慢性肾脏病胰岛素抵抗的发病机制、治疗策略及中药的干预作用

Pathogenesis and treatment of insulin resistance in chronic kidney disease and interventional effects of Chinese herbal medicine

肾脏是胰岛素的靶器官,具备丰富的胰岛素受体,其中,肾脏固有细胞,如肾小球足细胞、内皮细胞、系膜细胞以及肾小管、集合管上皮细胞都是胰岛素高度敏感的效应细胞,其结构和功能的异常与胰岛素及其受体活性密切相关。慢性肾脏病(chronic kidney disease,CKD)患者存在全身或肾组织胰岛素抵抗(insulin resistance,IR)。IR既是CKD致病因素,又是其进展的机制之一。CKD患者IR的致病因素包括全身性因素和存在于肌肉、脂肪细胞的局部因素;其发病机制涉及肾小球、近端肾小管、集合管以及相应的肾脏固有细胞,如足细胞、系膜细胞和肾小管、集合管上皮细胞。IR相关信号调控途径包括胰岛素受体底物(insulin receptor substrate,IRS)/磷脂酰肌醇3激酶(phosphatidylinositol-3-kinase,PI3K)/丝氨酸-苏氨酸激酶(serine-threonine kinase,Akt)通路、单磷酸腺苷活化蛋白激酶(adenosine monophosphate activated protein kinase,AMPK)通路、葡萄糖转运蛋白4(glucose transporter4,GLUT4)通路、核因子(nuclear factor,NF)-κB通路以及丝裂原活化蛋白激酶(mitogen-activated protein kinase,MAPK)通路等,其中,IRS1/PI3K/Akt2通路是肾小球足细胞IR的主要信号调控途径,干预其活性就可以改善足细胞损伤。临床上,一些经典的口服降糖药和利尿剂,如二甲双胍、罗格列酮、格列本脲、噻唑烷二酮、安体舒通等,还有一些单味中药的提取物,如黄芪多糖、槲皮素、葛根素、大黄素、小檗碱、姜黄素以及栀子苷等可以干预胰岛素及其受体活性以及IR相关信号调控途径,改善IR,缓解CKD进展。总之,基于CKD肾脏固有细胞IR信号调控途径的相关药理学研究是今后的发展方向之一。

The kidney is the target organ of insulin with abundant insulin receptors. Thereinto, the renal intrinsic cells including glomerular podocytes, endothelial cells, mesangial cells, renal tubular epitheliums and collecting duct epithelial cells are all highly sensi- tive to insulin as the effector cells. Furthermore,the structural and functional abnormalities of these cells are closely related to insulin and its receptors activity. It is reported that the chronic kidney disease（CKD） patients have systemic or renal insulin resistance（IR）. IR is not only the pathogenic factor of CKD but also one of the mechanisms of CKD progression. The pathogenic factors of IR in the CKD patients include the systemic factors and the local factors in muscles and fat cells. The pathogenesis of IR is related to glomeruli, proximal tubules, collecting ducts and corresponding renal intrinsic cells such as podocytes, mesangial cells, renal tubular epitheliums and collecting duct epithelial cells. IR-related signaling pathways include insulin receptor substrate （IRS）/phosphatidylinositol 3 kinase （PI3K）/serine threonine kinase（Akt） pathway,adenosine monophosphate activated protein kinase（AMPK） pathway, glucose transport- er4（GLUT4） pathway, nuclear factor（ NF）-KB pathway and mitogen activated protein kinase （MAPK）pathway. Among them, IRS1/ PI3K/Akt2 is the main signaling pathway of IR in podoeytes of glomeruli, thus intervening its activity can improve podocyte injury. In clinic, some classical oral hypoglycemic agents and diuretic including metformin, rosiglitazone, glibenclamide, thiazolidinedione and spi- ronolactone, as well as some extracts from Chinese herbal medicines including astragalus polysaecharides, quercetin, puerarin, emodin, berberine, curcumin and geniposide can both affect insulin and its receptor activity, and regulate IR-related signaling pathways ,thereby ameliorating IR and CKD progression. Overall, the pharmacological studies based on IR-related signaling pathways in the renal intrinsic cells of CKD will become one of the developmental directions in the future.