Personal Chair in Endocrinology
My Research in a Nutshell
Excessive activity of glucocorticoids (eg cortisol) causes Cushing's syndrome, with hypertension, obesity, glucose intolerance and accelerated cardiovascular disease. Brian Walker’s research using a wide range of translational tools (rodent models, detailed integrative physiology in humans, and epidemiology) has systematically documented that cortisol contributes to the association between multiple risk factors for cardiovascular disease (‘metabolic syndrome’) in the population, how glucocorticoids influence vascular lesions and their complications,and that manipulation of cortisol action offers novel therapeutic approaches in type 2 diabetes and cardiovascular disease.
With BHF support, in epidemiological studies Walker and colleagues showed that plasma cortisol levels are elevated in subjects with metabolic syndrome, in particular those born with low birth weight, and that hypercortisolaemia is an independent prospective cardiovascular risk factor. In parallel pharmaco-epidemiological studies involving >250,000 participants, Walker and colleagues also documented that exposure to exogenous glucocorticoids increases the risk of cardiovascular disease. He then established the CORtisol NETwork (CORNET) consortium, undertaking genome wide association metaanalysis in a sample of >20,000; this provided a genetic instrument with which to establish the causal relationship of hypercortisolaemia with cardiovascular disease; and identified novel biological determinants of tissue-specific cortisol action which his group are now dissecting under a Wellcome Trust Investigator award.
One of the determinants of cortisol action identified by Walker and colleagues has proven to be a tractable therapeutic target. In the mid-1990s the intracellular enzyme 11b-hydroxysteroid dehydrogenase type 1 (11b-HSD1)was thought to inactivate cortisol, and perhaps ‘protect’ liver, adipose tissue, and blood vessels from excessive exposure to cortisol. The Edinburgh group showed, initially in liver, that 11b-HSD1 in fact regenerates active cortisol from cortisone. In a seminal 1995 paper, Walker showed that inhibition of 11b-HSD1 reduces cortisol generation and enhances insulin sensitivity in human liver. His group developed novel stable isotope tracers and other tools to investigate this system comprehensively in vivo in humans, and found that 11b-HSD1 expression is increased selectively within adipose tissue in obesity. Walker also discovered 11b-HSD1 in vascular smooth muscle in the early 1990s. Recently, with colleagues in the Centre for Cardiovascular Science, they showed that glucocorticoids generated within the vessel wall inhibit angiogenesis. By deleting 11b-HSD1 new vessel growth is enhanced, eg following myocardial infarction in mice. This offers the exciting prospect of 11b-HSD1 inhibitors enhancing revascularisation following ischaemia. These findings spawned intensive efforts in the pharmaceutical industry to make 11b-HSD1 inhibitors (>200 new chemical entity patents filed). Supported by a Wellcome Trust Seeding Drug Discovery award, Walker and colleagues discovered novel 11b-HSD1 inhibitors, developed these to clinical trials and in commercial partnership are exemplifying their efficacy in metabolic, cardiovascular and also cognitive disease.
Another mechanism dictating tissue-specific responsiveness to glucocorticoids is the local expression of ABC transporters. Walker's group showed that ABCC1 is expressed in the absence of ABCB1 in adipose tissue, resulting in excretion of corticosterone but not cortisol from adipose tissue. They are now pursuing the therapeutic implication of this result, that corticosterone might be as effective as cortisol (hydrocortisone) in steroid replacement therapy without inducing side effects mediated in adipose tissue, such as obesity.
Walker's group have applied their unique tools and expertise to explain alterations in steroid metabolism and action in clinical settings from sepsis to heart failure, and to dissect the cardiometabolic consequences of manipulating additional components of steroid signalling, including 5a-reductases (in prostate disease) and aromatase (in breast disease). Already, this work has identified steroids with selective anti-inflammatory rather than dysmetabolic properties, and novel tissue-specific determinants of intracellular steroid concentrations, that have important therapeutic potential.
Diabetes Obesity & Metabolism