Angiotensin II-induced insulin resistance is associated with enhanced insulin signaling.
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.
Ogihara
Takehide
T
Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, Japan.
Asano
Tomoichiro
T
Ando
Katsuyuki
K
Chiba
Yuko
Y
Sakoda
Hideyuki
H
Anai
Motonobu
M
Shojima
Nobuhiro
N
Ono
Hiraku
H
Onishi
Yukiko
Y
Fujishiro
Midori
M
Katagiri
Hideki
H
Fukushima
Yasushi
Y
Kikuchi
Masatoshi
M
Noguchi
Noriko
N
Aburatani
Hiroyuki
H
Komuro
Issei
I
Fujita
Toshiro
T
D017667:Adipocytes / Q000166:cytology / Q000378:metabolism; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002478:Cells, Cultured; D003497:Cyclic N-Oxides / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism / Q000493:pharmacokinetics; D015309:Glucose Clamp Technique; D051275:Glucose Transporter Type 4; D006006:Glycogen Synthase / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006946:Hyperinsulinism / Q000097:blood / Q000139:chemically induced; D066298:In Vitro Techniques; D007262:Infusions, Intravenous; D007328:Insulin / Q000097:blood / Q000494:pharmacology / Q000502:physiology*; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D009004:Monosaccharide Transport Proteins / Q000378:metabolism; D009124:Muscle Proteins; D018482:Muscle, Skeletal / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013113:Spin Labels
D000804:Angiotensin II; D000975:Antioxidants; D003497:Cyclic N-Oxides; D005947:Glucose; D051275:Glucose Transporter Type 4; D006006:Glycogen Synthase; D007328:Insulin; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D013113:Spin Labels; C495694:Slc2a4 protein, rat; C494920:Akt1 protein, rat; C001803:tempol