Description:
<jats:p><jats:bold>Aim: </jats:bold> 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.</jats:p><jats:p><jats:bold>Methods: </jats:bold> The <jats:italic>in vitro</jats:italic> 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 <jats:italic>in vitro</jats:italic> 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 <jats:italic>db/db</jats:italic> mice treated twice daily for 6 weeks.</jats:p><jats:p><jats:bold>Results: </jats:bold> 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 <jats:italic>db/db</jats:italic> mice following 6‐week administration. The chronic treatment with Poly‐GLP‐1 improved glucose tolerance and insulin sensitivity and increased β‐cell mass and proliferation in <jats:italic>db/db</jats:italic> mice. There was little effect on normal mice treated in the same manner.</jats:p><jats:p><jats:bold>Conclusions: </jats:bold> Our results indicated that Poly‐GLP‐1, a novel GLP‐1 polymer, has long‐lasting and potent effects on glycaemic control <jats:italic>in vivo</jats:italic>, and these beneficial effects may be because of improvement of insulin sensitivity and promotion of islet growth and function.</jats:p>