Glucagon-like peptide 1 receptor agonist ZP10A increases insulin mRNA expression and prevents diabetic progression in db/db mice
Glucagon-like peptide 1 receptor agonist ZP10A increases insulin mRNA expression and prevents diabetic progression in db/db mice
复制标题
DOI：
10.1124/jpet.103.051987
复制
发表时间：
2003-11-01
影响因子：
3.5
通讯作者：
Petersen, JS
中科院分区：
文献类型：
--
作者：
Thorkildsen, C;Neve, S;Petersen, JS
我们表征了新的、合理设计的肽类胰高血糖素样肽1（GLP-1）受体激动剂H-HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPSK KKKKK-NH 2（ZP 10A）。受体结合研究表明，ZP 10A对人GLP-1受体的亲和力是GLP-1（7-36）酰胺亲和力的4倍。在糖尿病db/db小鼠的口服葡萄糖耐量试验（OGTT）中，ZP 10A显示出葡萄糖耐量的剂量依赖性改善，腹膜内ED 50值为0.02 nmol/kg。治疗42天后，ZP 10A剂量依赖性地（0、1、10或100 nmol/kg b.i.d.; n = 10/组），糖化血红蛋白（HbA（1C））从8.4 +/- 0.4%（溶剂）降至最低6.2 +/- 0.3%（100 nmol/kg b.i.d.; p < 0.05相对于载体）。与载体处理的对照组相比，用ZP 10A处理90天的小鼠的空腹血糖（FBG）、OGTT后的葡萄糖耐量和HbA（1C）水平显著改善。有趣的是，仅在研究的前50天期间用ZP 10A处理的db/db小鼠在药物停止后40天保留了这些效果。实时聚合酶链反应测量表明，ZP 10A早期治疗的抗糖尿病作用与胰腺胰岛素mRNA表达相对于溶剂处理的小鼠增加有关。总之，用ZP 10A长期治疗糖尿病db/db小鼠导致FBG、葡萄糖耐量和血糖控制的剂量依赖性改善。我们的数据表明ZP 10A保留了β细胞功能。ZP 10A被认为是预防和治疗2型糖尿病的最有前途的候选新药之一。
We characterized the novel, rationally designed peptide glucagon-like peptide 1 (GLP-1) receptor agonist H-HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPSK KKKKK-NH2 (ZP10A). Receptor binding studies demonstrated that the affinity of ZP10A for the human GLP-1 receptor was 4-fold greater than the affinity of GLP-1 (7-36) amide. ZP10A demonstrated dose-dependent improvement of glucose tolerance with an ED50 value of 0.02 nmol/kg i.p. in an oral glucose tolerance test (OGTT) in diabetic db/db mice. After 42 days of treatment, ZP10A dose-dependently (0, 1, 10, or 100 nmol/kg b.i.d.; n = 10/group), decreased glycosylated hemoglobin (HbA(1C)) from 8.4 +/- 0.4% (vehicle) to a minimum of 6.2 +/- 0.3% (100 nmol/kg b.i.d.; p < 0.05 versus vehicle) in db/db mice. Fasting blood glucose (FBG), glucose tolerance after an OGTT, and HbA(1C) levels were significantly improved in mice treated with ZP10A for 90 days compared with vehicle-treated controls. Interestingly, these effects were preserved 40 days after drug cessation in db/db mice treated with ZP10A only during the first 50 days of the study. Real-time polymerase chain reaction measurements demonstrated that the antidiabetic effect of early therapy with ZP10A was associated with an increased pancreatic insulin mRNA expression relative to vehicle-treated mice. In conclusion, long-term treatment of diabetic db/db mice with ZP10A resulted in a dose-dependent improvement of FBG, glucose tolerance, and blood glucose control. Our data suggest that ZP10A preserves β-cell function. ZP10A is considered one of the most promising new drug candidates for preventive and therapeutic intervention in type 2 diabetes.