11ß-Hydroxysteroid dehydrogenase type 1: relevance of its modulation in the pathophysiology of obesity, the metabolic syndrome and type 2 diabetes mellitus.

Recent evidence strongly argues for a pathogenic role of glucocorticoids and 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) in obesity and the metabolic syndrome, a cluster of risk factors for atherosclerotic cardiovascular disease and type 2 diabetes mellitus (T2DM) that includes insulin resistance (IR), dyslipidaemia, hypertension and visceral obesity. This has been partially prompted not only by the striking clinical resemblances between the metabolic syndrome and Cushing's syndrome (a state characterized by hypercortisolism that associates with metabolic syndrome components) but also from monogenic rodent models for the metabolic syndrome (e.g. the leptin-deficient ob/ob mouse or the leptin-resistant Zucker rat) that display overall increased secretion of glucocorticoids. However, systemic circulating glucocorticoids are not elevated in obese patients and/or patients with metabolic syndrome. The study of the role of 11ß-HSD system shed light on this conundrum, showing that local glucocorticoids are finely regulated in a tissue-specific manner at the pre-receptor level. The system comprises two microsomal enzymes that either activate cortisone to cortisol (11ß-HSD1) or inactivate cortisol to cortisone (11ß-HSD2). Transgenic rodent models, knockout (KO) for HSD11B1 or with HSD11B1 or HSD11B2 overexpression, specifically targeted to the liver or adipose tissue, have been developed and helped unravel the currently undisputable role of the enzymes in metabolic syndrome pathophysiology, in each of its isolated components and in their prevention. In the transgenic HSD11B1 overexpressing models, different features of the metabolic syndrome and obesity are replicated. HSD11B1 gene deficiency or HSD11B2 gene overexpression associates with improvements in the metabolic profile. In face of these demonstrations, research efforts are now being turned both into the inhibition of 11ß-HSD1 as a possible pharmacological target and into the role of dietary habits on the establishment or the prevention of the metabolic syndrome, obesity and T2DM through 11ß-HSD1 modulation. We intend to review and discuss 11ß-HSD1 and obesity, the metabolic syndrome and T2DM and to highlight the potential of its inhibition for therapeutic or prophylactic approaches in those metabolic diseases.

Hypercorticism blunts circadian variations of osteocalcin regardless of nutritional status.

Anorexia nervosa (AN) and Cushing's syndrome (CS) are both responsible for osteoporosis. The mechanisms leading to osteoporosis in AN include hypogonadism, nutritional depletion, and in some cases hypercorticism. Osteocalcin circulating level is a serum marker of osteoblastic activity that follows a circadian rhythm (OCR). Serum osteocalcin is decreased in both CS and AN and can be increased with treatment. In this study we analyzed the influence of combined cortisol and nutritional status on osteocalcin levels and its circadian rhythm in these two different models of hypercorticism, one nutritionally replete (CS) and one nutritionally deplete (AN), and we evaluated the effects of their treatment (surgical cure and weight gain, respectively). Before treatment, osteocalcin levels were lower in CS (n = 16) and AN (n = 42) than in controls and in the AN patient subgroup with hypercorticism (n = 13) compared to those without (n = 29). OCR was absent in CS and in AN patients with hypercorticism, whereas their circadian cortisol cycle was maintained. In CS, successful surgical treatment increased osteocalcin levels (n = 5) and restored OCR. In AN, weight gain (n = 13) induced a significant decrease in cortisol levels in hypercortisolic AN patients, and restored normal osteocalcin levels and OCR. In conclusion, we found that hypercorticism was associated with a decrease in osteocalcin levels in nutritionally replete or deplete patients and that OCR was more affected by cortisol levels than by cortisol cycle.

[Variations of the renin aldosterone system in Cushing's disease (author's transl)]. / Variations du système rénine angiotensine aldostérone dans la maladie de Cushing.

The renin aldosterone system was studied in 5 cases of Cushing's disease (bilateral benign hyperplasia) without medication. For a daily sodium intake of 120 mmol plasma angiotensinogen was abnormally increased, plasma renin activity (PRA) remained normal, but without significant diurnal variation. Plasma aldosterone (PA) was normal and its circadian rhythm was maintained. One hour active orthostatism and low sodium diet (20 mmol of sodium during 4 days) induced a normal PRA increase but an insufficient PA response. Positive significant correlations were found between PRA and PA and between plasma angiotensinogen and plasma cortisol. The mechanisms underlying this functional hypoaldosteronism were discussed.