A novel DPP-IV-resistant analog of glucagon-like peptide-1 (GLP-1): KGLP-1 alone or in combination with long-acting PLGA microspheres.
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.
Gao
Zhihui
Z
Department of Microbiology, College of Life Sciences, Nankai University, Tianjin, 300071, China.
Tang
Yu
Y
Chen
Jiaqi
J
Bai
Ru
R
Zhang
Qi
Q
Hou
Yuanyuan
Y
Lu
Yaxin
Y
Bai
Gang
G
D000818:Animals; D002460:Cell Line; D003921:Diabetes Mellitus, Experimental; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D004339:Drug Compounding; D005260:Female; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives / Q000378:metabolism; D005951:Glucose Tolerance Test; D006801:Humans; D019344:Lactic Acid / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D008863:Microspheres; D011100:Polyglycolic Acid / Q000737:chemistry / Q000378:metabolism*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D051381:Rats; D017208:Rats, Wistar
D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D052216:Glucagon-Like Peptide 1; D018819:Dipeptidyl Peptidase 4