Mechanism of improving effect of losartan on insulin sensitivity of non-insulin-dependent diabetes mellitus rats.
The specific inhibition of angiotensin II action at AT(1) receptors by losartan has been shown to decrease peripheral insulin resistance in type 2 diabetic patients and animal models. We examined the effect of losartan on the expression of insulin receptor substrate 1 (IRS-1), protein kinase B (PKB) and glucose transporter 4 (GLUT4), as well as the phosphorylation status of IRS-1 and the association between IRS-1 and phosphatidylinositol (PI) 3-kinase in skeletal muscle from fat-fed and-streptozotocin (STZ)-treated rats, an animal model of type 2 diabetes mellitus. In addition, the effects of losartan on GLUT4 translocation in muscle cells and on insulin sensitivity were also evaluated. Muscle tissues were isolated from male losartan-treated and untreated normal or non-insulin-dependent diabetes mellitus (NIDDM) rats with a dose of 4 mg/kg per day for 6 weeks. Oral administration of losartan improved insulin sensitivity, which was determined by an oral glucose tolerance test (OGTT). In skeletal muscles, the protein levels of IRS-1, PKB and GLUT4 in NIDDM rats were not significantly different from those of the control rats, and they were not affected by losartan. The levels of IRS-1 tyrosine phosphorylation, PI 3-kinase activity associated with IRS-1 and PKB activation after stimulation with insulin in muscle tissue of NIDDM rats were significantly decreased (P<0.01) compared with those in the control rats, while they were not increased by losartan. Losartan had a major effect on GLUT4 translocation in myocytes, as it significantly increased (P<0.05) the insulin-induced amounts of GLUT4 in plasma membrane (PM) and T-tubules (TT) in myocytes from NIDDM rats. Consistent with these results, the plasma glucose level in losartan-treated NIDDM rats was decreased (P<0.05) compared with that in untreated NIDDM rats. Our results suggest that losartan may exert beneficial effects on insulin resistance by increasing the translocation of GLUT4 in muscle tissue, which is probably associated with a non-PI 3-kinase-dependent mechanism.
Wu
Yong
Y
Department of Pathophysiology, The College of Medicine, Wuhan University, Wuhan, Hubei 430071, China.
Ouyang
Jing-Ping
JP
Zhou
Yun-Feng
YF
Wu
Ke
K
Zhao
De-Hai
DH
Wen
Chong-Yuan
CY
D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000097:blood* / Q000188:drug therapy; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000188:drug therapy / Q000503:physiopathology; D051275:Glucose Transporter Type 4; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance; D019808:Losartan / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D009004:Monosaccharide Transport Proteins / Q000096:biosynthesis* / Q000235:genetics; D009124:Muscle Proteins / Q000096:biosynthesis* / Q000235:genetics; D018482:Muscle, Skeletal / Q000378:metabolism; D010750:Phosphoproteins / Q000096:biosynthesis / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D017207:Rats, Sprague-Dawley
D051275:Glucose Transporter Type 4; D055504:Insulin Receptor Substrate Proteins; C526296:Irs1 protein, rat; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; C495694:Slc2a4 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D019808:Losartan