An ancient polymorphic regulatory region within the BDNF gene associated with obesity modulates anxiety-like behaviour in mice and humans (preprint)

Obesity and anxiety are morbidities notable for their increased impact on society during the recent COVID-19 pandemic. Understanding the mechanisms governing susceptibility to these conditions will increase quality of life and our resilience to future pandemics. In the current study we explored the function of a highly conserved regulatory region (BE5.1) within the BDNF gene that harbours a polymorphism strongly associated with obesity (rs10767664; p = 4.69x10− 26). Analysis in primary cells suggested that the major T-allele of BE5.1 was an enhancer whereas the obesity associated A-allele was not. However, CRISPR/CAS9 deletion of BE5.1 from the mouse genome (BE5.1KO) produced no significant effect on the expression of BDNF transcripts in the hypothalamus, no change in weight gain after 28 days and only a marginally significant increase in food intake. Nevertheless, transcripts were significantly increased in the amygdala of female mice and elevated zero maze and marble burying tests demonstrated a significant increase in anxiety-like behaviour that could be reversed by diazepam. Consistent with these observations, human GWAS cohort analysis demonstrated a significant association between rs10767664 and anxiousness in human populations. Intriguingly, interrogation of the human GTEx eQTL database demonstrated no effect on BDNF mRNA levels associated with rs10767664 but a highly significant effect on BDNF-antisense (BDNF-AS) gene expression and splicing. The subsequent observation that deletion of BE5.1 also significantly reduced BDNF-AS expression in mice suggests a novel mechanism in the regulation of BDNF expression common to mice and humans which contributes to the modulation of mood and anxiety in both species.

Use of a Continuous Glucose Monitoring System in High-Risk Hospitalized Noncritically Ill Patients With Diabetes After Cardiac Surgery and During Their Transition of Care From the Intensive Care Unit During COVID-19: A Pilot Study.

OBJECTIVE: Continuous glucose monitoring (CGM) has demonstrated benefits in managing inpatient diabetes. We initiated this single-arm pilot feasibility study during the COVID-19 pandemic in 11 patients with diabetes to determine the feasibility and accuracy of real-time CGM in patients who underwent cardiac surgery and whose care was being transitioned from the intensive care unit. METHODS: A Clarke error grid analysis was used to compare CGM and point-of-care measurements. The mean absolute relative difference (MARD) of the paired measurements was calculated to assess the accuracy of CGM for glucose measurements during the first 24 hours on CGM, the remaining time on CGM, and for different chronic kidney disease (CKD) strata. RESULTS: Overall MARD between point-of-care and CGM measurements was 14.80%. MARD for patients without CKD IV and V with an estimated glomerular filtration rate (eGFR) of ≥20 mL/min/1.73 m2 was 12.13%. Overall, 97% of the CGM values were within the no-risk zone of the Clarke error grid analysis. For the first 24 hours, a sensitivity analysis of the overall MARD for all patients and those with an eGFR of ≥20 mL/min/1.73 m2 was 15.42% ± 14.44% and 12.80% ± 7.85%, respectively. Beyond the first 24 hours, overall MARD for all patients and those with an eGFR of ≥20 mL/min/1.73 m2 was 14.54% ± 13.21% and 11.86% ± 7.64%, respectively. CONCLUSION: CGM has shown great promise in optimizing inpatient diabetes management in the noncritical care setting and after the transition of care from the intensive care unit with high clinical reliability and accuracy. More studies are needed to further assess CGM in patients with advanced CKD.