Deborah J. Wake

Intra-adipose sex steroid metabolism and body fat distribution in idiopathic human obesity

Objective  Causes of visceral fat accumulation include glucocorticoid excess or decreased oestrogen/androgen ratio either in plasma or within adipose tissue. In obese subjects, the intra‐adipose cortisol‐generating enzyme 11β‐hydroxysteroid dehydrogenase type 1 (11β‐HSD1) is increased, but information on sex steroid signalling is sparse. We aimed to test associations between body fat or fat distribution and mRNA transcript levels for androgen and oestrogen receptors and for enzymes metabolizing sex steroids in adipose tissue.

11β-Hydroxysteroid dehydrogenase type 1 in obesity and the metabolic syndrome

Abstract 11β-Hydroxysteroid dehydrogenase type 1 (11HSD1) catalyses the in vivo conversion of inactive to active glucocorticoids. It is a widespread, highly regulated enzyme which amplifies the ligand available for intracellular glucocorticoid receptors. Excessive glucocorticoid exposure causes central obesity, hypertension, dyslipidaemia and insulin resistance, as seen with elevated plasma cortisol in Cushing’s syndrome. Transgenic mice over-expressing 11HSD1 in their white adipose tissue are obese, hypertensive, dyslipidaemic and insulin resistant. Further, 11HSD1 knockout mice are protected from these metabolic abnormalities. In human idiopathic obesity, circulating cortisol levels are not elevated but 11HSD1 mRNA and activity is increased in subcutaneous adipose. The impact of increased adipose 11HSD1 on pathways leading to metabolic complications remains unclear in humans. Pharmacological inhibition of 11HSD1 has been achieved in liver with carbenoxolone, which enhances hepatic insulin sensitivity. Newer selective 11HSD1 inhibitors are in development, which may achieve reduced cortisol action in adipose tissue and confer therapeutic benefit in obese patients.

Glucocorticoid metabolism within superficial subcutaneous rather than visceral adipose tissue is associated with features of the metabolic syndrome in South African women.

Objective  Glucocorticoid hyperactivity in adipose tissue, due to up‐regulation of local glucocorticoid reactivation by 11β‐hydroxysteroid dehydrogenase‐1 (11HSD1) or of glucocorticoid receptors (GR), may underpin susceptibility to the metabolic syndrome. This hypothesis has been tested extensively in subcutaneous adipose tissue (SAT) but inadequately in visceral adipose tissue (VAT). The aim of the study was therefore to examine expression of 11HSD1, GRα and hexose‐6‐phosphate dehydrogenase (H6PDH), which supplies cofactor for 11HSD1, in abdominal adipose tissue compartments and to characterize their relation to metabolic syndrome parameters.

Blood transfusion in developing countries : problems, priorities and practicalities

The acute medical services could not exist without blood transfusions—life-savers in many situations. But transfusions can also be a quick and easy route for the transmission of infectious agents such as HIV, HBV, HCV and malaria. Infection through blood supply is a major issue in all countries but particularly in those with economic constraints which limit safety. This study was carried out in India (March—May 1997) and involved centres in Delhi, Calcutta and Vellore. It examined many aspects of blood transfusion including donor screening, use of professional donors, blood testing and criteria for blood use1. The many problems in Indian blood transfusion services are mirrored in other countries. Here we examine the problems, priorities and practicalities of blood transfusion particularly in developing countries.

Salicylate Downregulates 11β-HSD1 Expression in Adipose Tissue in Obese Mice and in Humans, Mediating Insulin Sensitization

Recent trials show salicylates improve glycemic control in type 2 diabetes, but the mechanism is poorly understood. Expression of the glucocorticoid-generating enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in adipose tissue is increased in vitro by proinflammatory cytokines and upregulated in obesity. 11β-HSD1 inhibition enhances insulin sensitivity. We hypothesized that salicylates downregulate 11β-HSD1 expression, contributing to their metabolic efficacy. We treated diet-induced obese (DIO) 11β-HSD1–deficient mice and C57Bl/6 mice with sodium salicylate for 4 weeks. Glucose tolerance was assessed in vivo. Tissue transcript levels were assessed by quantitative PCR and enzyme activity by incubation with 3H-steroid. Two weeks’ administration of salsalate was also investigated in a randomized double-blind placebo-controlled crossover study in 16 men, with measurement of liver 11β-HSD1 activity in vivo and adipose tissue 11β-HSD1 transcript levels ex vivo. In C57Bl/6 DIO mice, salicylate improved glucose tolerance and downregulated 11β-HSD1 mRNA and activity selectively in visceral adipose. DIO 11β-HSD1–deficient mice were resistant to these metabolic effects of salicylate. In men, salsalate reduced 11β-HSD1 expression in subcutaneous adipose, and in vitro salicylate treatment reduced adipocyte 11β-HSD1 expression and induced adiponectin expression only in the presence of 11β-HSD1 substrate. Reduced intra-adipose glucocorticoid regeneration by 11β-HSD1 is a novel mechanism that contributes to the metabolic efficacy of salicylates.

