Cortisol--cause and cure for metabolic syndrome?
Similarities between the metabolic syndrome and Cushing's syndrome, and reversibility of the features of Cushing's syndrome, suggest that cortisol may contribute to the pathophysiology of both conditions and that reducing cortisol action may provide a novel therapeutic approach in the 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 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 obese people, intracellular cortisol levels within adipose tissue are further amplified by increased local regeneration of cortisol by the enzyme 11beta-HSD type 1. In mice, transgenic manipulations of 11beta-HSD1 have potent effects on obesity and associated features of the metabolic syndrome. Promising preclinical data suggest that novel 11beta-HSD1 inhibitors will have a role in lowering intracellular cortisol levels as a treatment for the 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 suggest that 11beta-HSD1 within the blood vessel wall influences vascular remodelling and angiogenesis, for example in the myocardium following coronary artery occlusion. Thus, glucocorticoid signalling provides a potentially tractable system to influence both risk factors for, and the outcome of, Type 2 diabetes and cardiovascular disease.
Walker
B R
BR
Endocrinology Unit, Centre for Cardiovascular Science, University of Edinburgh, Queen's Medical Research Institute, Edinburgh, UK. b.walker@ed.ac.uk
D042842:11-beta-Hydroxysteroid Dehydrogenases / Q000378:metabolism*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D003480:Cushing Syndrome / Q000150:complications; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000201:enzymology*; D003925:Diabetic Angiopathies / Q000188:drug therapy / Q000201:enzymology* / Q000209:etiology; D005938:Glucocorticoids / Q000378:metabolism*; D006801:Humans; D006854:Hydrocortisone; D008297:Male; D024821:Metabolic Syndrome / Q000188:drug therapy / Q000201:enzymology* / Q000209:etiology; D051379:Mice
D000893:Anti-Inflammatory Agents; D005938:Glucocorticoids; D042842:11-beta-Hydroxysteroid Dehydrogenases; D006854:Hydrocortisone