Endocrine Abstracts (2010) 21 P358

Hepatic vein cannulation and stable isotope tracer infusion reveals that liver cortisol regeneration by 11[beta]-HSD1 is sustained in obese men with type 2 diabetes mellitus, providing a target for enzyme inhibition

Roland Stimson1, Ruth Andrew1, Norma McAvoy2, Dhiraj Tripathi2, Peter Hayes2 & Brian Walker1

1Endocrinology Unit, University of Edinburgh, Edinburgh, UK; 2Liver Unit, Royal Infirmary of Edinburgh, Edinburgh, UK.

Inhibitors of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) are being developed to prevent cortisol regeneration from cortisone in liver and adipose tissue in type 2 diabetes (T2DM). However, the target patient group is uncertain. In obesity 11β-HSD1 activity is increased in adipose tissue but decreased in liver, as judged indirectly by plasma cortisol levels after oral cortisone administration. However, in T2DM, urinary steroid ratios suggest liver 11β-HSD1 may be preserved. To quantify cortisol regeneration in the liver precisely, we cannulated the hepatic vein during stable isotope tracer infusions in obese men with T2DM and lean controls.

Ten obese men with diet- or tablet-controlled T2DM and seven lean healthy controls (BMI 35.0±1.0 vs 23.5±1.1 kg/m2) were given 1 mg oral dexamethasone the night prior to infusion of cortisol (60%) and 9,11,12,12-[2H]4-cortisol (40%) at 1.74 mg/h. Blood was obtained from the hepatic vein and an arterialised hand vein at steady state. Cortisone (5 mg) was then administered orally and appearance of cortisol in hepatic vein quantified by tracer dilution. Indocyanine green was infused to measure hepatic blood flow. Local ethical approval was obtained. Data are mean±S.E.M.

Whole body d3-cortisol appearance (a specific measure of 11β-HSD1 activity) was increased in obese T2DM (35.0±2.2 vs 28.9±1.4 nmol/min, P<0.05). Although basal splanchnic d3-cortisol release was similar (28.8±0.9 vs 29.5±5.9 nmol/min), cortisol appearance in the hepatic vein after oral cortisone was increased in obese T2DM (275±13 vs 203±25 nmol/min, P<0.05).

In contrast with down-regulation of liver 11β-HSD1 and lack of change in whole body cortisol regeneration which occurs in euglycaemic obesity, in obese men with T2DM liver 11β-HSD1 is sustained and whole body cortisol regeneration is increased. This further implicates insulin-dependent mechanisms in the regulation of liver 11β-HSD1 in humans, and highlights the potential therapeutic benefit of hepatic 11β-HSD1 inhibition in obesity-associated diabetes.

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