Chronic angiotensin II blockade enhances insulin sensitivity in adipose tissue of obese Zucker rats

MUÑOZ MC; GIANI JF; DOMINICI FP; TOBLLI JE; TURYN D

Ouro Preto, Minas Gerais, Brasil.

Simposio; Vasoactive Peptides - VII International Symposium; 2008

Insulin resistance is associated with a number of common disorders, including type 2 diabetes, dyslipidemia, hypertension, central obesity and cardiovascular disease known as Metabolic Syndrome. In recent years, several studies revealed the existence of a cross-talk between the insulin and angiotensin signalling system. Angiotensin II (ANG II) is able to negatively modulate insulin signaling at multiple levels, such as the insulin receptor (IR), IR substrate-1 (IRS-1), phosphatidylinositol 3 kinase (PI3K) and Akt through an ANG II Type-1 receptor (AT1R) mediated mechanism. Accordingly, selective blockade of the AT1R improves insulin sensitivity and enhances the response to insulin at various steps of the insulin signaling cascade. Several studies have suggested that insulin–stimulated activation of PI3K pathway is impaired in adipose tissue of insulin-resistant rodent and human. A state of insulin resistance involves increased lipolysis and decreased glucose transport in the adipocyte. In addition, it has been proposed that increased formation of ANG II by large insulin-resistant adipocytes inhibits recruitment of preadipocytes, resulting in increased storage of lipids in muscle and liver. In contrast RAS blockade promotes recruitment of preadipocytes, thereby increasing the number of small insulin-sensitive adipocytes. In the present study, we evaluated the effects of selective AT1R antagonism with irbesartan (50 mg/kg/day, during six months) on insulin signaling in adipose tissue from obese Zucker rat (OZR).  The extent of phosphorylation of several components of the insulin signaling system was assessed by immunoblotting with phosphospecific antibodies. Additionally, adipocyte volume was determined by hematoxylin and eosin staining. OZR displayed a marked attenuation in the in vivo phosphorylation of several components of the insulin signaling pathways in adipose tissue together with a significantly higher average adipocyte size when compared with lean Zucker rats. We found that, in liver of OZR, long-term administration of irbesartan is associated with: 1) increased insulin-stimulated insulin receptor tyrosine phosphorylation (57 %, p<0.001 vs. OZR) augmented IRS-1 tyrosine phosphorylation (p<0.05 vs. OZR), 3) increased insulin-induced Akt phosphorylation (59 %, p<0.01 vs. OZR), 4) increased GLUT-4 protein content (38%, p<0.05 vs. OZR) and 5) decreased size of adipocytes. Our results show that selective ANG II blockade by irbesartan improves insulin signaling and it is associated with decreased in adipocyte size.