title: A novel GLP-1 analog, a dimer of GLP-1 via covalent linkage by a lysine, prolongs the action of GLP-1 in the treatment of type 2 diabetes.
abstract: GLP-1 is an incretin hormone that can effectively lower blood glucose, however, the short time of biological activity and the side effect limit its therapeutic application. Many methods have been tried to optimize GLP-1 to extend its in vivo half-time, reduce its side effect and enhance its activity. Here we have chosen the idea to dimerize GLP-1 with a C-terminal lysine to form a new GLP-1 analog, DLG3312. We have explored the structure and the biological property of DLG3312, and the results indicated that DLG3312 not only remained the ability to activate the GLP-1R, but also strongly stimulated Min6 cell to secrete insulin. The in vivo bioactivities have been tested on two kinds of animal models, the STZ induced T2DM mice and the db/db mice, respectively. DLG3312 showed potent anti-diabetic ability in glucose tolerance assay and single-dose administration of DLG3312 could lower blood glucose for at least 10 hours. Long-term treatment with DLG3312 can reduce fasted blood glucose, decrease water consumption and food intake and significantly reduce the HbA1c level by 1.80% and 2.37% on STZ induced T2DM mice and the db/db mice, respectively. We also compared DLG3312 with liraglutide to investigate its integrated control of the type 2 diabetes. The results indicated that DLG3312 almost has the same effect as liraglutide but with a much simpler preparation process. In conclusion, we, by using C-terminal lysine as a linker, have synthesized a novel GLP-1 analog, DLG3312. With simplified preparation and improved physiological characterizations, DLG3312 could be considered as a promising candidate for the type 2 diabetes therapy.
authors.affiliation: School of Life Science, East China Normal University, Shanghai, China.
authors.forename: Yingying
authors.initials: Y
authors.lastname: Pan
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Siwei
authors.initials: S
authors.lastname: Shi
authors.affiliation: School of Life Science, East China Normal University, Shanghai, China.
authors.forename: Xun
authors.initials: X
authors.lastname: Lao
authors.affiliation: School of Life Science, East China Normal University, Shanghai, China.
authors.forename: Jinlong
authors.initials: J
authors.lastname: Zhang
authors.affiliation: School of Life Science, East China Normal University, Shanghai, China.
authors.forename: Shiming
authors.initials: S
authors.lastname: Tan
authors.affiliation: School of Life Science, East China Normal University, Shanghai, China.
authors.forename: Zirong
authors.initials: Z
authors.lastname: Wu
authors.affiliation: School of Life Science, East China Normal University, Shanghai, China. Electronic address: jhuang@bio.ecnu.edu.cn.
authors.forename: Jing
authors.initials: J
authors.lastname: Huang
mesh_terms: D000818:Animals; D001786:Blood Glucose; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D052216:Glucagon-Like Peptide 1 / Q000008:administration & dosage* / Q000378:metabolism; D000067757:Glucagon-Like Peptide-1 Receptor / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000378:metabolism; D007328:Insulin / Q000097:blood*; D051379:Mice
chemical_list: D001786:Blood Glucose; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D007328:Insulin; D052216:Glucagon-Like Peptide 1
keywords: Animal experiment; Dimerization; GLP-1 analog; Long-term treatment; Type 2 diabetes