Endocrine Abstracts

Background/aims: The transcription factor neurogenin 3 (NGN3) is required for pancreatic islet cell specification from multipotent progenitor cells; yet we have limited understanding of the downstream genetic program it directly initiates. A 3 Mb centromeric region on chromosome 20p contains a number of genes activated downstream of NGN3 including INSM1 and NKX2.2. We proposed that NGN3 alters the expression of other genes within this region as poten...

Glucocorticoids (GCs) are potent anti-inflammatory agents, but a variable therapeutic response occurs. We have used microarray analysis to explore the basis for inter-individual differences in the GC sensitivity of a healthy volunteer population, and identified genes predictive of response to GCs. Three such discriminating genes were then selected to be investigated for their potential to interact with the Glucocorticoid Receptor (GR). These are the Bone Morphogenetic Protein ...

The incretin hormone glucagon-like peptide-1 (GLP-1) has been proposed to increase beta cell mass, via effects on proliferation, apoptosis and neogenesis. However, the role of GLP-1 during normal human development is unclear. We have addressed this in human fetuses by quantifying GLP-1 secretion during fetal development and determining how GLP-1 signalling impacts on early human fetal pancreas in explant culture.GLP-1 is first secreted by the stomach, du...

Rheumatoid arthritis (RA) is a common chronic systemic inflammatory disease. Several new therapies exist for RA but long-term patient management remains problematic.We have discovered that hypoxia, a characteristic of inflamed tissues, potently inhibits glucocorticoid (Gc) sensitivity. This effect is mediated, in part by HIF1α, whose activity is induced in hypoxia. HIF1α gene expression is also induced in primary peripheral blood mononuclear ce...

Many glucocorticoid (Gc) actions are of rapid onset, and therefore require acute regulation of intracellular signalling cascades. We have previously identified rapid Gc-dependent activation of the caveolae specific integral membrane protein caveolin, and the cytosolic kinase PKB in the lung epithelial cells, A549.Immunofluorescence studies demonstrate the appearance of activated glucocorticoid receptor (P-ser211-GR) localised to focal points around the c...

Synthetic peroxisome proliferator-activated receptor gamma (PPARγ) ligands are used clinically to improve insulin sensitivity. Although designed as specific ligands for PPARγ, there is evidence for some ‘off target’ effects being mediated by a non-classical, non-PPARγ mechanism. Recent evidence further suggests that some of these effects may be glucocorticoid receptor (GR)-dependent.To analyse activation of GR following exposure ...

Glioblastoma (GBM) is a highly aggressive form of brain cancer with a median survival time of 12–15 months from diagnosis. Standard therapies utilise a combination of radiotherapy, chemotherapy, and surgery. Patients also receive high doses of the potent anti-inflammatory glucocorticoid (Gc), Dexamethasone (Dex).Recent studies show that patients receiving the highest dose of Dex also have reduced survival time. Defining pathways under Gc control relevant to GBM is necessa...

Congenital adrenal hyperplasia due to P450 oxidoreductase (POR) deficiency (ORD) results in disordered sex development (DSD) in individuals of both sexes. POR provides electrons to CYP17A1 thereby facilitating synthesis of the major androgen precursor dehydroepiandrosterone (DHEA). ORD disrupts this enzymatic step, resulting in deficient synthesis of 5α-dihydrotestosterone (DHT) via DHEA, readily explaining undervirilisation (46,XY DSD) in male ORD neonates. Female virili...

Understanding how fate choices are made by multipotent progenitors during pancreas development is valuable information in the quest for regenerative medicine and cell therapy to treat diabetes mellitus. Pancreatic differentiation is well defined and understood in rodents however, human data are comparably scarce. Specifically, when human pancreatic progenitors are multipotent is unknown as are the epigenetic changes that these cells undergo during their differentiation to beta...

Synthetic glucocorticoids (Gc) are the most potent anti-inflammatory agents known and are widely used to treat a range of chronic inflammatory diseases including rheumatoid arthritis and asthma. However their therapeutic utility is limited by the development of Gc resistance over time – particularly at sites of inflammation. Understanding the underlying mechanisms that control Gc sensitivity is essential to overcome this. Previous studies have measured the average transcr...