The role of small molecule GPR119 agonist, AS1535907, in glucose-stimulated insulin secretion and pancreatic β-cell function.
OBJECTIVE
AS1535907, a small molecule agonist of GPR119, was assessed for its glucose-stimulated insulin secretory activity and pancreatic β-cell function in type 2 diabetes.


METHODS
Both in vitro and in vivo tests were conducted using NIT-1 and HEK293 cell lines, male normal and db/db mice and isolated perfused rat pancreas preparations.


RESULTS
AS1535907 had an EC₅₀ value of 1.5 µM for human GPR119 transfected in HEK293 cells. AS1535907 enhanced insulin secretion in NIT-1 cells and in the perfused rat pancreas. A transient increase in the human insulin promoter activity was also observed in NIT-1 cells. First-phase insulin secretion was particularly more evident in the AS1535907-treated perfused rat pancreas than that in the nateglinide or glibenclamide-treated group. Oral glucose tolerance improved following a single dose of AS1535907 in normal and db/db mice. Subsequently, 2 weeks of multiple dosing significantly increased plasma insulin levels and decreased blood glucose levels in db/db mice. After 3 weeks of treatment in db/db mice, the numbers of insulin and proliferation cell nuclear antigen-positive cells and the islet area were significantly higher than those in the vehicle-treated mice. As compared with the vehicle, gene expression analysis revealed that AS1535907 significantly upregulated transcription factors (Nkx 2.2, Nkx 6.1, NeuroD and activin A), responsible for β-cell regulation and prohormone-converting enzyme 1 responsible for insulin biosynthesis.


CONCLUSIONS
These results suggest that AS1535907 can potentially regulate first-phase insulin secretion and exert a protective effect on pancreatic β-cell function via regulation of transcription factors.
Astellas Pharma Inc., Tsukuba, Ibaraki, Japan. shigeru.yoshida@jp.astellas.com
S
S
Yoshida
T
T
Ohishi
T
T
Matsui
H
H
Tanaka
H
H
Oshima
Y
Y
Yonetoku
M
M
Shibasaki
D000818:Animals; D003497:Cyclic N-Oxides / Q000494:pharmacology*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism*; D005951:Glucose Tolerance Test; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000378:metabolism*
C554427:2-(4-bromophenyl)-6-methyl-N-(2-(1-oxidopyridin-3-yl)ethyl)pyrimidin-4-amine; D003497:Cyclic N-Oxides; C519854:GPR119 protein, human; D007004:Hypoglycemic Agents; D007328:Insulin; D011725:Pyridines; D043562:Receptors, G-Protein-Coupled