on October 21, 2002
Published online before print October 21, 2002, doi: 10.1161/01.HYP.0000040262.48405.A8
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Submitted on June 14, 2002
From the Department of Internal Medicine, Graduate School of
Medicine, University of Tokyo (T.O., T.A., K.A., Y.C., N.S., M.F.,
H.K., Y.F., T.F.), Tokyo; The Institute for Adult Diseases, Asahi Life
Foundation (T.O., H.S., M.A., H.O., Y.O., M.K.), Tokyo; Research Center
for Advanced Science and Technology, University of Tokyo (N.N., H.A.),
Tokyo; and Department of Cardiovascular Science and
Medicine, Chiba University Graduate School of Medicine (I.K.), Chiba,
Japan. * To whom correspondence should be addressed. E-mail: asano-tky{at}umin.ac.jp.
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.
Revised on July 1, 2002
Angiotensin II-Induced Insulin
Resistance Is Associated With Enhanced Insulin
Signaling
Takehide Ogihara;
Key words: angiotensin II • insulin resistance • oxidative stress • glucose clamp technique • sodium • kinase
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