Insulin-Induced Generation of Reactive Oxygen Species and Uncoupling of Nitric Oxide Synthase Underlie the Cerebrovascular Insulin Resistance in Obese Rats

Hyperinsulinemia accompanying insulin resistance (IR) is an independent risk factor for stroke. The objective is to examine the cerebrovascular actions of insulin in Zucker obese (ZO) rats with IR and Zucker lean (ZL) control rats. Diameter measurements of cerebral arteries showed diminished insulin...

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Bibliographic Details
Published in:Journal of cerebral blood flow and metabolism 2012-05, Vol.32 (5), p.792-804
Main Authors: Katakam, Prasad VG, Snipes, James A, Steed, Mesia M, Busija, David W
Format: Article
Language:English
Subjects:
AKT protein
Animals
Antihypertensive agents
Arteries
Bioavailability
Biological and medical sciences
Biopterins - analogs & derivatives
Biopterins - pharmacology
Cardiovascular system
Cerebral Arteries - metabolism
Cerebral Arteries - physiopathology
Cerebral blood flow
Cerebrovascular Circulation - drug effects
Extracellular signal-regulated kinase
Fluorescence
Gene Expression Regulation, Enzymologic - drug effects
GTP
GTP Cyclohydrolase
Hypoglycemic Agents - metabolism
Hypoglycemic Agents - pharmacology
Insulin
Insulin - metabolism
Insulin - pharmacology
Insulin Resistance
Medical sciences
NAD(P)H oxidase
NADPH Oxidases - metabolism
Neurology
Nitric Oxide - metabolism
Nitric Oxide Synthase Type I - antagonists & inhibitors
Nitric Oxide Synthase Type I - metabolism
Nitric-oxide synthase
Obesity
Original
Pharmacology. Drug treatments
Phosphorylation
Phosphorylation - drug effects
Prostaglandin-Endoperoxide Synthases - metabolism
Protein kinase C
Proto-Oncogene Proteins c-akt - metabolism
Rats
Rats, Sprague-Dawley
Rats, Zucker
Reactive oxygen species
Reactive Oxygen Species - metabolism
Stroke
Supplementation
tetrahydrobiopterin
Vascular diseases and vascular malformations of the nervous system
Vasoconstriction
Vasodilation
Vasodilation - drug effects
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Summary:Hyperinsulinemia accompanying insulin resistance (IR) is an independent risk factor for stroke. The objective is to examine the cerebrovascular actions of insulin in Zucker obese (ZO) rats with IR and Zucker lean (ZL) control rats. Diameter measurements of cerebral arteries showed diminished insulin-induced vasodilation in ZO compared with ZL. Endothelial denudation revealed vasoconstriction to insulin that was greater in ZO compared with ZL. Nonspecific inhibition of nitric oxide synthase (NOS) paradoxically improved vasodilation in ZO. Scavenging of reactive oxygen species (ROS), supplementation of tetrahydrobiopterin (BH4) precursor, and inhibition of neuronal NOS or NADPH oxidase or cyclooxygenase (COX) improved insulin-induced vasodilation in ZO. Immunoblot experiments revealed that insulin-induced phosphorylation of Akt, endothelial NOS, and expression of GTP cyclohydrolase-I (GTP-CH) were diminished, but phosphorylation of PKC and ERK was enhanced in ZO arteries. Fluorescence studies showed increased ROS in ZO arteries in response to insulin that was sensitive to NOS inhibition and BH4 supplementation. Thus, a vicious cycle of abnormal insulin-induced ROS generation instigating NOS uncoupling leading to further ROS production underlies the cerebrovascular IR in ZO rats. In addition, decreased bioavailability and impaired synthesis of BH4 by GTP-CH induced by insulin promoted NOS uncoupling.
ISSN:0271-678X
1559-7016
DOI:10.1038/jcbfm.2011.181