Park Cheol Whee, Kim Hyeong Wook, Ko Seung Hyun, Lim Ji Hee, Ryu Gyeong Ryul, Chung Hyun Wha, Han Sang Woo, Shin Seog Jun, Bang Byung Kee, Breyer Matthew D, Chang Yoon Sik
Division of Nephrology, Department of Internal Medicine, The Catholic University of Korea, #62 Yoido-Dong, Youngdungpo-Ku, Seoul, Korea 150-713.
J Am Soc Nephrol. 2007 Apr;18(4):1227-38. doi: 10.1681/ASN.2006070778. Epub 2007 Mar 14.
Glucagon-like peptide-1 (GLP-1) is a gut incretin hormone and is a new clinically available class of agents for improving of insulin resistance in both animals and humans with type 2 diabetes. These studies aimed to determine whether long-term treatment with a long-acting GLP-1 analog, exendin-4, delayed the progression of diabetes. Male db/db mice and db/m mice at 8 wk of age were treated with exendin-4 for 8 wk, whereas the control db/db mice received only vehicle. Urinary albumin excretion was significantly decreased in db/db mice that were treated with 1 nmol/kg exendin-4 compared with those in db/db mice that were treated with 0.5 nmol/kg exendin-4 and control db/db mice (P < 0.005). Intraperitoneal glucose tolerance test was improved in db/db mice that were treated with 1 nmol/kg exendin-4 compared with other groups (P < 0.05). Despite this, fasting blood glucose, glycated hemoglobin, and creatinine concentrations were not significantly different among db/db mice. Renal histology studies further demonstrated that glomerular hypertrophy, mesangial matrix expansion, TGF-beta1 expression, and type IV collagen accumulation and associated glomerular lipid accumulation were significantly decreased in db/db mice that were treated with 1 nmol/kg exendin-4. Furthermore, there were fewer infiltrating inflammatory cells and apoptotic cells in the glomeruli of db/db mice that were treated with 1 nmol/kg exendin-4 compared with those in the other groups accompanied by an increase in the renal immunoreactivity of peroxisome proliferator-activated receptor alpha and GLP-1 receptor-positive cells and a decrease in 24-h urinary 8-hydroxy-deoxyguanosine levels (P < 0.01, respectively) along with decreases in lipid content. Taken together, exendin-4 treatment seems to ameliorate diabetic nephropathy together with improvement of the metabolic anomalies. These results suggest that exendin-4 could provide a therapeutic role in diabetic nephropathy that results from type 2 diabetes.
胰高血糖素样肽-1（GLP-1）是一种肠促胰岛素激素，是临床上新出现的一类可用于改善2型糖尿病动物和人类胰岛素抵抗的药物。这些研究旨在确定长效GLP-1类似物艾塞那肽-4的长期治疗是否能延缓糖尿病的进展。8周龄的雄性db/db小鼠和db/m小鼠接受艾塞那肽-4治疗8周，而对照db/db小鼠仅接受赋形剂。与接受0.5 nmol/kg艾塞那肽-4治疗的db/db小鼠和对照db/db小鼠相比，接受1 nmol/kg艾塞那肽-4治疗的db/db小鼠尿白蛋白排泄显著降低（P<0.005）。与其他组相比，接受1 nmol/kg艾塞那肽-4治疗的db/db小鼠腹腔内葡萄糖耐量试验得到改善（P<0.05）。尽管如此，db/db小鼠之间的空腹血糖、糖化血红蛋白和肌酐浓度并无显著差异。肾脏组织学研究进一步表明，接受1 nmol/kg艾塞那肽-4治疗的db/db小鼠肾小球肥大、系膜基质扩张、转化生长因子-β1表达、IV型胶原积累及相关肾小球脂质积累均显著减少。此外，与其他组相比，接受1 nmol/kg艾塞那肽-4治疗的db/db小鼠肾小球中浸润性炎症细胞和凋亡细胞较少，同时过氧化物酶体增殖物激活受体α和GLP-1受体阳性细胞的肾脏免疫反应性增加，24小时尿8-羟基脱氧鸟苷水平降低（分别为P<0.01），脂质含量也降低。综上所述，艾塞那肽-4治疗似乎能改善糖尿病肾病并改善代谢异常。这些结果表明，艾塞那肽-4可能在2型糖尿病所致的糖尿病肾病中发挥治疗作用。
