Searchable abstracts of presentations at key conferences in endocrinology
Endocrine Abstracts (2012) 28 YEP1.2

1Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom; 2Rowett Institute of Nutrition and Health, University of Aberdeen, Aberdeen, United Kingdom; 3Liver Unit, Royal Infirmary of Edinburgh, Edinburgh, United Kingdom; 4Department of Public Health and Clinical Medicine, Umea University Hospital, Umea, Sweden.


Tissue cortisol levels are amplified by the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). In mice, transgenic overexpression of 11β-HSD1 causes the metabolic syndrome, consequently 11β-HSD1 inhibitors are a promising therapeutic target. However, determining the importance of 11β-HSD1 in humans has proved more complicated, in part due to difficulty quantifying in vivo activity. We hypothesized that cortisol regeneration by 11β-HSD1 is dysregulated in obesity-associated type two diabetes (T2DM), and that nutritional factors regulate in vivo activity. To quantify 11β-HSD1 activity in humans, we developed a stable isotope tracer, 9,11,12,12-[2H]4-cortisol. We combined this technique with selective venous cannulation to quantify whole body, liver, visceral and subcutaneous adipose tissue 11β-HSD1 activity, and to quantify dysregulation in obese men with T2DM. Furthermore, we have examined tissue-specific regulation of in vivo 11β-HSD1 activity by acute and more chronic changes in dietary macronutrient content, and by improving insulin sensitivity using metformin or rosiglitazone. Extra-adrenal cortisol regeneration by 11β-HSD1 was of similar magnitude to adrenal production, with the majority (~90%) from the liver and a smaller contribution from subcutaneous adipose tissue. In obese men with T2DM, whole body activity was significantly increased and liver activity was sustained. In parallel with this work, in vivo 11β-HSD1 activity was highly regulated by nutrition. In euglycaemic obese men, whole body (predominantly liver) but not adipose tissue 11β-HSD1 activity was increased by a 4-week low carbohydrate diet. Similarly, the insulin-sensitising drug metformin but not rosiglitazone increased whole body 11β-HSD1 activity. In addition to chronic dietary regulation, specific macronutrients acutely increased cortisol production by either the adrenal or by 11β-HSD1 within minutes. 11β-HSD1 is an important determinant of tissue glucocorticoid levels in humans. 11β-HSD1 activity is increased in obesity-associated T2DM, highlighting the potential benefit of 11β-HSD1 inhibitors. Dysregulation of hepatic 11β-HSD1 in metabolic disease is most likely caused by abnormal insulin secretion.

Declaration of interest: There is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding: Declaration of Funding: This work was supported by the British Heart Foundation.

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