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Poly‐GLP‐1, a novel long‐lasting glucagon‐like peptide‐1 polymer, ameliorates hyperglycaemia by improving insulin sensitivity and increasing pancreatic beta‐cell proliferation
Author(s) -
Ma X.,
Hui H.,
Liu Z.,
He G.,
Hu J.,
Meng J.,
Guan L.,
Luo X.
Publication year - 2009
Publication title -
diabetes, obesity and metabolism
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.445
H-Index - 128
eISSN - 1463-1326
pISSN - 1462-8902
DOI - 10.1111/j.1463-1326.2009.01070.x
Subject(s) - medicine , endocrinology , glucagon like peptide 1 , islet , insulin , glucagon , in vitro , chemistry , somatostatin , pancreatic islets , diabetes mellitus , type 2 diabetes , biochemistry
Aim: 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 β‐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.