PMID- 26417688
OWN - NLM
STAT- MEDLINE
DCOM- 20160426
LR  - 20191114
IS  - 1090-2104 (Electronic)
IS  - 0006-291X (Linking)
VI  - 466
IP  - 4
DP  - 2015 Oct 30
TI  - Yhhu4488, a novel GPR40 agonist, promotes GLP-1 secretion and exerts 
      anti-diabetic effect in rodent models.
PG  - 740-7
LID - S0006-291X(15)30647-1 [pii]
LID - 10.1016/j.bbrc.2015.09.130 [doi]
AB  - G protein-coupled receptor 40 (GPR40) is predominantly expressed in pancreatic 
      beta-cells and activated by long-chain fatty acids. GPR40 has drawn considerable 
      interest as a potential therapeutic target for type 2 diabetes mellitus (T2DM) 
      due to its important role in enhancing glucose-stimulated insulin secretion 
      (GSIS). Encouragingly, GPR40 is also proven to be highly expressed in 
      glucagon-like peptide-1 (GLP-1)-producing enteroendocrine cells afterwards, which 
      opens a potential role of GPR40 in enhancing GLP-1 secretion to exert additional 
      anti-diabetic efficacy. In the present study, we discovered a novel GPR40 
      agonist, yhhu4488, which is structurally different from other reported GPR40 
      agonists. Yhhu4488 showed potent agonist activity with EC50 of 49.96 nM, 70.83 nM 
      and 58.68 nM in HEK293 cells stably expressing human, rat and mouse GPR40, 
      respectively. Yhhu4488 stimulated GLP-1 secretion from fetal rat intestinal cells 
      (FRIC) via triggering endogenous calcium store mobilization and extracellular 
      calcium influx. The effect of yhhu4488 on GLP-1 secretion was further confirmed 
      in type 2 diabetic db/db mice. Yhhu4488 exhibited satisfactory potency in in vivo 
      studies. Single administration of yhhu4488 improved glucose tolerance in SD rats. 
      Chronic administration of yhhu4488 effectively decreased fasting blood glucose 
      level, improved beta-cell function and lipid homeostasis in type 2 diabetic ob/ob 
      mice. Taken together, yhhu4488 is a novel GPR40 agonist that enhances GLP-1 
      secretion, improves metabolic control and beta-cell function, suggesting its 
      promising potential for the treatment of type 2 diabetes.
CI  - Copyright (c) 2015 Elsevier Inc. All rights reserved.
FAU - Guo, Dan-yang
AU  - Guo DY
AD  - State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, 
      Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, PR China.
FAU - Li, De-wen
AU  - Li DW
AD  - State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, 
      Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, PR China.
FAU - Ning, Meng-meng
AU  - Ning MM
AD  - State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, 
      Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, PR China.
FAU - Dang, Xiang-yu
AU  - Dang XY
AD  - State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, 
      Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, PR China.
FAU - Zhang, Li-na
AU  - Zhang LN
AD  - State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, 
      Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, PR China.
FAU - Zeng, Li-min
AU  - Zeng LM
AD  - State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, 
      Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, PR China.
FAU - Hu, You-hong
AU  - Hu YH
AD  - State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, 
      Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, PR China. 
      Electronic address: yhhu@mail.shcnc.ac.cn.
FAU - Leng, Ying
AU  - Leng Y
AD  - State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, 
      Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, PR China. 
      Electronic address: yleng@simm.ac.cn.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150928
PL  - United States
TA  - Biochem Biophys Res Commun
JT  - Biochemical and biophysical research communications
JID - 0372516
RN  - 0 (FFAR1 protein, human)
RN  - 0 (Ffar1 protein, mouse)
RN  - 0 (G-protein-coupled receptor 40, rat)
RN  - 0 (Hypoglycemic Agents)
RN  - 0 (Phenylpropionates)
RN  - 0 (Pyridines)
RN  - 0 (Receptors, G-Protein-Coupled)
RN  - 0 (Yhhu4488)
RN  - 89750-14-1 (Glucagon-Like Peptide 1)
SB  - IM
MH  - Animals
MH  - Diabetes Mellitus, Type 2/drug therapy/physiopathology
MH  - Female
MH  - Glucagon-Like Peptide 1/*metabolism
MH  - Glucose Tolerance Test
MH  - Humans
MH  - Hypoglycemic Agents/*pharmacology
MH  - Insulin-Secreting Cells/drug effects/physiology
MH  - Male
MH  - Mice
MH  - Mice, Mutant Strains
MH  - Phenylpropionates/*pharmacology
MH  - Pregnancy
MH  - Pyridines/*pharmacology
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Receptors, G-Protein-Coupled/*agonists
OTO - NOTNLM
OT  - GPR40
OT  - Glucagon-like peptide-1
OT  - Insulin
OT  - Type 2 diabetes mellitus
OT  - Yhhu4488
EDAT- 2015/09/30 06:00
MHDA- 2016/04/27 06:00
CRDT- 2015/09/30 06:00
PHST- 2015/09/18 00:00 [received]
PHST- 2015/09/23 00:00 [accepted]
PHST- 2015/09/30 06:00 [entrez]
PHST- 2015/09/30 06:00 [pubmed]
PHST- 2016/04/27 06:00 [medline]
AID - S0006-291X(15)30647-1 [pii]
AID - 10.1016/j.bbrc.2015.09.130 [doi]
PST - ppublish
SO  - Biochem Biophys Res Commun. 2015 Oct 30;466(4):740-7. doi: 
      10.1016/j.bbrc.2015.09.130. Epub 2015 Sep 28.