Endocrine Abstracts

Similarities between the metabolic syndrome and Cushing’s syndrome, and reversibility of the features of Cushing’s syndrome, suggest that cortisol may contribute to pathophysiology in both conditions and that reducing cortisol action may provide a novel therapeutic approach in metabolic syndrome.

There is substantial evidence that circulating cortisol concentrations are higher in people with hypertension and glucose intolerance. The basis for this activation of the hypothalamic-pituitary-adrenal (HPA) axis remains uncertain, but it may be attributable to ‘programming’ effects of events in early life since it is associated with low birth weight.

In people who become obese, intracellular cortisol levels within adipose tissue are further amplified by increased local re-generation of cortisol by the enzyme 11β-HSD type 1. Recent evidence highlights the role of nutrition and inflammation in regulating 11β-HSD1 in rodents and in humans. In mice, transgenic manipulations of 11β-HSD1 have potent effects on obesity and associated features of the metabolic syndrome. Promising pre-clinical data suggest that novel 11β-HSD1 inhibitors will have a role in lowering intra-cellular cortisol levels as a treatment for metabolic syndrome.

In addition to their metabolic effects, glucocorticoids act in the blood vessel wall. Pharmacoepidemiological studies suggest that glucocorticoid excess is an independent risk factor for cardiovascular disease. Recent data in rodents suggest that 11β-HSD1 within the blood vessel wall influences vascular remodelling and angiogenesis, for example in the myocardium following coronary artery occlusion.

Thus, HPA axis hyperactivity may provide a lifelong susceptibility to metabolic syndrome which is amplified by altered cortisol metabolism in obesity. Glucocorticoid signalling provides a potentially tractable system to influence both risk factors for, and the outcome of, type 2 diabetes and cardiovascular disease.