Sudre Béatrice, Broqua Pierre, White Richard B, Ashworth Doreen, Evans D Michael, Haigh Robert, Junien Jean-Louis, Aubert Michel L
Ferring Research Institute and Division of Biology of Growth and Reproduction, Department of Pediatrics, University of Geneva School of Medicine, Geneva, Switzerland.
Diabetes. 2002 May;51(5):1461-9. doi: 10.2337/diabetes.51.5.1461.
Acute suppression of dipeptidyl peptidase IV (DPP-IV) activity improves glucose tolerance in the Zucker fatty rat, a rodent model of impaired glucose tolerance, through stabilization of glucagon-like peptide (GLP)-1. This study describes the effects of a new and potent DPP-IV inhibitor, FE 999011, which is able to suppress plasma DPP-IV activity for 12 h after a single oral administration. In the Zucker fatty rat, FE 999011 dose-dependently attenuated glucose excursion during an oral glucose tolerance test and increased GLP-1 (7-36) release in response to intraduodenal glucose. Chronic treatment with FE 999011 (10 mg/kg, twice a day for 7 days) improved glucose tolerance, as suggested by a decrease in the insulin-to-glucose ratio. In the Zucker diabetic fatty (ZDF) rat, a rodent model of type 2 diabetes, chronic treatment with FE 999011 (10 mg/kg per os, once or twice a day) postponed the development of diabetes, with the twice-a-day treatment delaying the onset of hyperglycemia by 21 days. In addition, treatment with FE 999011 stabilized food and water intake to prediabetic levels and reduced hypertriglyceridemia while preventing the rise in circulating free fatty acids. At the end of treatment, basal plasma GLP-1 levels were increased, and pancreatic gene expression for GLP-1 receptor was significantly upregulated. This study demonstrates that DPP-IV inhibitors such as FE 999011 could be of clinical value to delay the progression from impaired glucose tolerance to type 2 diabetes.
急性抑制二肽基肽酶IV（DPP-IV）活性可通过稳定胰高血糖素样肽（GLP）-1来改善Zucker肥胖大鼠（一种糖耐量受损的啮齿动物模型）的糖耐量。本研究描述了一种新型强效DPP-IV抑制剂FE 999011的作用，单次口服给药后，该抑制剂能够抑制血浆DPP-IV活性达12小时。在Zucker肥胖大鼠中，FE 999011在口服葡萄糖耐量试验中剂量依赖性地减弱葡萄糖波动，并增加十二指肠内葡萄糖刺激后的GLP-1（7-36）释放。FE 999011慢性治疗（10 mg/kg，每日两次，共7天）改善了糖耐量，胰岛素与葡萄糖比值降低表明了这一点。在2型糖尿病啮齿动物模型Zucker糖尿病肥胖（ZDF）大鼠中，FE 999011慢性治疗（10 mg/kg口服，每日一次或两次）延缓了糖尿病的发展，每日两次治疗使高血糖发作延迟了21天。此外，FE 999011治疗使食物和水摄入量稳定在糖尿病前期水平，降低了高甘油三酯血症，同时防止循环游离脂肪酸升高。治疗结束时，基础血浆GLP-1水平升高，GLP-1受体的胰腺基因表达显著上调。本研究表明，像FE 999011这样的DPP-IV抑制剂对于延缓从糖耐量受损进展到2型糖尿病可能具有临床价值。
