Increased Whole-Body and Sustained Liver Cortisol Regeneration by 11 beta-Hydroxysteroid Dehydrogenase Type 1 in Obese Men With Type 2 Diabetes Provides a Target for Enzyme Inhibition

Roland H Stimson, Ruth Andrew, Norma C McAvoy, Dhiraj Tripathi, Peter C Hayes, Brian R Walker

Research output: Contribution to journalArticlepeer-review

Abstract

OBJECTIVE-The cortisol-regenerating enzyme 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD1) amplifies glucocorticoid levels in liver and adipose tissue. 11 beta-HSD1 inhibitors are being developed to treat type 2 diabetes. In obesity, 11 beta-HSD1 is increased in adipose tissue but decreased in liver. The benefits of pharmacological inhibition may be reduced if hepatic 11 beta-HSD1 is similarly decreased in obese patients with type 2 diabetes. To examine this, we quantified in vivo whole-body, splanchnic, and hepatic 11 beta-HSD1 activity in obese type 2 diabetic subjects.

RESEARCH DESIGN AND METHODS-Ten obese men with type 2 diabetes and seven normal-weight control subjects were infused with 9,11,12,12-[H-2](4)cortisol (40%) and cortisol (60%) at 1.74 mg/h. Adrenal cortisol secretion was suppressed with dexamethasone. Samples were obtained from the hepatic vein and an arterialized hand vein at steady state and after oral administration of cortisone (5 mg) to estimate whole-body and liver 11 beta-HSD1 activity using tracer dilution.

RESULTS-In obese type 2 diabetic subjects, the appearance rate of 9,12,12-[H-2](3)cortisol in arterialized blood was increased (35 +/- 2 vs. 29 +/- 1 nmol/min, P < 0.05), splanchnic 9,12,12-[H-2](3)cortisol production was not reduced (29 +/- 6 vs. 29 +/- 6 nmol/min), and cortisol appearance in the hepatic vein after oral cortisone was unchanged.

CONCLUSIONS-Whole-body 11 beta-HSD1 activity is increased in obese men with type 2 diabetes, whereas liver 11 beta-HSD1 activity is sustained, unlike in euglycemic obesity. This supports the concept that inhibitors of 11 beta-HSD1 are likely to be most effective in obese type 2 diabetic subjects.

Original languageEnglish
Pages (from-to)720-725
Number of pages6
JournalDiabetes
Volume60
Issue number3
DOIs
Publication statusPublished - Mar 2011

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