was negatively correlated with birth weight (r=-0.19, p=0.025) and birth length (r=-0.24, p=0.005) z scores in GDM pregnancies, while there were no significant correlations in euglycemic pregnancies (tests for interaction: p=0.014 for birth length, p=0.013 for birth length). Adjusting for maternal and neonatal characteristics, the differential associations remained. CONCLUSIONS: GDM was not associated with cord blood fetuin-A levels. Fetuin-A was negatively associated with fetal growth in GDM but not in euglycemic pregnancies. This novel observation suggests a GDM-conditional negative correlation of fetuin-A with fetal growth.

Polygenic Profile and Exercise-Induced Muscle Damage by a Competitive Half-Ironman.

Del Coso, J, Salinero, JJ, Lara, B, Gallo-Salazar, C, Areces, F, Herrero, D, and Puente, C. Polygenic profile and exercise-induced muscle damage by a competitive half-ironman. J Strength Cond Res 34(5): 1400-1408, 2020-To date, it is still unknown why some individuals develop higher levels of muscle damage than other individuals, despite participating in exercise with comparable levels of physical intensity. The aim of this investigation was to analyze 7 single-nucleotide polymorphisms (SNPs) that are candidates to explain individual variations in the level of muscle damage attained during a half-ironman competition. Using the model of Williams and Folland (2, 1, and 0 points for optimal, intermediate, and suboptimal genotype), we determined the total genotype score from the accumulated combination of 7 SNPs (ACE = 287bp Ins/Del; ACTN3 = p.R577X; creatine kinase, muscle type = NcoI; insulin-like growth factor 2 = C13790G; interleukin-6 = 174G>C; myosin light chain kinase = C37885A; and tumor necrosis factor-α = 308G>A) in 22 experienced triathletes. Before and after the race, a sample of venous blood was obtained to measure serum markers of muscle damage. Two groups of triathletes were established according to their postcompetition serum CK concentration: low CK responders (n = 10; 377 ± 86 U·L) vs. high CK responders (n = 12; 709 ± 136 U·L). At the end of the race, low CK responders had lower serum myoglobin concentrations (384 ± 243 vs. 597 ± 293 ng·ml, p = 0.04). Although the groups were similar in age, anthropometric characteristics, and training habits, total genotype score was higher in low CK responders than in high CK responders (7.7 ± 1.1 vs. 5.5 ± 1.1 point, p < 0.01). A favorable polygenic profile can contribute to reducing the level of muscle damage developed during endurance exercise.

Long non-coding RNA SNHG16 promotes lipopolysaccharides-induced acute pneumonia in A549 cells via targeting miR-370-3p/IGF2 axis.

BACKGROUND: Pneumonia is an infectious lung inflammation in children with high mortality and morbidity rates. Small nucleolar RNA host gene 16 (SNHG16) has been verified to accelerate the progression of acute pneumonia. However, the role of SNHG16 in acute pneumonia has not yet been fully elucidated. The study was aimed to explore the regulatory mechanism of SNHG16 in LPS-induced acute pneumonia in A549 cells. METHODS: The levels of SNHG16, miR-370-3p and IGF2 in serum samples and LPS-induced A549 cells were detected by quantitative real-time polymerase chain reaction (qRT-PCR). The cell viability and apoptosis of A549 cells were examined by Cell Counting Kit-8 (CCK-8) assay and flow cytometer, respectively. The levels of interleukin 1ß (IL-1ß), interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α) were determined by enzyme-linked immunosorbent assay (ELISA). The binding relationships among SNHG16, miR-370-3p and IGF2 were predicted by online database and verified by Dual-luciferase reporter and RNA immunoprecipitation (RIP) assays. The protein levels of IGF2 were tested by Western blot. RESULTS: SNHG16 and IGF2 were upregulated while miR-370-3p was downregulated in serum of acute pneumonia patients and LPS-induced A549 cells. SNHG16 regulated proliferation, apoptosis and inflammatory cytokines by inhibiting miR-370-3p in LPS-induced A549 cells. MiR-370-3p targeted IGF2 and inhibited LPS-induced inflammatory injury via IGF2 in A549 cells. Furthermore, SNHG16 was verified to promote IGF2 expression by sponging miR-370-3p in A549 cells. CONCLUSION: SNHG16 impeded cell viability and promoted apoptosis, inflammatory injury by targeting IGF2 mediated by miR-370-3p in LPS-induced A549 cells.