Irbesartan enhances GLUT4 translocation and glucose transport in skeletal muscle cells.
Irbesartan, an angiotensin II type 1 receptor blocker has been reported to alleviate metabolic disorder in animal studies and human clinical trials. Although this effect may be related to the ability of irbesartan to serve as a partial agonist for the peroxisome proliferator-activated receptor (PPAR)-γ, the target tissues on which irbesartan acts remain poorly defined. As muscle glucose transport plays a major role in maintaining systemic glucose homeostasis, we investigated the effect of irbesartan on glucose uptake in skeletal muscle cells. In C2C12 myotubes, 24-h treatment with irbesartan significantly promoted both basal and insulin-stimulated glucose transport. In L6-GLUT4myc myoblasts, irbesartan caused a significant increase in glucose transport and GLUT4 translocation to the cell surface in a concentration-dependent manner. Valsartan, another angiotensin II type 1 receptor blocker had no effect on either glucose uptake or GLUT4 translocation, implying that these actions on glucose transport are independent of angiotensin II receptor blockade. Moreover, irbesartan exerted these effects in an additive manner with insulin, but not with acute treatment for 3 h, suggesting that they may require the synthesis of new proteins. Finally, in insulin-resistant Zucker fatty rat, irbesartan (50 mg/kg/day for 3 weeks) significantly ameliorated insulin resistance without increasing weight gain. We conclude that irbesartan has a direct action, which can be additive to insulin, of promoting glucose transport in skeletal muscle. This may be beneficial for ameliorating obesity-related glucose homeostasis derangement.
Kobayashi
Tatsuo
T
Discovery Research Laboratories, Shionogi & Co., Ltd., Osaka 561-0825, Japan. tatsuo.kobayashi@shionogi.co.jp
Akiyama
Yuko
Y
Akiyama
Nobuteru
N
Katoh
Hideaki
H
Yamamoto
Sachiko
S
Funatsuki
Kenzo
K
Yanagimoto
Toru
T
Notoya
Mitsuru
M
Asakura
Kenji
K
Shinosaki
Toshihiro
T
Hanasaki
Kohji
K
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D001713:Biphenyl Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D001835:Body Weight / Q000187:drug effects; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D051275:Glucose Transporter Type 4 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D000077405:Irbesartan; D008297:Male; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism; D009765:Obesity / Q000188:drug therapy / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D011924:Rats, Zucker; D013777:Tetrazoles / Q000494:pharmacology* / Q000627:therapeutic use
D047228:Angiotensin II Type 1 Receptor Blockers; D001713:Biphenyl Compounds; D051275:Glucose Transporter Type 4; D007004:Hypoglycemic Agents; D007328:Insulin; D047495:PPAR gamma; C495694:Slc2a4 protein, rat; D013777:Tetrazoles; D005947:Glucose; D000077405:Irbesartan