Suet Ching Chen

Metformin suppresses adipogenesis through both AMP-activated protein kinase (AMPK)-dependent and AMPK-independent mechanisms

People with Type 2 diabetes mellitus (T2DM) have reduced bone mineral density and an increased risk of fractures due to altered mesenchymal stem cell (MSC) differentiation in the bone marrow. This leads to a shift in the balance of differentiation away from bone formation (osteogenesis) in favour of fat cell development (adipogenesis). The commonly used anti-diabetic drug, metformin, activates the osteogenic transcription factor Runt-related transcription factor 2 (Runx2), which may suppress adipogenesis, leading to improved bone health. Here we investigate the involvement of the metabolic enzyme, AMP-activated protein kinase (AMPK), in these protective actions of metformin. The anti-adipogenic actions of metformin were observed in multipotent C3H10T1/2 MSCs, in which metformin exerted reciprocal control over the activities of Runx2 and the adipogenic transcription factor, PPARγ, leading to suppression of adipogenesis. These effects appeared to be independent of AMPK activation but rather through the suppression of the mTOR/p70S6K signalling pathway. Basal AMPK and mTOR/p70S6K activity did appear to be required for adipogenesis, as demonstrated by the use of the AMPK inhibitor, compound C. This observation was further supported by using AMPK knockout mouse embryo fibroblasts (MEFs) where adipogenesis, as assessed by reduced lipid accumulation and expression of the adipogeneic transcription factor, C/EBPβ, was found to display an absolute requirement for AMPK. Further activation of AMPK in wild type MEFS, with either metformin or the AMPK-specific activator, A769662, was also associated with suppression of adipogenesis. It appears, therefore, that basal AMPK activity is required for adipogenesis and that metformin can inhibit adipogenesis through AMPK-dependent or -independent mechanisms, depending on the cellular context.

Factors influencing uptake of influenza A (H1N1) vaccine amongst healthcare workers in a regional pediatric centre: lessons for improving vaccination rates.

BACKGROUND Influenza A (H1N1) vaccination has been recommended for all frontline healthcare workers (HCWs) in the UK since October 2009, to protect individuals and their patients from infection. Understanding the factors influencing vaccine uptake by HCW may improve future vaccination programmes in current and subsequent years. AIMS To assess the uptake of influenza A (H1N1) vaccine, and factors affecting vaccine uptake, in frontline healthcare workers in a large pediatric hospital. METHOD A cross-sectional questionnaire survey conducted in a regional Pediatric Hospital in Scotland incorporating intensive care and ECMO services. One page, anonymised questionnaires were distributed to all frontline HCW in high risk departments of the hospital. RESULTS 260 questionnaires were completed, capturing an estimated 52% of all staff. Vaccination rate was 49.6%, and was significantly higher amongst doctors (OR 2.4, 95% CI 1.3-4.5, P=0.005). Commonest reasons for vaccine uptake were high risk of contact with H1N1 (88%) and responsibility to protect patients (71%). Uncertainty about vaccine side-effects (47%), concern about vaccine safety (33%) and being too busy to attend the vaccine clinic (22%) were the commonest reasons for non-vaccination. Reasons for vaccination varied between staff grouping and department. 36% of non-vaccinated staff would accept the vaccine if offered. CONCLUSIONS Vaccine uptake may be increased by addressing HCW knowledge and attitudes and access to vaccine. Future vaccination programmes should include targeted education and vaccine delivery, at the convenience of staff, and in their own department.

Corrigendum to “Metformin suppresses adipogenesis through both AMP-activated protein kinase (AMPK)-dependent and AMPK-independent mechanisms” [Mol. Cell. Endocrinol. 440 15 January 2017 57–68]

