Searchable abstracts of presentations at key conferences in endocrinology

ea0019oc12 | Neuroendocrine and Steroids | SFEBES2009

Absence of hexose-6-phosphate dehydrogenase specifically induces skeletal myopathy in mice

Semjonous N , Lavery G , Walker E , Stewart P

Murine 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) catalyses the conversion of inactive 11-dehydrocorticosterone (A) to active corticosterone (B) and plays a key role in metabolic homeostasis. The directionality of this enzyme is dependent upon the presence of NADPH, a cofactor produced by hexose-6-phosphate dehydrogenase (H6PDH). In accord with this, H6PDH KO mice have no reductase and increased dehydrogenase activity of 11βHSD1. Interestingly, H6PDH KO m...

ea0019p330 | Steroids | SFEBES2009

Glucocorticoid regulation of 11β-hydroxysteroid dehydrogenase type 1 in dermal fibroblasts

Tiganescu A , Dekker P , Mayes A E , Stewart P , Walker E A

Topical glucocorticoid therapy causes adverse effects in human skin including a reduction in dermal fibroblast proliferation and extracellular matrix protein secretion (e.g. collagen 1) and epidermal thinning – effects paralleled in photoexposed and elderly skin. These cause reduced wound healing rates and a loss of elasticity with increased fragility and transepidermal water loss – signs also typical of Cushing’s syndrome characterised by raised circulating cor...

ea0009p17 | Diabetes and metabolism | BES2005

Targeted inactivation of hexose-6-phosphate dehydrogenase (H6PDH) results in impaired reactivation of glucocorticoids and endorses a pivotal role for H6PDH in regulating 11beta-hydroxysteroid dehydrogenase type 1

Lavery G , Draper N , Parker K , Walker E , Stewart P

Glucocorticoid excess results in central obesity and insulin resistance/diabetes mellitus. At a pre-receptor level, 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) modulates glucocorticoid levels and has been implicated in the pathogenesis of the metabolic syndrome. 11beta-HSD1 is a bi-directional NADP(H) dependant enzyme, but keto-reductase activity predominates in-vivo. Recent studies indicate that the enzyme H6PDH ensures reductive metabolism (cortisone to c...

ea0009p130 | Steroids | BES2005

Refolding and purification of recombinant human hexose-6-phosphate dehydrogenase from bacterial inclusion bodies

Walker O , Walker E , Stewart P , Ride J

11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) has been implicated in the pathogenesis of human obesity and insulin resistance through 11-oxoreductase activation of cortisone (E) to cortisol (F) within the endoplasmic reticulum (ER) of adipocytes and hepatocytes. In its purified state 11beta-HSD1 is principally a dehydrogenase, converting F to E. Oxo-reductase activity can be regained by the addition of an NADPH regeneration system. In vivo hexose-6-phosphate ...

ea0007p219 | Steroids | BES2004

Hexose 6-phosphate dehydrogenase expression confers reductase activity upon 11 beta-HSD1 in adipose tissue

Bujalska I , Tomlinson J , Draper N , Walker E , Stewart P

Glucocorticoids are an important adipogenic factor. In man, circulating cortisol excess causes visceral obesity, but in simple obesity glucocorticoid levels are usually normal. However, in adipose tissue cortisol availability to bind to the glucocorticoid receptor (GR) is modulated by 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD1). Human preadipocytes display both dehydrogenase (cortisol to cortisone) and oxo-reductase (cortisone to cortisol) activity. Recent genet...

ea0005p219 | Steroids | BES2003

Mutagenesis studies on recombinant human 11beta-hydroxysteroid dehydrogenase type 1

Walker E , Hughes S , Ride J , Hewison M , Stewart P

11beta-hydroxysteroid dehydrogenase type 1 (11B-HSD1) catalyses the inter-conversion of cortisone and cortisol, and has been implicated in the pathogenesis of a number of disorders including insulin resistance and obesity. The enzyme is a glycosylated membrane-bound protein, located in the lumen of the endoplasmic reticulum (ER) and has proved difficult to purify in an active state. Previously, we reported the successful expression and purification of human 11B-HSD1 from E. co...

ea0009p18 | Diabetes and metabolism | BES2005

Murine expression of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) and hexose-6-phosphate dehydrogenase (H6PDH)

Hewitt K , Bujalska I , Draper N , Onyimba C , Walker E , Stewart P

In humans, glucocorticoids (GC) are implicated in the pathogenesis of obesity and insulin resistance. GCs are regulated at the prereceptor level by 11beta-HSDs. 11beta-HSD1 predominately displays oxo-reductase activity (cortisone/11-dehydrocorticosterone to cortisol/ corticosterone), requiring the cofactor NADPH. Recently, studies in humans have shown that the enzyme H6PDH, by generating NAPDH in the endoplasmic reticulum (ER) is crucial for oxo-reductase activity. This study ...

ea0007oc38 | Diabetes and metabolism | BES2004

Bacterial and yeast co-expression studies reveal hexose-6-phosphate dehydrogenase to be a crucial regulator of 11beta-hydroxysteroid dehydrogenase type 1 oxoreductase activity

Walker O , Schneider S , Edelstein M , Walker E , Arlt W , Stewart P

11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) has been implicated in the pathogenesis of human obesity and insulin resistance through 11-oxoreductase activation of cortisol (F) from cortisone (E) stimulating adipocyte differentiation and hepatic glucose output. In its purified state however, 11beta-HSD1 is a dehydrogenase inactivating F to E. In patients with cortisone reductase deficiency we recently identified two inactivating mutations, delta29bp and R453Q, withi...

ea0007p222 | Steroids | BES2004

A model for evaluating 11beta-hydroxysteroid dehydrogenase type 1 activity in ocular and orbital tissues

Walker E , Tomlinson J , Hughes S , Wood P , Murray P , Stewart P , Rauz S

11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) activates cortisol (F) from cortisone (E). Our recent human studies identified 11beta-HSD1 to the non-pigmented layer (NPE) of the ocular ciliary epithelium, confirming that this enzyme is integral to the physiology of aqueous humour (AH) production vital for the maintenance of intraocular pressure (IOP). 11beta-HSD1 has also been implicated in the pathogenesis of obesity, and our previous data have defined this enzyme i...

ea0007p223 | Steroids | BES2004

11beta-hydroxysteroid dehydrogenase type 1 and the production of cerebrospinal fluid

Rauz S , Walker E , Tomlinson J , Hughes S , Wood P , Stewart P , Murray P

The epithelial cells of the choroid plexus (CP) are responsible for cerebrospinal fluid (CSF) secretion into the ventricles of the brain, which then drains principally into the dural sinuses. The balance between production and drainage, in part, facilitates a normal intracranial pressure. The secretion of sodium and anions by the CP, creates an osmotic gradient driving the movement of water into the ventricles. This mechanism is analogous to that found in the ocular ciliary ep...