Angiotensin II Type-1 Receptor Blocker Valsartan Enhances Insulin Sensitivity in Skeletal Muscles of Diabetic Mice

• Published in: Hypertension (Dallas, Tex. 1979) Tex. 1979), 2004-05, Vol.43 (5), p.1003-1010
• Main Authors: Shiuchi, Tetsuya, Iwai, Masaru, Li, Huan-Sheng, Wu, Lan, Min, Li-Juan, Li, Jian-Mei, Okumura, Midori, Cui, Tai-Xing, Horiuchi, Masatsugu
• Format: Article
• Language: English
• Subjects: Angiotensin II Type 1 Receptor Blockers; Animals; Antihypertensive agents; Arterial hypertension. Arterial hypotension; Biological and medical sciences; Blood and lymphatic vessels; Blood Glucose - analysis; Cardiology. Vascular system; Cardiovascular system; Clinical manifestations. Epidemiology. Investigative techniques. Etiology; Crosses, Genetic; Deoxyglucose - pharmacokinetics; Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - metabolism; Disease Models, Animal; Energy Intake - drug effects; Gene Expression Regulation - drug effects; Glucose Transporter Type 4; Imidazoles - pharmacology; Insulin - blood; Insulin Receptor Substrate Proteins; Insulin Resistance; Male; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Mice, Obese; Monosaccharide Transport Proteins - metabolism; Muscle Proteins - metabolism; Muscle, Skeletal - drug effects; Muscle, Skeletal - metabolism; Pharmacology. Drug treatments; Phosphoproteins - metabolism; Phosphorylation - drug effects; Protein Processing, Post-Translational - drug effects; Protein Transport - drug effects; Pyridines - pharmacology; Signal Transduction - drug effects; Superoxides - metabolism; Tetrazoles - pharmacology; Tetrazoles - therapeutic use; Tumor Necrosis Factor-alpha - biosynthesis; Tumor Necrosis Factor-alpha - genetics; Valine - analogs & derivatives; Valine - pharmacology; Valine - therapeutic use; Valsartan
• ISSN: 0194-911X; 1524-4563
• DOI: 10.1161/01.HYP.0000125142.41703.64

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-[H]deoxy-d-glucose (2-[H]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-[H]DG uptake into skeletal muscle was not influenced in AT2 receptor null mice, and an AT2 receptor blocker, PD123319, did not affect 2-[H]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-α (TNF-α) 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.