Andrews Robert C, Herlihy Olive, Livingstone Dawn E W, Andrew Ruth, Walker Brian R
University of Edinburgh, Endocrinology Unit, Department of Medical Sciences, Western General Hospital, Edinburgh EH4 2XU, United Kingdom.
J Clin Endocrinol Metab. 2002 Dec;87(12):5587-93. doi: 10.1210/jc.2002-020048.
Recent evidence suggests that increased cortisol secretion, altered cortisol metabolism, and/or increased tissue sensitivity to cortisol may link insulin resistance, hypertension, and obesity. Whether these changes are important in type 2 diabetes mellitus (DM) is unknown. We performed an integrated assessment of glucocorticoid secretion, metabolism, and action in 25 unmedicated lean male patients with hyperglycemia (20 with type 2 diabetes and 5 with impaired glucose intolerance by World Health Organization criteria) and 25 healthy men, carefully matched for body mass index, age, and blood pressure. Data are mean +/- SE. Patients with hyperglycemia (DM) had higher HbA(1c) (6.9 +/- 0.2% vs. 6.0 +/- 0.1%, P < 0.0001) and triglycerides. Cortisol secretion was not different, as judged by 0900 h plasma cortisol and 24 h total urinary cortisol metabolites. However, the proportion of cortisol excreted as 5alpha- and 5beta-reduced metabolites was increased in DM patients. Following an oral dose of cortisone 25 mg, generation of plasma cortisol by hepatic 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD 1) was impaired in DM patients (area under the curve, 3617 +/- 281 nM.2 h vs. 4475 +/- 228; P < 0.005). In contrast, in sc gluteal fat biopsies from 17 subjects (5 DM and 12 controls) in vitro 11beta-HSD 1 activity was not different (area under the curve, 128 +/- 56% conversion.30 h DM vs. 119 +/- 21, P = 0.86). Sensitivity to glucocorticoids was increased in DM patients both centrally (0900 h plasma cortisol after overnight 250 micro g oral dexamethasone 172 +/- 16 nM vs. 238 +/- 20 nM, P < 0.01) and peripherally (more intense forearm dermal blanching following overnight topical beclomethasone; 0.56 +/- 0.92 ratio to vehicle vs. 0.82 +/- 0.69, P < 0.05). In summary, in patients with glucose intolerance, cortisol secretion, although normal, is inappropriately high given enhanced central and peripheral sensitivity to glucocorticoids. Normal 11beta-HSD 1 activity in adipose tissue with impaired hepatic conversion of cortisone to cortisol suggests that tissue-specific changes in 11beta-HSD 1 activity in hyperglycemia differ from those in primary obesity but may still be susceptible to pharmacological inhibition of the enzyme to reduce intracellular cortisol concentrations. Thus, altered cortisol action occurs not only in obesity and hypertension but also in glucose intolerance, and could therefore contribute to the link between these multiple cardiovascular risk factors.
近期证据表明，皮质醇分泌增加、皮质醇代谢改变和/或组织对皮质醇的敏感性增加可能与胰岛素抵抗、高血压和肥胖相关。这些变化在2型糖尿病（DM）中是否重要尚不清楚。我们对25例未接受药物治疗的血糖升高的瘦男性患者（20例2型糖尿病患者和5例根据世界卫生组织标准诊断为糖耐量受损患者）和25例健康男性进行了糖皮质激素分泌、代谢及作用的综合评估，这些患者在体重指数、年龄和血压方面进行了仔细匹配。数据为均值±标准误。血糖升高（DM）患者的糖化血红蛋白（HbA1c）（6.9±0.2% 对6.0±0.1%，P<0.0001）和甘油三酯水平更高。根据上午9点血浆皮质醇和24小时尿总皮质醇代谢产物判断，皮质醇分泌无差异。然而，DM患者中以5α-和5β-还原代谢产物形式排泄的皮质醇比例增加。口服25mg可的松后，DM患者肝脏11β-羟类固醇脱氢酶1型（11β-HSD 1）生成血浆皮质醇的能力受损（曲线下面积，3617±281nM·2小时对4475±228；P<0.005）。相反，在17名受试者（5例DM患者和12例对照）的臀大肌皮下脂肪活检中，体外11β-HSD 1活性无差异（曲线下面积，DM患者30小时转化率为128±56%对119±21，P = 0.86）。DM患者对糖皮质激素的敏感性在中枢（过夜口服250μg地塞米松后上午9点血浆皮质醇172±16nM对238±20nM，P<0.01）和外周（过夜局部应用倍氯米松后前臂皮肤更明显的苍白；与赋形剂的比值为0.56±0.92对0.82±0.69，P<0.05）均增加。总之，在糖耐量受损患者中，尽管皮质醇分泌正常，但鉴于中枢和外周对糖皮质激素的敏感性增强，其水平仍过高。脂肪组织中11β-HSD 1活性正常而肝脏可的松向皮质醇转化受损表明，高血糖时11β-HSD 1活性的组织特异性变化与原发性肥胖不同，但仍可能对该酶的药物抑制敏感，从而降低细胞内皮质醇浓度。因此，皮质醇作用改变不仅发生在肥胖和高血压中，也发生在糖耐量受损中，因此可能导致这些多种心血管危险因素之间的关联。
