title: Poly-GLP-1, a novel long-lasting glucagon-like peptide-1 polymer, ameliorates hyperglycaemia by improving insulin sensitivity and increasing pancreatic beta-cell proliferation.
abstract: OBJECTIVE
  The clinical value of glucagon-like peptide-1 (GLP-1) is restricted because of its short half-life. To overcome this limitation, a new polymer of GLP-1 was developed by prodrug strategy, termed Poly-GLP-1, and its pharmacological properties were investigated.
  
  
  METHODS
  The in vitro release kinetics of GLP-1 from Poly-GLP-1 was analysed by Western blot. Plasma GLP-1 levels following a single administration of Poly-GLP-1 were determined by enzyme-linked immunosorbent assay. The in vitro effects of Poly-GLP-1 were evaluated using isolated pancreatic islets. The acute effects on glycaemic control and food intake were investigated in C57BL/6J mice s.c. administered with Poly-GLP-1. The chronic effects of Poly-GLP-1 on glycaemic control were further assessed in C57BL/6J and db/db mice treated twice daily for 6 weeks.
  
  
  RESULTS
  Pro-GLP-1 dose dependently increased insulin secretion and decreased glucose, but did not exhibit the insulinotropic action in isolated pancreatic islets without plasma. The glucose-lowering actions of Poly-GLP-1 (3 nmol/kg) remained no less than 12 h after a single injection. Poly-GLP-1 caused a durable restoration of glycaemic control, food intake and body weight gain in db/db mice following 6-week administration. The chronic treatment with Poly-GLP-1 improved glucose tolerance and insulin sensitivity and increased beta-cell mass and proliferation in db/db mice. There was little effect on normal mice treated in the same manner.
  
  
  CONCLUSIONS
  Our results indicated that Poly-GLP-1, a novel GLP-1 polymer, has long-lasting and potent effects on glycaemic control in vivo, and these beneficial effects may be because of improvement of insulin sensitivity and promotion of islet growth and function.
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: X
authors.initials: X
authors.lastname: Ma
authors.forename: H
authors.initials: H
authors.lastname: Hui
authors.forename: Z
authors.initials: Z
authors.lastname: Liu
authors.forename: G
authors.initials: G
authors.lastname: He
authors.forename: J
authors.initials: J
authors.lastname: Hu
authors.forename: J
authors.initials: J
authors.lastname: Meng
authors.forename: L
authors.initials: L
authors.lastname: Guan
authors.forename: X
authors.initials: X
authors.lastname: Luo
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004797:Enzyme-Linked Immunosorbent Assay; D052216:Glucagon-Like Peptide 1 / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D006943:Hyperglycemia / Q000188:drug therapy*; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects*; D051379:Mice; D008807:Mice, Inbred BALB C; D011108:Polymers; D011355:Prodrugs / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D011108:Polymers; D011355:Prodrugs; D052216:Glucagon-Like Peptide 1