Endocrine Abstracts

11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) converts inactive glucocorticoid to their active form (cortisone to cortisol in humans, 11-dehydrocorticosterone (11-DHC) to corticosterone in mice), and is dependent upon the presence of cofactor NADPH generated by the enzyme hexose-6-phosphate (H6PDH) for its activity. The 11β-HSD1/H6PDH system is implicated in the pathogenesis of the metabolic syndrome by generating tissue specific glucocorticoid excess. The ...

6-Phosphogluconate dehydrogenase (6PGDH) is the third enzyme of the oxidative phase of the pentose phosphate pathway. The cytosolic form of this pathway is well characterised, but the details and significance of the endoplasmic reticulum (ER) version are only beginning to be understood. We have previously identified hexose-6-phosphate dehydrogenase (H6PDH), which catalyses the first two steps of this pathway within the lumen of the ER, as a pivotal regulator of ER reductases s...

Glucocorticoids are highly detrimental to skin integrity and function both when used locally for anti-inflammatory treatments and during conditions of raised systemic concentrations such as Cushing’s syndrome. Many of the adverse effects of glucocorticoids on skin are also symptoms associated with natural intrinsic aging and extrinsic photoaging.Locally, glucocorticoid availability is regulated independently of circulating levels by 11β-hydroxy...

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...

Patients with glucocorticoid (GC) excess, Cushing’s syndrome, develop a classical phenotype characterized by insulin resistance and central obesity. Whilst it is clear that GCs are essential for adipocyte differentiation, their impact upon many of the processes that regulate lipid accumulation has not been explored in detail. De novo lipogenesis involves carboxylation of acetyl CoA to malonyl-CoA by acetyl CoA carboxylase (ACC), which is subsequently converted to p...

The incidence of type 2 diabetes (T2DM) has doubled over the past decade. Obesity induced insulin resistance is associated with T2DM and the metabolic syndrome (including hypertension, and dyslipidemia). Diets high in saturated fat are largely to blame for the current obesity epidemic. High-fat feeding of animals increases circulating corticosterone levels, in addition to changes in glucose homeostasis. The relationship between insulin sensitivity and abnormal hypothalamic&#15...

NADPH generated by hexose-6-phosphate dehydrogenase (H6PDH) within the lumen of the endoplasmic reticulum (ER) drives the reductase activity of 11β-hydroxysteroid dehydrogenase type 1 (11-βHSD1) allowing the production of active glucocorticoids. H6PDH knockout (H6PDHKO) mice develop a vacuolating myopathy, reduced muscle mass and display activation of the ER stress response. However, the role of glucocorticoids and 11β-HSD1 in the myopathy phenotype is not clear...

Medullary thyroid cancer (MTC) is rare and mainly sporadic. About ≤25% of cases are inherited from a Ret protooncogene (RET) mutation. >90% of positive mutations develop MTC, either as familial (FMTC), or as part of MEN2. Early detection and treatment of MTC with total thyroidectomy improves prognosis.In 2006, as part of a project to deliver genetics into mainstream medicine, a multidisciplinary clinic (MDC) comprising a specialist thyroid surg...

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...

Background: Children receiving chemotherapy for ALL may be susceptible to fractures and avascular necrosis (AVN).Aim: To determine the incidence and risk factors for bone-related morbidity in children on ALL chemotherapy.Patients and methods: The medical records of all (n, 186, male: 122) children presenting with ALL between 1997 and 2007 and treated with ALL97/01or UKALL 2003 at one centre were studied. Bone morbidity was d...