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Departments of 1 Nutrition, 2 Pharmacology, and 3 Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106
Insulin resistance
is associated with both obesity and hypertension. However, the cellular
mechanisms of insulin resistance in genetic models of
obese-hypertension have not been identified. The objective of the
present study was to investigate the effects of genetic obesity on a
background of inherited hypertension on initial components of the
insulin signal transduction pathway and glucose transport in skeletal
muscle and liver. Oral glucose tolerance testing in SHROB demonstrated
a sustained postchallenge elevation in plasma glucose at 180 and 240 min compared with lean spontaneously hypertensive rat (SHR)
littermates, which is suggestive of glucose intolerance. Fasting plasma
insulin levels were elevated 18-fold in SHROB. The rate of
insulin-stimulated 3-O-methylglucose transport was reduced 68% in isolated epitrochlearis muscles from the
SHROB compared with SHR. Insulin-stimulated tyrosine phosphorylation of
the insulin receptor 
-subunit and insulin receptor substrate-1 (IRS-1) in intact skeletal muscle of SHROB was reduced by 36 and 23%,
respectively, compared with SHR, due primarily to 32 and 60% decreases
in insulin receptor and IRS-1 protein expression, respectively. The
amounts of p85
regulatory subunit of phosphatidylinositol-3-kinase and GLUT-4 protein were reduced by 28 and 25% in SHROB muscle compared
with SHR. In the liver of SHROB, the effect of insulin on tyrosine
phosphorylation of IRS-1 was not changed, but insulin receptor
phosphorylation was decreased by 41%, compared with SHR, due to a 30%
reduction in insulin receptor levels. Our observations suggest that the
leptin receptor mutation
fak imposed on a
hypertensive background results in extreme hyperinsulinemia, glucose
intolerance, and decreased expression of postreceptor insulin signaling
proteins in skeletal muscle. Despite these changes, hypertension is not
exacerbated in SHROB compared with SHR, suggesting these metabolic
abnormalities may not contribute to hypertension in this
model of Syndrome X.
Syndrome X; tyrosine phosphorylation, leptin receptor
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