Insulin resistance in chronic kidney disease is ameliorated by spironolactone in rats and humans
Insulin resistance in chronic kidney disease is ameliorated by spironolactone in rats and humans
复制标题
DOI：
10.1038/ki.2014.348
复制
发表时间：
2015-04-01
影响因子：
19.6
通讯作者：
Itoh, Hiroshi
中科院分区：
文献类型：
--
作者：
Hosoya, Kozi;Minakuchi, Hitoshi;Itoh, Hiroshi
在这项研究中，我们研究了慢性肾脏病 (CKD) 与胰岛素抵抗之间的关联。在非糖尿病 2-5 期 CKD 患者队列中，估计肾小球滤过率 (eGFR) 呈负相关，血浆醛固酮浓度与胰岛素抵抗的稳态模型评估独立相关。使用盐皮质激素受体阻滞剂螺内酯治疗可改善患者的胰岛素抵抗，并且在第五/第六只肾切除大鼠中，糖耐量受损得到部分逆转。在这些大鼠中，胰岛素诱导的信号转导减弱，尤其是在脂肪组织中。肾切除大鼠脂肪组织中，核盐皮质激素受体表达、盐皮质激素受体靶分子SGK-1表达、组织醛固酮含量、醛固酮生成酶CYP11B2表达增加。螺内酯可逆转脂肪组织中盐皮质激素受体的激活。在肾切除大鼠的脂肪组织中，不对称二甲基精氨酸（ADMA；一种与尿毒症和胰岛素抵抗相关的尿毒症物质）增加，ADMA降解酶DDAH1和DDAH2的表达减少，氧化应激增加。所有这些变化都被螺内酯逆转。在成熟脂肪细胞中，醛固酮下调 DDAH1 和 DDAH2 的表达，而 ADMA 抑制胰岛素诱导的细胞信号传导。因此，盐皮质激素受体的激活和由此产生的 ADMA 在脂肪组织中的积累在一定程度上与 CKD 胰岛素抵抗的发展有关。
In this study, we examined the association between chronic kidney disease (CKD) and insulin resistance. In a patient cohort with nondiabetic stages 2-5 CKD, estimated glomerular filtration rate (eGFR) was negatively correlated and the plasma aldosterone concentration was independently associated with the homeostasis model assessment of insulin resistance. Treatment with the mineralocorticoid receptor blocker spironolactone ameliorated insulin resistance in patients, and impaired glucose tolerance was partially reversed in fifth/sixth nephrectomized rats. In these rats, insulin-induced signal transduction was attenuated, especially in the adipose tissue. In the adipose tissue of nephrectomized rats, nuclear mineralocorticoid receptor expression, expression of the mineralocorticoid receptor target molecule SGK-1, tissue aldosterone content, and expression of the aldosterone-producing enzyme CYP11B2 increased. Mineralocorticoid receptor activation in the adipose tissue was reversed by spironolactone. In the adipose tissue of nephrectomized rats, asymmetric dimethylarginine (ADMA; an uremic substance linking uremia and insulin resistance) increased, the expression of the ADMA-degrading enzymes DDAH1 and DDAH2 decreased, and the oxidative stress increased. All of these changes were reversed by spironolactone. In mature adipocytes, aldosterone downregulated both DDAH1 and DDAH2 expression, and ADMA inhibited the insulin-induced cellular signaling. Thus, activation of mineralocorticoid receptor and resultant ADMA accumulation in adipose tissue has, in part, a relevant role in the development of insulin resistance in CKD.