Angiotensin II-induced insulin resistance is associated with enhanced insulin signaling

Takehide Ogihara, Tomoichiro Asano, Katsuyuki Ando, Yuko Chiba, Hideyuki Sakoda, Motonobu Anai, Nobuhiro Shojima, Hiraku Ono, Yukiko Onishi, Midori Fujishiro, Hideki Katagiri, Yasushi Fukushima, Masatoshi Kikuchi, Noriko Noguchi, Hiroyuki Aburatani, Issei Komuro, Toshiro Fujita

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212 Citations (Scopus)

Abstract

Angiotensin II (AII) is involved in the pathogenesis of both hypertension and insulin resistance, though few studies have examined the relationship between the two. We therefore investigated the effects of chronic AII infusion on blood pressure and insulin sensitivity in rats fed a normal (0.3% NACl) or high-salt (8% NACl) diet. AII infusion for 12 days significantly elevated blood pressure and significant insulin resistance, assessed by a hyperinsulinemic-euglycemic clamp study and glucose uptake into isolated muscle and adipocytes. High-salt loading exacerbated the effects of AII infusion significantly. Despite the insulin resistance, insulin-induced tyrosine phosphorylation of the insulin receptor and insulin receptor substrates, activation of phosphatidylinositol (PI) 3-kinase, and phosphorylation of Akt were all enhanced by AII infusion. Subsequently, to investigate whether oxidative stress induced by AII contributes to insulin resistance, the membrane-permeable superoxide dismutase mimetic, tempol, was administered to AII-infused rats. Chronic AII infusion induced an accumulated plasma cholesterylester hydroperoxide levels, indicating the increased oxidative stress, whereas the treatment with tempol normalized plasma cholesterylester hydroperoxide levels in AII-infused rats. In addition, the treatment with tempol normalized insulin resistance in AII-infused rats, shown as a decreased glucose infusion rate in the hyperinsulinemic euglycemic clamp study and a decreased insulin-induced glucose uptake into isolated skeletal muscle, as well as enhanced insulin-induced PI 3-kinase activation to those in the control rats. These results strongly suggest that AII-induced insulin resistance cannot be attributed to impairment of early insulin-signaling steps and that increased oxidative stress, possibly through impaired insulin signaling located downstream from PI 3-kinase activation, is involved in AII-induced insulin resistance.

Original languageEnglish
Pages (from-to)872-879
Number of pages8
JournalHypertension
Volume40
Issue number6
DOIs
Publication statusPublished - 2002 Dec 1
Externally publishedYes

Keywords

  • Angiotensin II
  • Glucose clamp technique
  • Insulin resistance
  • Kinase
  • Oxidative stress
  • Sodium

ASJC Scopus subject areas

  • Internal Medicine

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  • Cite this

    Ogihara, T., Asano, T., Ando, K., Chiba, Y., Sakoda, H., Anai, M., Shojima, N., Ono, H., Onishi, Y., Fujishiro, M., Katagiri, H., Fukushima, Y., Kikuchi, M., Noguchi, N., Aburatani, H., Komuro, I., & Fujita, T. (2002). Angiotensin II-induced insulin resistance is associated with enhanced insulin signaling. Hypertension, 40(6), 872-879. https://doi.org/10.1161/01.HYP.0000040262.48405.A8