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Glucose uptake stimulator YM‐138552 activates gene expression and translocation of glucose transporter isotype 4
Author(s) -
Shimokawa Teruhiko,
Kato Miyuki,
Kagami Mitsuhiro,
Ueda Yoshitaka,
Kurosaki Eiji,
Maruyama Tatsuya,
Shibasaki Masayuki,
Katoh Masao
Publication year - 2000
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/1098-2299(20000901)51:1<43::aid-ddr5>3.0.co;2-f
Subject(s) - glut4 , glucose transporter , glucose uptake , endocrinology , medicine , insulin , chromosomal translocation , stimulation , skeletal muscle , c2c12 , myocyte , chemistry , biology , myogenesis , biochemistry , gene
In this study, we examined the effect of YM‐138552 on the glucose uptake, gene expression, and transport activities of the insulin‐regulatable glucose transporter isotype 4 (Glut4) in skeletal muscle cells. YM‐138552 stimulated medium glucose consumption in a dose‐dependent manner (EC 50 = 0.07 μM) in myoblast muscle C2C12 cells under differentiation conditions with 2% horse serum supplement. The stimulatory effect of glucose consumption was verified by radiolabeled 2‐DG uptake assay. The compound showed dose‐dependent stimulation of 2‐DG uptake in G8 myoblast muscle cells up to a 1 μM concentration (EC 50 = 0.19 μM). To investigate the mechanism of glucose uptake stimulation by YM‐138552, the mRNA level of Glut4 was determined using real‐time quantitative RT‐PCR. The Glut4 mRNA level expressed in C2C12 cells treated with YM‐138552 increased up to at least 24 h (227% vs. control), after which it gradually decreased to the initial level at 36 h. In addition, we established that C2C12 cells stably expressed the myc‐tagged Glut4 protein (C2C12‐Glut4myc) and measured the Glut4 translocation activity. The Glut4 translocation activity was stimulated by treatment of YM‐138552 without insulin in a dose‐dependent manner (EC 50 = 0.62 μM), and no insulin effect (100 nM) was observed. This suggests that YM‐138552 has an insulin‐like effect. These results suggest that the stimulation of glucose uptake by YM‐138552 in muscle cells was partly due to upregulation of the Glut4 gene expression and its translocation activation. Our findings on the in vitro effects of YM‐138552 glucose uptake stimulation through the Glut4 transporter may suggest a direction for the development of new drugs for the treatment of NIDDM. Drug Dev. Res. 51:43–48, 2000. © 2000 Wiley‐Liss, Inc.