Insulin and IGF1 signalling pathways in human astrocytes <i>in vitro</i> and <i>in vivo</i>; characterisation, subcellular localisation and modulation of the receptors.

Background The insulin/IGF1 signalling (IIS) pathways are involved in longevity regulation and are dysregulated in neurons in Alzheimer’s disease (AD). We previously showed downregulation in IIS gene expression in astrocytes with AD-neuropathology progression, but IIS in astrocytes remains poorly understood. We therefore examined the IIS pathway in human astrocytes and developed models to reduce IIS at the level of the insulin or the IGF1 receptor (IGF1R). Results We determined IIS was present and functional in human astrocytes by immunoblotting and showed astrocytes express the insulin receptor (IR)-B isoform of Ir. Immunocytochemistry and cell fractionation followed by western blotting revealed the phosphorylation status of insulin receptor substrate (IRS1) affects its subcellular localisation. To validate IRS1 expression patterns observed in culture, expression of key pathway components was assessed on post-mortem AD and control tissue using immunohistochemistry. Insulin signalling was impaired in cultured astrocytes by treatment with insulin + fructose and resulted in decreased IR and Akt phosphorylation (pAkt S473). A monoclonal antibody against IGF1R (MAB391) induced degradation of IGF1R receptor with an associated decrease in downstream pAkt S473. Neither treatment affected cell growth or viability as measured by MTT and Cyquant® assays or GFAP immunoreactivity. Discussion IIS is functional in astrocytes. IR-B is expressed in astrocytes which differs from the pattern in neurons, and may be important in differential susceptibility of astrocytes and neurons to insulin resistance. The variable presence of IRS1 in the nucleus, dependent on phosphorylation pattern, suggests the function of signalling molecules is not confined to cytoplasmic cascades. Down-regulation of IR and IGF1R, achieved by insulin + fructose and monoclonal antibody treatments, results in decreased downstream signalling, though the lack of effect on viability suggests that astrocytes can compensate for changes in single pathways. Changes in signalling in astrocytes, as well as in neurons, may be important in ageing and neurodegeneration

Latent trajectories of adaptive behaviour in infants at high and low familial risk for autism spectrum disorder

Background: Autism Spectrum Disorder (ASD) is characterized by persisting difficulties in everyday functioning. Adaptive behaviour is heterogeneous across individuals with ASD, and it is not clear to what extent early development of adaptive behaviour relates to ASD outcome in toddlerhood. This study aims to identify subgroups of infants based on early development of adaptive skills and investigate their association with later ASD outcome. Methods: Adaptive behaviour was assessed on infants at high (n=166) and low (n=74) familial risk for ASD between 8 and 36 months using the Vineland Adaptive Behavior Scales (VABS-II). The four domains of VABS-II were modelled in parallel using growth mixture modelling to identify distinct classes of infants based on adaptive behaviour. Then, we associated class membership with clinical outcome and ASD symptoms at 36 months, and longitudinal measures of cognitive development. Results: We observed three classes characterised by: decreasing trajectories below age-appropriate norms (8.3%); stable trajectories around age-appropriate norms (73.8%); increasing trajectories reaching average scores by age 2 (17.9%). Infants with declining adaptive behaviour had a higher risk [odd ratio, OR=4.40 (confidence interval, CI: 1.90; 12.98)] for ASD and higher parent-reported symptoms in the social, communication and repetitive behaviour domains at 36 months. Furthermore, there was a discrepancy between adaptive and cognitive functioning as the class with improving adaptive skills showed stable cognitive development around average scores. Conclusions: Findings confirm the heterogeneity of trajectories of adaptive functioning in infancy, with a higher risk for ASD in toddlerhood linked to a plateau in the development of adaptive functioning after the first year of life

Disordered Eating, Food Insecurity, and Weight Status Among Transgender and Gender Nonbinary Youth and Young Adults: A Cross-Sectional Study Using a Nutrition Screening Protocol

Purpose: The purpose of this study was to describe the prevalence of and relationships among disordered eating, food insecurity, and weight status among transgender and gender nonbinary youth and young adults. Methods: This cross-sectional study involved a screening protocol to assess disordered eating and food insecurity risk from September to December of 2019 at a gender clinic using five validated measures: (1) previous eating disorder diagnosis (yes/no); (2) Sick, Control, One Stone, Fat, Food Questionnaire (SCOFF); (3) Adolescent Binge Eating Disorder Questionnaire (ADO-BED); (4) Nine-Item Avoidant/Restrictive Food Intake Disorder Screen (NIAS); and (5) Hunger Vital Sign. Age, assigned sex at birth, gender identity, stage of medical transition, and body mass index were collected. Pearson\u27s r correlation coefficients, between-groups t-tests, one-way analysis of variance tests, and Tukey\u27s honest significant difference test were used to characterize the relationships between variables. Results: A total of 164 participants ages 12–23 years completed the screener. Using assigned sex at birth, 1.8% were underweight, 53% were a healthy weight, 17.1% were overweight, and 28.0% were obese. An estimated 8.7% reported a previous eating disorder diagnosis, 28.0% screened positive on the SCOFF, 9.1% on the ADO-BED, 75.0% on the NIAS, and 21.2% on the Hunger Vital Sign. Transgender males scored higher on the NIAS than transgender females (p = 0.03). Those with a previous eating disorder diagnosis scored significantly higher on the Hunger Vital Sign (p \u3c 0.05). Conclusion: Gender clinics should routinely screen for disordered eating, food insecurity, overweight, and obesity to identify patients in need of further evaluation and referral

Disordered eating, food insecurity, and weight status among transgender and gender nonbinary youth and young adults: A Cross-sectional study using a nutrition screening protocol

Purpose: The purpose of this study was to describe the prevalence of and relationships among disordered eating, food insecurity, and weight status among transgender and gender nonbinary youth and young adults. Methods: This cross-sectional study involved a screening protocol to assess disordered eating and food insecurity risk from September to December of 2019 at a gender clinic using five validated measures: (1) previous eating disorder diagnosis (yes/no); (2) Sick, Control, One Stone, Fat, Food Questionnaire (SCOFF); (3) Adolescent Binge Eating Disorder Questionnaire (ADO-BED); (4) Nine-Item Avoidant/Restrictive Food Intake Disorder Screen (NIAS); and (5) Hunger Vital Sign. Age, assigned sex at birth, gender identity, stage of medical transition, and body mass index were collected. Pearson\u27s r correlation coefficients, between-groups t-tests, one-way analysis of variance tests, and Tukey\u27s honest significant difference test were used to characterize the relationships between variables. Results: A total of 164 participants ages 12–23 years completed the screener. Using assigned sex at birth, 1.8% were underweight, 53% were a healthy weight, 17.1% were overweight, and 28.0% were obese. An estimated 8.7% reported a previous eating disorder diagnosis, 28.0% screened positive on the SCOFF, 9.1% on the ADO-BED, 75.0% on the NIAS, and 21.2% on the Hunger Vital Sign. Transgender males scored higher on the NIAS than transgender females (p = 0.03). Those with a previous eating disorder diagnosis scored significantly higher on the Hunger Vital Sign (p \u3c 0.05). Conclusion: Gender clinics should routinely screen for disordered eating, food insecurity, overweight, and obesity to identify patients in need of further evaluation and referral