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The antidiabetic agent, gliclazide, reduces high insulin–enhanced neutrophil‐transendothelial migration through direct effects on the endothelium
Author(s) -
Okouchi Masahiro,
Okayama Naotsuka,
Omi Hitoshi,
Imaeda Kenro,
Fukutomi Tatsuya,
Nakamura Atsushi,
Itoh Makoto
Publication year - 2004
Publication title -
diabetes/metabolism research and reviews
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.307
H-Index - 110
eISSN - 1520-7560
pISSN - 1520-7552
DOI - 10.1002/dmrr.444
Subject(s) - gliclazide , insulin , glibenclamide , endothelium , endothelial stem cell , medicine , endothelial dysfunction , pharmacology , endocrinology , biology , diabetes mellitus , biochemistry , in vitro
Background and aim Many lines of evidence indicate that hyperinsulinemia might be associated with coronary athrosclerosis, and, currently, there are no effective strategies for preventing this. We previously reported that high insulin enhances neutrophil‐transendothelial migration, a process that involves increased surface presentation of platelet endothelial cell adhesion molecule‐1 (PECAM‐1) through a mitogen‐activated protein (MAP) kinase–dependent event. In this current study, we examined if antidiabetic agents, especially K ATP channel blockers, might similarly protect against the leukocyte‐endothelial cell interactions enhanced by high insulin. Methods Neutrophils transmigration across umbilical vein endothelial cells (in high insulin medium) with or without K ATP channel blockers was performed. Neutrophil migration was quantified by measuring myeloperoxidase, and surface expression of endothelial PECAM‐1 was examined using cell‐surface enzyme immunoassay. Results Neutrophil‐transendothelial migration and PECAM‐1 expression were enhanced by insulin (100 µU/mL, 24 h) and were attenuated by gliclazide (20 µM), but not by other K ATP channel blockers (glibenclamide, nateglinide, and glimepiride). Neutrophil migration and PECAM‐1 expression were also increased by the mitogen‐activated protein (MAP) kinase activator, anisomycin (1 µM), and also attenuated by gliclazide. Nitric oxide (NO) synthase inhibitors did not modify either gliclazide effect. Conclusions Our results suggest that the K ATP channel blocker, gliclazide, blocks high insulin–mediated neutrophil migration and PECAM‐1 expression. These gliclazide effects may be mediated through the inhibition of MAP kinase activation and are unrelated to NO production. Copyright © 2004 John Wiley & Sons, Ltd.