PMID- 26621478
OWN - NLM
STAT- MEDLINE
DCOM- 20160628
LR  - 20181113
IS  - 2041-1723 (Electronic)
IS  - 2041-1723 (Linking)
VI  - 6
DP  - 2015 Dec 1
TI  - Autocrine selection of a GLP-1R G-protein biased agonist with potent antidiabetic 
      effects.
PG  - 8918
LID - 10.1038/ncomms9918 [doi]
LID - 8918
AB  - Glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) agonists have emerged as 
      treatment options for type 2 diabetes mellitus (T2DM). GLP-1R signals through 
      G-protein-dependent, and G-protein-independent pathways by engaging the scaffold 
      protein beta-arrestin; preferential signalling of ligands through one or the other 
      of these branches is known as 'ligand bias'. Here we report the discovery of the 
      potent and selective GLP-1R G-protein-biased agonist, P5. We identified P5 in a 
      high-throughput autocrine-based screening of large combinatorial peptide 
      libraries, and show that P5 promotes G-protein signalling comparable to GLP-1 and 
      Exendin-4, but exhibited a significantly reduced beta-arrestin response. Preclinical 
      studies using different mouse models of T2DM demonstrate that P5 is a weak 
      insulin secretagogue. Nevertheless, chronic treatment of diabetic mice with P5 
      increased adipogenesis, reduced adipose tissue inflammation as well as hepatic 
      steatosis and was more effective at correcting hyperglycaemia and lowering 
      haemoglobin A1c levels than Exendin-4, suggesting that GLP-1R G-protein-biased 
      agonists may provide a novel therapeutic approach to T2DM.
FAU - Zhang, Hongkai
AU  - Zhang H
AD  - Department of Cell and Molecular Biology, The Scripps Research Institute, La 
      Jolla, California 92037, USA.
FAU - Sturchler, Emmanuel
AU  - Sturchler E
AD  - Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, 
      Florida 33458, USA.
FAU - Zhu, Jiang
AU  - Zhu J
AD  - Department of Immunology and Microbial Science, The Scripps Research Institute, 
      La Jolla, California 92037, USA.
FAU - Nieto, Ainhoa
AU  - Nieto A
AD  - Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, 
      Florida 33458, USA.
FAU - Cistrone, Philip A
AU  - Cistrone PA
AD  - Department of Chemistry, The Scripps Research Institute, La Jolla, California 
      92037, USA.
FAU - Xie, Jia
AU  - Xie J
AD  - Department of Cell and Molecular Biology, The Scripps Research Institute, La 
      Jolla, California 92037, USA.
FAU - He, LinLing
AU  - He L
AD  - Department of Immunology and Microbial Science, The Scripps Research Institute, 
      La Jolla, California 92037, USA.
FAU - Yea, Kyungmoo
AU  - Yea K
AD  - Shanghai Institute for Advance Immunological Studies, Shanghai Tech University, 
      Shanghai 200031, China.
FAU - Jones, Teresa
AU  - Jones T
AD  - Department of Cell and Molecular Biology, The Scripps Research Institute, La 
      Jolla, California 92037, USA.
FAU - Turn, Rachel
AU  - Turn R
AD  - Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, 
      Florida 33458, USA.
FAU - Di Stefano, Peter S
AU  - Di Stefano PS
AD  - Zebra Biologics Inc., Concord, Massachusetts 01742, USA.
FAU - Griffin, Patrick R
AU  - Griffin PR
AD  - Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, 
      Florida 33458, USA.
FAU - Dawson, Philip E
AU  - Dawson PE
AD  - Department of Immunology and Microbial Science, The Scripps Research Institute, 
      La Jolla, California 92037, USA.
FAU - McDonald, Patricia H
AU  - McDonald PH
AD  - Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, 
      Florida 33458, USA.
FAU - Lerner, Richard A
AU  - Lerner RA
AD  - Department of Cell and Molecular Biology, The Scripps Research Institute, La 
      Jolla, California 92037, USA.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20151201
PL  - England
TA  - Nat Commun
JT  - Nature communications
JID - 101528555
RN  - 0 (Glp1r protein, mouse)
RN  - 0 (Glucagon-Like Peptide-1 Receptor)
RN  - 0 (Hypoglycemic Agents)
RN  - 0 (Insulin)
RN  - 0 (Peptides)
SB  - IM
MH  - Adipogenesis/drug effects
MH  - Adipose Tissue/drug effects/metabolism
MH  - Animals
MH  - Diabetes Mellitus, Type 2/*drug therapy/genetics/metabolism/physiopathology
MH  - Drug Evaluation, Preclinical
MH  - Glucagon-Like Peptide-1 Receptor/*antagonists & inhibitors/genetics/metabolism
MH  - Humans
MH  - Hypoglycemic Agents/*administration & dosage
MH  - Insulin/metabolism
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Peptides/*administration & dosage
PMC - PMC4686834
COIS- P.S.D.S. is an employee of Zebra Biologics, Inc. and is a shareholder of Zebra 
      Biologics, Inc. R.A.L is a shareholder of Zebra Biologics, Inc.
EDAT- 2015/12/02 06:00
MHDA- 2016/06/29 06:00
PMCR- 2015/12/22
CRDT- 2015/12/02 06:00
PHST- 2015/05/12 00:00 [received]
PHST- 2015/10/16 00:00 [accepted]
PHST- 2015/12/02 06:00 [entrez]
PHST- 2015/12/02 06:00 [pubmed]
PHST- 2016/06/29 06:00 [medline]
PHST- 2015/12/22 00:00 [pmc-release]
AID - ncomms9918 [pii]
AID - 10.1038/ncomms9918 [doi]
PST - epublish
SO  - Nat Commun. 2015 Dec 1;6:8918. doi: 10.1038/ncomms9918.