title: Angiotensin II type-1 receptor blocker valsartan enhances insulin sensitivity in skeletal muscles of diabetic mice.
abstract: Angiotensin II has been shown to contribute to the pathogenesis of insulin resistance; however, the mechanism is not well understood. The present study was undertaken to investigate the potential effect of an angiotensin II type-1 (AT1) receptor blocker, valsartan, to improve insulin resistance and to explore the signaling basis of cross-talk of the AT1 receptor- and insulin-mediated signaling in type 2 diabetic KK-Ay mice. Treatment of KK-Ay mice with valsartan at a dose of 1 mg/kg per day, which did not influence systolic blood pressure, significantly increased insulin-mediated 2-[3H]deoxy-d-glucose (2-[3H]DG) uptake into skeletal muscle and attenuated the increase in plasma glucose concentration after a glucose load and plasma concentrations of glucose and insulin. In contrast, insulin-mediated 2-[3H]DG uptake into skeletal muscle was not influenced in AT2 receptor null mice, and an AT2 receptor blocker, PD123319, did not affect 2-[3H]DG uptake and superoxide production in skeletal muscle of KK-Ay mice. Moreover, we observed that valsartan treatment exaggerated the insulin-induced phosphorylation of IRS-1, the association of IRS-1 with the p85 regulatory subunit of phosphoinositide 3 kinase (PI 3-K), PI 3-K activity, and translocation of GLUT4 to the plasma membrane. It also reduced tumor necrosis factor-alpha (TNF-alpha) expression and superoxide production in skeletal muscle of KK-Ay mice. Specific AT1 receptor blockade increases insulin sensitivity and glucose uptake in skeletal muscle of KK-Ay mice via stimulating the insulin signaling cascade and consequent enhancement of GLUT4 translocation to the plasma membrane.
authors.affiliation: Department of Medical Biochemistry, Ehime University School of Medicine, Shigenobu, Onsen-gun, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Shiuchi
authors.forename: Masaru
authors.initials: M
authors.lastname: Iwai
authors.forename: Huan-Sheng
authors.initials: HS
authors.lastname: Li
authors.forename: Lan
authors.initials: L
authors.lastname: Wu
authors.forename: Li-Juan
authors.initials: LJ
authors.lastname: Min
authors.forename: Jian-Mei
authors.initials: JM
authors.lastname: Li
authors.forename: Midori
authors.initials: M
authors.lastname: Okumura
authors.forename: Tai-Xing
authors.initials: TX
authors.lastname: Cui
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Horiuchi
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D003433:Crosses, Genetic; D003847:Deoxyglucose / Q000493:pharmacokinetics; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism; D004195:Disease Models, Animal; D002149:Energy Intake / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D051275:Glucose Transporter Type 4; D007093:Imidazoles / Q000494:pharmacology; D007328:Insulin / Q000097:blood; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008820:Mice, Obese; D009004:Monosaccharide Transport Proteins / Q000378:metabolism; D009124:Muscle Proteins / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013481:Superoxides / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology* / Q000627:therapeutic use; D000068756:Valsartan
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001786:Blood Glucose; D051275:Glucose Transporter Type 4; D007093:Imidazoles; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; D010750:Phosphoproteins; D011725:Pyridines; C495693:Slc2a4 protein, mouse; D013777:Tetrazoles; D014409:Tumor Necrosis Factor-alpha; D013481:Superoxides; C073402:PD 123319; D000068756:Valsartan; D003847:Deoxyglucose; D014633:Valine