Sandeep Thekkepat C, Andrew Ruth, Homer Natalie Z M, Andrews Robert C, Smith Ken, Walker Brian R
Endocrinology Unit, School of MolecularClinical Medicine, University of Edinburgh, Western General Hospital, Edinburgh, EH4 2XU, U.K.
Diabetes. 2005 Mar;54(3):872-9. doi: 10.2337/diabetes.54.3.872.
11beta-Hydroxysteroid dehydrogenase type 1 (11HSD1) regenerates cortisol from cortisone within adipose tissue and liver. 11HSD1 inhibitors may enhance insulin sensitivity in type 2 diabetes and be most efficacious in obesity when 11HSD1 is increased in subcutaneous adipose biopsies. We examined the regeneration of cortisol in vivo in obesity, and the effects of the 11HSD1 inhibitor carbenoxolone. We compared six lean and six obese men and performed a randomized, placebo-controlled crossover study of carbenoxolone in obese men. The obese men had no difference in their whole-body rate of regenerating cortisol (measured with 9,11,12,12-[(2)H(4)]cortisol tracer), but had more rapid conversion of [(3)H]cortisone to [(3)H]cortisol in abdominal subcutaneous adipose tissue (measured with microdialysis). During insulin infusion, adipose 11HSD1 activity fell markedly in lean but not in obese men. Carbenoxolone inhibited whole-body cortisol regeneration, but did not significantly inhibit adipose 11HSD1 and had no effects on insulin sensitivity (measured by [(2)H(2)]glucose infusion with or without hyperinsulinemia). Thus, in vivo cortisol generation is increased selectively within adipose tissue in obesity, perhaps reflecting resistance to insulin-mediated downregulation of 11HSD1. However, obese men are less susceptible than lean men to the insulin-sensitizing effects of carbenoxolone. To be useful in obese patients, 11HSD1 inhibitors will need to inhibit the enzyme more effectively in adipose tissue.
11β-羟基类固醇脱氢酶1型（11HSD1）在脂肪组织和肝脏中可将可的松转化为皮质醇。在2型糖尿病中，11HSD1抑制剂可能会增强胰岛素敏感性，并且当皮下脂肪活检中11HSD1升高时，在肥胖人群中最为有效。我们研究了肥胖状态下体内皮质醇的再生情况以及11HSD1抑制剂甘草次酸的作用。我们比较了6名瘦人和6名肥胖男性，并对肥胖男性进行了一项随机、安慰剂对照的甘草次酸交叉研究。肥胖男性在全身皮质醇再生率（用9,11,12,12-[(2)H(4)]皮质醇示踪剂测量）上没有差异，但在腹部皮下脂肪组织中[(3)H]可的松向[(3)H]皮质醇的转化更快（用微透析测量）。在输注胰岛素期间，脂肪组织中的11HSD1活性在瘦人身上显著下降，但在肥胖男性中没有。甘草次酸抑制了全身皮质醇的再生，但没有显著抑制脂肪组织中的11HSD1，并且对胰岛素敏感性没有影响（通过输注[(2)H(2)]葡萄糖并伴有或不伴有高胰岛素血症来测量）。因此，在肥胖状态下，体内皮质醇的生成在脂肪组织中选择性增加，这可能反映了对胰岛素介导的11HSD1下调的抵抗。然而，肥胖男性比瘦人对甘草次酸的胰岛素增敏作用更不敏感。要对肥胖患者有用，11HSD1抑制剂需要更有效地抑制脂肪组织中的该酶。
