Centre of Translational Medicine and Therapeutics, William Harvey Research Institute, Barts and the London, Queen Mary University of London, London EC1M 6BQ, United Kingdom.
Proc Natl Acad Sci U S A. 2014 Mar 11;111(10):3817-22. doi: 10.1073/pnas.1312436111. Epub 2014 Feb 25.
Insulin resistance and associated metabolic sequelae are common in chronic kidney disease (CKD) and are positively and independently associated with increased cardiovascular mortality. However, the pathogenesis has yet to be fully elucidated. 11β-Hydroxysteroid dehydrogenase type 1 (11βHSD1) catalyzes intracellular regeneration of active glucocorticoids, promoting insulin resistance in liver and other metabolic tissues. Using two experimental rat models of CKD (subtotal nephrectomy and adenine diet) which show early insulin resistance, we found that 11βHSD1 mRNA and protein increase in hepatic and adipose tissue, together with increased hepatic 11βHSD1 activity. This was associated with intrahepatic but not circulating glucocorticoid excess, and increased hepatic gluconeogenesis and lipogenesis. Oral administration of the 11βHSD inhibitor carbenoxolone to uremic rats for 2 wk improved glucose tolerance and insulin sensitivity, improved insulin signaling, and reduced hepatic expression of gluconeogenic and lipogenic genes. Furthermore, 11βHSD1(-/-) mice and rats treated with a specific 11βHSD1 inhibitor (UE2316) were protected from metabolic disturbances despite similar renal dysfunction following adenine experimental uremia. Therefore, we demonstrate that elevated hepatic 11βHSD1 is an important contributor to early insulin resistance and dyslipidemia in uremia. Specific 11βHSD1 inhibitors potentially represent a novel therapeutic approach for management of insulin resistance in patients with CKD.
胰岛素抵抗和相关代谢后果在慢性肾脏病（CKD）中很常见，并且与心血管死亡率的增加呈正相关且独立相关。然而，其发病机制尚未完全阐明。11β-羟类固醇脱氢酶 1（11βHSD1）催化细胞内活性糖皮质激素的再生，促进肝脏和其他代谢组织中的胰岛素抵抗。我们使用两种具有早期胰岛素抵抗的 CKD 实验大鼠模型（肾部分切除术和腺嘌呤饮食），发现肝组织和脂肪组织中 11βHSD1mRNA 和蛋白增加，同时肝 11βHSD1 活性增加。这与肝内但不是循环内糖皮质激素过多有关，并增加了肝糖异生和脂肪生成。在尿毒症大鼠中口服 11βHSD 抑制剂 carbenoxolone 治疗 2 周，可改善葡萄糖耐量和胰岛素敏感性，改善胰岛素信号，并减少肝糖异生和脂肪生成基因的表达。此外，11βHSD1（-/-）小鼠和用特异性 11βHSD1 抑制剂（UE2316）治疗的大鼠尽管在腺嘌呤实验性尿毒症后肾功能相似，但仍能免受代谢紊乱的影响。因此，我们证明升高的肝 11βHSD1 是尿毒症中早期胰岛素抵抗和血脂异常的重要原因。特异性 11βHSD1 抑制剂可能代表治疗 CKD 患者胰岛素抵抗的一种新的治疗方法。
