11beta-hydroxysteroid dehydrogenase type 1 and obesity.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 dehydroggenase. Transgenic mice over-expressing 11HSD1 in their 11betz adipose tissue are obese, hypertensive, dyslipidaemic and insulin resistant. Further, 11HSD1 knockout mice are protected tren marruecos espana 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.
11beta-hydroxysteroid dehydrogenase type 1 and obesity. - PubMed - NCBI
An exciting era is upon us in terms of new therapies for patients with diabetes, obesity, and metabolic syndrome. One such advance is the ability to selectively manipulate tissue levels of glucocorticoids through targeted inhibition of cortisol metabolic pathways. Perhaps the best paradigm for metabolic syndrome comes from patients with Cushing's syndrome, with their characteristic central obesity, glucose intolerance, hypertension, and premature cardiovascular mortality.
The autocrine consequences of this are clear: But what is the overall contribution, if any, of this generation of cortisol from liver and fat to circulating concentrations? In this issue of Diabetes , Stimson et al. Selective catheterization of hepatic vein, portal vein, and abdominal vascular beds confirms that the liver is a major cortisol producer; the absolute values differ markedly from study to study, and some results seen are incompatible with normal daily cortisol secretion rates.
For example, Basu et al. Both studies, however, are quite clear in showing no apparent release of cortisol from the viscera: The data confirm earlier canine studies performed in the laboratory of R. Rizza 11 but seem to contradict earlier studies by Walker and colleagues 12 that suggested that up to two-thirds of splanchnic cortisol production might originate from the viscera.
There are some additional caveats. Such invasive studies are not possible on healthy volunteers. Patients studied had either severe obesity and were undergoing bariatric surgery or had severe liver disease and were undergoing portal venous shunting; both scenarios have been shown to significantly alter cortisol secretion and metabolism.
Furthermore, the catheterization procedures do not specifically sample omental fat but reflect drainage into the whole portal vein that may cause some dilution from other visceral tissues. These issues aside, it seems unlikely that visceral fat contributes a significant delivery of cortisol to the liver.
However, the longer-term beneficial effects of blocking the autocrine actions of cortisol in omental adipose tissue should not be dismissed. This may not impact on exposure of the liver to portal vein steroids, but the reduction in adipogenesis will improve body composition and potentially improve other cardiovascular risk factors such as dyslipidemia and hypertension.
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Skip to main content. Stewart and Jeremy W. Diabetes Jan; 58 1: Acknowledgments No potential conflicts of interest relevant to this article were reported. Footnotes Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. Cortisol effects on body mass, blood pressure, and cholesterol in the general population.
Selective inhibition of 11beta-hydroxysteroid dehydrogenase type 1 decreases blood glucose concentrations in hyperglycaemic mice. J Exp Med Depot-specific modulation of rat intraabdominal adipose tissue lipid metabolism by pharmacological inhibition of 11beta-hydroxysteroid dehydrogenase type 1. Liver is the site of splanchnic cortisol production in obese nondiabetic humans.
Splanchnic cortisol production in dogs occurs primarily in the liver: The contribution of visceral adipose tissue to splanchnic cortisol production in healthy humans. In this Issue January , 58 1. Table of Contents Index by Author. Search for this keyword.
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