详细记录  
题名:Novel GPR40 agonist AS2575959 exhibits glucose metabolism improvement and synergistic effect with sitagliptin on insulin and incretin secretion.
作者:TANAKA H; YOSHIDA S; MINOURA H; NEGORO K; SHIMAYA A; SHIMOKAWA T; SHIBASAKI M;
来源:Life Sci. 2014 Jan 17;94(2):115-21. doi: 10.1016/j.lfs.2013.11.010. Epub 2013 Nov [ IF= 0.00 ] ]
URL :10.1016/j.lfs.2013.11.010
日期:20140217
摘要:AIMS: GPR40 is a free fatty acid receptor that regulates glucose-dependent
insulin secretion at pancreatic beta-cells and glucagon-like peptide-1 (GLP-1),
one of the major incretins, secretion at the endocrine cells of the
gastrointestinal tract. We investigated the synergistic effect of AS2575959, a
novel GPR40 agonist, in combination with sitagliptin, a major dipeptidyl
peptidase-IV (DPP-IV) inhibitor, on glucose-dependent insulin secretion and GLP-1
secretion. In addition, we investigated the chronic effects of AS2575959 on
whole-body glucose metabolism. MAIN METHODS: We evaluated acute glucose
metabolism on insulin and GLP-1 secretion using an oral glucose tolerance test
(OGTT) as well as assessed the chronic glucose metabolism in diabetic ob/ob mice
following the repeated administration of AS2575959. KEY FINDINGS: We discovered
the novel GPR40 agonist sodium
[(3S)-6-({4'-[(3S)-3,4-dihydroxybutoxy]-2,2',6'-trimethyl[1,1'-biphenyl]-3-yl}met
hoxy)-3H-spiro[1-benzofuran-2,1'-cyclopropan]-3-yl]acetate (AS2575959) and found
that the compound influenced glucose-dependent insulin secretion both in vitro
pancreas beta-cell-derived cells and in vivo mice OGTT. Further, we observed a
synergistic effect of AS2575959 and DPP-IV inhibitor on insulin secretion and
plasma GLP-1 level. In addition, we discovered the improvement in glucose
metabolism on repeated administration of AS2575959. SIGNIFICANCE: To our
knowledge, this study is the first to demonstrate the synergistic effect of a
GPR40 agonist and DPP-IV inhibitor on the glucose-dependent insulin secretion and
GLP-1 concentration increase. These findings suggest that GPR40 agonists may
represent a promising therapeutic strategy for the treatment of type 2 diabetes
mellitus, particularly when used in combination with DPP-IV inhibitors.

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