Corrigendum to “Metformin suppresses adipogenesis through both AMP-activated protein kinase (AMPK)-dependent and AMPKindependent mechanisms” [Mol. Cell. Endocrinol. 440 15 January 2017 57e68] S.C. Chen a, , R. Brooks , J. Houskeeper , S.K. Bremner , J. Dunlop , B. Viollet c, d, , P.J. Logan , I.P. Salt , S.F. Ahmed , S.J. Yarwood g, * a The Developmental Endocrinology Research Group, School of Medicine, University of Glasgow, Glasgow G51 4TF, UK b Institute of Molecular, Cell and Systems Biology, University Avenue, University of Glasgow, Glasgow G12 8QQ, UK c INSERM, U1016, Institut Cochin, Paris, France d CNRS, UMR8104, Paris, France e Universit e Paris Descartes, Sorbonne Paris Cit e, France f Institute of Cardiovascular and Medical Sciences, University Avenue, University of Glasgow, Glasgow G12 8QQ, UK g Institute of Biological Chemistry, Biophysics and Bioengineering, Edinburgh Campus, Heriot-Watt University, Edinburgh EH14 4AS, UK

Predicting, Monitoring, and Managing Hypercalcemia Secondary to 13-Cis-Retinoic Acid Therapy in Children With High-risk Neuroblastoma.

13-cis-retinoic acid is an established component of treatment for children with high-risk neuroblastoma. However, significant hypercalcemia is increasingly recognized as a potentially life-threatening dosage-related side effect. We present 2 patients with significant hypercalcemia secondary to 13-cis-retinoic acid and their management, and identified the predictive factors for susceptibility to hypercalcemia. Assessing glomerular filtration rate and concomitant medication help predict individual susceptibility to hypercalcemia. Calcium levels should be monitored at days 1, 7, and 14 of each course of retinoic acid. An algorithm for the management of hypercalcemia during the affected and subsequent cycles of retinoid therapy is proposed.

Early identification of pituitary dysfunction in congenital nasal pyriform aperture stenosis: recommendations based on experience in a single centre.

Background: Congenital nasal pyriform aperture stenosis (CNPAS) is an increasingly recognised cause of upper airway obstruction associated with midline abnormalities. Studies have described pituitary dysfunction in 40% of patients. We aimed to develop guidelines for: (a) the early identification of pituitary insufficiency to minimise surgical risk and (b) to stratify patients for follow-up. Methods: Retrospective case note review of patients with CNPAS between 2000 and 2014 in a tertiary paediatric unit. Results: 20 patients (12 female:8 male) were analysed; 16 were diagnosed during the neonatal period while 4 were diagnosed later. There was no consistent approach in the evaluation of the pituitary axis at diagnosis. Pituitary dysfunction was identified in 3 (15%) patients, 2 of whom were found during evaluation of short stature in mid-late childhood. Hypoglycaemia and conjugated hyperbilirubinaemia, but not the degree of stenosis, were highly predictive of pituitary dysfunction (p < 0.05). Available height standard deviation score (SDS) data at 1 year of 70% of our patients identified both of the late-diagnosed growth hormone-deficient patients, with SDS of -2.6 and -3.6, respectively. Conclusion: All CNPAS patients should have MRI of the brain and baseline endocrine investigations at diagnosis. Growth monitoring for at least 1 year is recommended as low, or falling, height SDS at 1 year is a good predictor of pituitary dysfunction.

An update on diabetes related skeletal fragility

There are several mechanisms by which diabetes could affect bone mass and strength. These mechanisms include insulin deficiency; hyperglycemia; the accumulation of advanced glycation end products that may influence collagen characteristics; marrow adiposity and bone inflammation. Furthermore, associated diabetic complications and treatment with thaizolidinediones may also increase risk of fracturing. The following article provides its readers with an update on the latest information pertaining to diabetes related bone skeletal fragility. In the authors’ opinion, future studies are needed in order to clarify the impact of different aspects of diabetes metabolism, glycemic control, and specific treatments for diabetes on bone. Given that dual energy x-ray absorptiometry is a poor predictor of bone morbidity in this group of patients, there is a need to explore novel approaches for assessing bone quality. It is important that we develop a better understanding of how diabetes affects bone in order to improve our ability to protect bone health and prevent fractures in the growing population of adults with diabetes.

Metformin regulates the differentiation of murine mesenchymal stem cells via AMPK-independent suppression of p70s6-kinase

? ? Metformin regulates the differentiation of murine mesenchymal stem cells via AMPK-independent suppression of p70s6-kinase SC Chen1, R Brooks1, SF Ahmed1, SJ Yarwood2 1 Developmental Endocrinology Research Group, Royal Hospital for Sick Children, School of Medicine, University of Glasgow, UK 2 Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, UK