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: Tetsuya Shiuchi, Masaru Iwai, Huan-Sheng Li, Lan Wu, Li-Juan Min, Jian-Mei Li, Midori Okumura, Tai-Xing Cui, Masatsugu Horiuchi
• Journal: Hypertension (Dallas, Tex. : 1979) (Hypertension) Vol. 43 Issue 5 Pg. 1003-10 (May 2004) ISSN: 1524-4563 [Electronic] United States
• PMID: 15037562 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Angiotensin II Type 1 Receptor Blockers
• Blood Glucose
• Glucose Transporter Type 4
• Imidazoles
• Insulin
• Insulin Receptor Substrate Proteins
• Irs1 protein, mouse
• Monosaccharide Transport Proteins
• Muscle Proteins
• Phosphoproteins
• Pyridines
• Slc2a4 protein, mouse
• Tetrazoles
• Tumor Necrosis Factor-alpha
• Superoxides
• PD 123319
• Valsartan
• Deoxyglucose
• Valine

Topics

• Angiotensin II Type 1 Receptor Blockers
• Animals
• Blood Glucose (analysis)
• Crosses, Genetic
• Deoxyglucose (pharmacokinetics)
• Diabetes Mellitus, Type 2 (drug therapy, 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
• Mice
• Mice, Inbred C57BL
• Mice, Mutant Strains
• Mice, Obese
• Monosaccharide Transport Proteins (metabolism)
• Muscle Proteins (metabolism)
• Muscle, Skeletal (drug effects, metabolism)
• 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, therapeutic use)
• Tumor Necrosis Factor-alpha (biosynthesis, genetics)
• Valine (analogs & derivatives, pharmacology, therapeutic use)
• Valsartan