TY - JOUR
T1 - Molecular mechanisms underlying physiological and receptor pleiotropic effects mediated by GLP-1R activation
AU - Pabreja, Kavita
AU - Mohd, Muzaida
AU - Koole, Cassandra Renee
AU - Wootten, Denise Laura
AU - Furness, Sebastian George Barton
PY - 2014
Y1 - 2014
N2 - The incidence of type 2 diabetes in developed countries is increasing yearly with a significant negative impact on patient quality of life and an enormous burden on the healthcare system. Current biguanide and thiazolidinedione treatments for type 2 diabetes have a number of clinical limitations, the most serious long term limitation being the eventual need for insulin replacement therapy. Since 2007, drugs targeting the glucagon like peptide 1 (GLP-1) receptor have been marketed for the treatment of type 2 diabetes. These drugs have enjoyed a great deal of success even though our underlying understanding of the mechanisms for their pleiotropic effects remain poorly characterised even while major pharmaceutical companies actively pursue small molecule alternatives. Coupling of the GLP-1 receptor to more than one signalling pathway (pleiotropic signalling) can result in ligand dependent signalling bias and for a peptide receptor such as the GLP-1 receptor this can be exaggerated with the use of small molecule agonists. Better consideration of receptor signalling pleiotropy will be necessary future drug development. This is particularly important given the recent failure of taspoglutide, the report of increased risk of pancreatitis associated with GLP-1 mimetics and the observed clinical differences between liraglutide, exenatide and the newly developed long-acting exenatide long acting release, albiglutide and dulaglutide.
AB - The incidence of type 2 diabetes in developed countries is increasing yearly with a significant negative impact on patient quality of life and an enormous burden on the healthcare system. Current biguanide and thiazolidinedione treatments for type 2 diabetes have a number of clinical limitations, the most serious long term limitation being the eventual need for insulin replacement therapy. Since 2007, drugs targeting the glucagon like peptide 1 (GLP-1) receptor have been marketed for the treatment of type 2 diabetes. These drugs have enjoyed a great deal of success even though our underlying understanding of the mechanisms for their pleiotropic effects remain poorly characterised even while major pharmaceutical companies actively pursue small molecule alternatives. Coupling of the GLP-1 receptor to more than one signalling pathway (pleiotropic signalling) can result in ligand dependent signalling bias and for a peptide receptor such as the GLP-1 receptor this can be exaggerated with the use of small molecule agonists. Better consideration of receptor signalling pleiotropy will be necessary future drug development. This is particularly important given the recent failure of taspoglutide, the report of increased risk of pancreatitis associated with GLP-1 mimetics and the observed clinical differences between liraglutide, exenatide and the newly developed long-acting exenatide long acting release, albiglutide and dulaglutide.
UR - http://onlinelibrary.wiley.com/doi/10.1111/bph.12313/pdf
U2 - 10.1111/bph.12313
DO - 10.1111/bph.12313
M3 - Article
VL - 171
SP - 1114
EP - 1128
JO - British Journal of Pharmacology
JF - British Journal of Pharmacology
SN - 1476-5381
IS - 5
ER -