AT1 Receptor Blockade Restores Insulin Signaling Pathway in Liver of Obese Zucker Rats.

MUÑOZ MC,; ARGENTINO DP,; DOMINICI FP,; TURYN D,; TOBLLI JE.

NY, EEUU

Congreso; American Society of Hypertension; 2006

American Society of Hypertension

Angiotensin II (AII) has been shown to contribute to the pathogenesis of hypertension and insulin resistance. In addition, administration of AII type-1(AT1) receptor blockers has demonstratred to improve insulin sensitivity. However, only a few studies have addressed the molecular mechanisms involved in this association. We evaluate whether AT1R blockade by Irbesartan (IRB) can improve insulin resistance in liver of obese Zucker rats (OZR). G1 OZR; G2 OZR with IRB (OZR + IRB); G3 lean Zucker rats (LZR) as control. We examined the effects of 6 months treatment with Irbesartan (50mg/kg/day) on : a)systolic blood pressure (SBP) mmHg; b)insulin/glucose ratio (I/G ratio); c)triglycerides (TG) mmol/l; d)cholesterol mmol/l (C); e)hepatic AII levels f)hepatic insulin signaling system of obese Zucker rats. At the end of the study: a) SBP= G1:153 2 *; G2: 129 1; G3: 120.1 0.9; b) I/G ratio= G1: 69 2 *; G2: 40 2; G3: 10 2; c) TG= G1: 12.1 0.6 *; G2: 6.2 0.3; G3: 0.30 0.04 d) C= G1: 5.10 0.04 *; G2: 2.80 0.16; G3: 1.20 0.04; e) In the Immunohistochemical study, the liver of untreated OZR presented a remarkable (p < 0.01) higher immunostained AII area (12.3 3.2%) together with a higher proportion of macro and microvesicular steatosis in hepatocytes when compared with LZR (3.1 1.1%). No differences were observed between OZR rats and OZR with IRB concerning the percentage of immunostaining for AII in liver (12.3 3.2% and 11.8 2.6 %, respectively). A significant reduction in cytoplasm vacuolization of liver cells was observed in treated OZR when compared with OZR, * p<0.01 versus LZR; p<0.01 versus OZR+IRB; f) 1)increased (p<0.01) insulin-stimulated insulin receptor (IR) tyrosine phosphorylation, 2)decreased (p<0.01) IR serine 994 phosphorylation, 3)augmented (p<0.01) insulin receptor substrate(IRS)-1 and -2 abundance and tyrosine phosphorylation, 4)augmented (p<0.01) association between IRSs and the p85 regulatory subunit of phosphatidylinositol PI 3-kinase, and 5)increased (p<0.01) insulin-induced Akt phosphorylation. The present study provides information that demonstrates that long-term selective AII blockade improves insulin signaling through a reduction in IR serine 994 phosphorylation in the liver of OZR.