Selective angiotensin II receptor antagonism reduces insulin resistance in obese Zucker rats.

Abstract

Effects of oral administration of the angiotensin II receptor antagonist (selective AT(1)-subtype) irbesartan on glucose tolerance and insulin action on skeletal-muscle glucose transport were assessed in the insulin-resistant obese Zucker rat. In the acute study, obese rats received either vehicle (water) or irbesartan 1 hour before the experiment. Although irbesartan had no effect on glucose transport (2-deoxyglucose uptake) in the epitrochlearis muscle, which consists mainly of type IIb fibers, acute angiotensin II receptor antagonism led to a dose-dependent increase in insulin action in the predominantly type I soleus muscle. Irbesartan at 25 and 50 mg/kg induced significant increases (41% and 50%, respectively; P<0.05) in insulin-mediated glucose transport. Moreover, these acute irbesartan-induced improvements in soleus-muscle glucose transport were associated with enhancements in whole-body insulin sensitivity (r=-0.732; P<0.05), as assessed during an oral glucose tolerance test. After chronic administration of irbesartan (21 days at 50 mg. kg(-1). d(-1)), glucose tolerance was enhanced further, and insulin-mediated glucose transport was significantly elevated in both epitrochlearis (32%) and soleus (73%) muscle. Chronic angiotensin II receptor antagonism was associated with significant increases in glucose transporter-4 (GLUT-4) protein expression in soleus (22%) and plantaris (20%) muscle and myocardium (15%). Chronic irbesartan-induced increases in whole-body insulin sensitivity were associated with increased insulin-mediated glucose transport in both epitrochlearis (r=-0.677; P<0.05) and soleus (r=-0.892; P<0.05) muscle. In summary, angiotensin II receptor (AT(1)-subtype) antagonism, either acutely or chronically, improves glucose tolerance, at least in part because of an enhancement in skeletal-muscle glucose transport, and the effect of chronic angiotensin II receptor antagonism on type I skeletal-muscle glucose uptake is associated with an increase in GLUT-4 protein expression.

• Authors: E J Henriksen, S Jacob, T R Kinnick, M K Teachey, M Krekler
• Journal: Hypertension (Dallas, Tex. : 1979) (Hypertension) Vol. 38 Issue 4 Pg. 884-90 (Oct 2001) ISSN: 1524-4563 [Electronic] United States
• PMID: 11641303 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Angiotensin Receptor Antagonists
• Biphenyl Compounds
• Blood Glucose
• Fatty Acids, Nonesterified
• Glucose Transporter Type 4
• Insulin
• Monosaccharide Transport Proteins
• Muscle Proteins
• Slc2a4 protein, rat
• Tetrazoles
• Deoxyglucose
• Irbesartan

Topics

• Angiotensin Receptor Antagonists
• Animals
• Area Under Curve
• Biological Transport (drug effects)
• Biphenyl Compounds (pharmacology)
• Blood Glucose (drug effects, metabolism)
• Body Weight (drug effects)
• Deoxyglucose (pharmacokinetics)
• Dose-Response Relationship, Drug
• Fatty Acids, Nonesterified (metabolism)
• Female
• Glucose Tolerance Test
• Glucose Transporter Type 4
• Heart (growth & development)
• Insulin (blood, pharmacokinetics, pharmacology)
• Insulin Resistance
• Irbesartan
• Monosaccharide Transport Proteins (drug effects, metabolism)
• Muscle Proteins
• Muscle, Skeletal (drug effects, metabolism)
• Obesity (metabolism)
• Organ Size (drug effects)
• Rats
• Rats, Zucker
• Tetrazoles (pharmacology)