Department of Microbiology, College of Life Sciences, Nankai University, Tianjin, 300071, China.
Peptides. 2009 Oct;30(10):1874-81. doi: 10.1016/j.peptides.2009.07.020. Epub 2009 Aug 6.
Glucagon-like peptide-1 (GLP-1) is an important hormone peptide secreted from the gastrointestinal tract in response to nutrient ingestion. Its multifaceted actions make GLP-1 attractive as a candidate for the treatment of type 2 diabetes mellitus. However, its main limitation is an extremely short half-life, which is due to rapid inactivation by a ubiquitous enzyme, dipeptidyl peptidase-IV (DPP-IV). Therefore, here we describe the development of a novel GLP-1 analog, designated KGLP-1. Initial in vitro experiments revealed that KGLP-1 bound to and activated GLP-1R with similar efficacy as native GLP-1. Importantly, KGLP-1 showed marked resistance to inactivation by DPP-IV. Further in vivo studies confirmed that KGLP-1 had antihyperglycemic and insulinotropic actions after intraperitoneal injection to KM mice and alloxan-induced diabetic mice. Finally, we prepared KGLP-1-loaded poly (d,l-lactic-co-glycolic acid) microspheres (PLGA MS) using the solid in oil in oil (s/o/o) solvent extraction method, which achieved controlled release and biological efficacy over a period of 10 days after a single subcutaneous injection in alloxan-induced diabetic rats.
胰高血糖素样肽-1（GLP-1）是一种重要的激素肽，在摄入营养物质时从胃肠道中分泌出来。它的多方面作用使其成为治疗 2 型糖尿病的候选药物。然而，其主要限制是半衰期极短，这是由于其被广泛存在的二肽基肽酶-IV（DPP-IV）迅速失活。因此，我们在这里描述了一种新型 GLP-1 类似物的开发，命名为 KGLP-1。初步的体外实验表明，KGLP-1 与 GLP-1R 结合并激活其的效力与天然 GLP-1 相似。重要的是，KGLP-1 对 DPP-IV 的失活具有显著的抗性。进一步的体内研究证实，KGLP-1 在腹腔注射 KM 小鼠和链脲佐菌素诱导的糖尿病小鼠后具有降血糖和胰岛素促分泌作用。最后，我们使用固-油-油（s/o/o）溶剂萃取法制备了负载 KGLP-1 的聚（丙交酯-乙交酯）微球（PLGA MS），在单次皮下注射后，在链脲佐菌素诱导的糖尿病大鼠体内可实现长达 10 天的控释和生物疗效。
