title: Novel GLP-1 fusion chimera as potent long acting GLP-1 receptor agonist.
abstract: GLP-1 has a variety of anti-diabetic effects. However, native GLP-1 is not suitable for therapy of diabetes due to its short half-life (t1/2<2 min). To circumvent this, we developed a long-lasting GLP-1 receptor agonist by the fusion of GLP-1 with human IgG2 Fc (GLP-1/hIgG2). ELISA-based receptor binding assay demonstrated that GLP-1/hIgG2 had high binding affinity to the GLP-1R in INS-1 cells (Kd = 13.90±1.52 nM). Upon binding, GLP-1/hIgG2 was rapidly internalized by INS-1 cells in a dynamin-dependent manner. Insulin RIA showed that GLP-1/IgG2 dose-dependently stimulated insulin secretion from INS-1 cells. Pharmacokinetic studies in CD1 mice showed that with intraperitoneal injection (i.p.), the GLP-1/hIgG2 peaked at 30 minutes in circulation and maintained a plateau for >168 h. Intraperitoneal glucose tolerance test (IPGTT) in mice showed that GLP-1/hIgG2 significantly decreased glucose excursion. Furthermore, IPGTT performed on mice one week after a single drug-injection also displayed significantly reduced glucose excursion, indicating that GLP-1/hIgG2 fusion protein has long-lasting effects on the modulation of glucose homeostasis. GLP-1/hIgG2 was found to be effective in reducing the incidence of diabetes in multiple-low-dose streptozotocin-induced type 1 diabetes in mice. Together, the long-lasting bioactive GLP-1/hIgG2 retains native GLP-1 activities and thus may serve as a potent GLP-1 receptor agonist.
authors.affiliation: Division of Endocrinology and Metabolism, the Keenan Research Centre in the Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada. qinghua.wang@utoronto.ca
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Wang
authors.forename: Kui
authors.initials: K
authors.lastname: Chen
authors.forename: Rui
authors.initials: R
authors.lastname: Liu
authors.forename: Fang
authors.initials: F
authors.lastname: Zhao
authors.forename: Sandeep
authors.initials: S
authors.lastname: Gupta
authors.forename: Nina
authors.initials: N
authors.lastname: Zhang
authors.forename: Gerald J
authors.initials: GJ
authors.lastname: Prud'homme
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003920:Diabetes Mellitus / Q000188:drug therapy* / Q000378:metabolism; D004195:Disease Models, Animal; D052216:Glucagon-Like Peptide 1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D000067757:Glucagon-Like Peptide-1 Receptor; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D007074:Immunoglobulin G / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism; D007700:Kinetics; D008297:Male; D051379:Mice; D011485:Protein Binding; D051381:Rats; D018027:Receptors, Glucagon / Q000819:agonists* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology
chemical_list: C000593833:GLP1R protein, human; C000593834:Glp1r protein, mouse; C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D007074:Immunoglobulin G; D007328:Insulin; D018027:Receptors, Glucagon; D011993:Recombinant Fusion Proteins; D052216:Glucagon-Like Peptide 1