Inhibition of 11beta-hydroxysteroid dehydrogenase type 1 in obesity.

Excessive glucocorticoid exposure (Cushings syndrome) results in increased adiposity associated with dysmetabolic features (including insulin resistance, hyperlipidaemia, and hypertension). Circulating cortisol levels are not elevated in idiopathic obesity, although cortisol production and clearance are increased. However, tissue glucocorticoid exposure may be altered independently of circulating levels by 11β-hydroxysteroid dehydrogenase type 1 (11HSD1), an enzyme which generates active glucocorticoid within tissues, including in adipose tissue. Transgenic overexpression of 11HSD1 in mice causes obesity. In human obesity, 11HSD1 is altered in a tissue-specific manner with reduced levels in liver but elevated levels in adipose, which may lead to glucocorticoid receptor activation and contribute to the metabolic phenotype. The reasons for altered 11HSD1 in obesity are not fully understood. Although some polymorphisms have been demonstrated in intronic and upstream regions of the HSD11B1 gene, the functional significance of these is not clear. In addition, there is mounting evidence that 11HSD1 may be dysregulated secondarily to factors that are altered in obesity, including substrates for metabolism, hormones, and inflammatory mediators. 11HSD1 is a potential therapeutic target for the treatment of the metabolic syndrome. 11HSD1 knockout mice are protected from diet-induced obesity and associated metabolic dysfunction. Although many specific inhibitors of 11HSD1 have now been developed, and published data support their efficacy in the liver to reduce glucose production, their efficacy in enhancing insulin sensitivity in adipose tissue remains uncertain. The therapeutic potential of 11HSD1 in human obesity therefore remains highly promising but as yet unproven.

11β-Hydroxysteroid Dehydrogenase Type 1 in Adipose Tissue and Prospective Changes in Body Weight and Insulin Resistance

Objective: Increased mRNA and activity levels of 11β‐hydroxysteroid dehydrogenase type 1 (11βHSD1) in human adipose tissue (AT) are associated with obesity and insulin resistance. The aim of our study was to investigate whether 11βHSD1 expression or activity in abdominal subcutaneous AT of non‐diabetic subjects are associated with subsequent changes in body weight and insulin resistance [homeostasis model assessment of insulin resistance (HOMA‐IR)].

mHealth applications for diabetes: User preference and implications for app development:

Increasing diabetes prevalence has led to the need for more sustainable and person-centred services. The diabetes self-care mHealth marketplace is growing, but most effective/valued features are unknown. This study gauges diabetes app user opinion to inform development work. An analysis of diabetes mHealth apps informed design of a questionnaire sent to a random sample of 400 patients stratified by diabetes type and age. Responses were analysed by sub-group, and preferences were compared with current diabetes apps. App features included data storage/graphics, exercise tracking, health/diet, reminders/alarms, education. Questionnaire response rate was 59 per cent (234/400); 144/233 (62%) owned smartphones. Smartphone users expressed preference towards mHealth (101/142 (71%)), although diabetes use was low (12/163 (7%)). Respondents favoured many potential features, with similar preferences between diabetes types. This study demonstrates that while mHealth acceptance is high, current engagement is low. Engagement and functionality could be improved by including stakeholders in future development, driven by clinical/user need.

Definitions of eHealth

The advent of consumer and industry-standard technology has brought dramatic changes over the last 25 years, with these technologies becoming rapidly more common place throughout interactions in our day-to-day lives. The ubiquitous nature of these devices, transactions and services mean that it is quite possible to be dealing with technology without even realising it. These technologies aim to speed up our daily interactions and ensure that delays, inefficiencies and poor service can become a thing of the past.

Incidence of type 1 diabetes has doubled in Kuwaiti children 0-14 years over the last 20 years

This study had 2 aims: to report data on the incidence of childhood‐onset type 1 diabetes in Kuwaiti children aged 0‐14 years during 2011 to 2013 and to compare the recent data with those collected during 1992 to 1997.