http://circres.ahajournals.org/content/113/4/352.extract.html?etoc
Type 2 diabetes mellitus and the metabolic syndrome greatly
increase the risk of cardiovascular disease, manifested as myocardial
infarction and stroke. Although it is well known
that this risk is largely the result of increased atherosclerosis, the
cellular
and molecular events within the artery wall
responsible for the worsening of atherosclerosis associated with type 2
diabetes
mellitus and the metabolic syndrome are less
clear. These states are frequently associated with several
cardiovascular risk
factors, including dyslipidemia, hypertension,
obesity, hyperglycemia, and systemic insulin resistance, each of which
may
contribute to atherosclerosis.
Article, see p 418
Insulin resistance in now known to
affect the vascular wall itself, in addition to the better-studied
insulin target tissues
liver, skeletal muscle, and adipose tissue.
Vascular endothelial cells, which play critical roles in atherosclerosis
by allowing
monocytes and other immune cells to enter the
atherosclerotic lesion and by producing proatherogenic and
antiatherogenic molecules,
develop insulin resistance in both humans and
mice concomitant with dyslipidemia and systemic insulin resistance.1 Endothelial cells can also contribute to systemic insulin resistance.2
Insulin has important biological
effects in endothelial cells that affect atherosclerosis. Activation of
the insulin receptor
results in tyrosine phosphorylation of insulin
receptor substrate 1 and 2 and subsequent activation of phosphoinositide
3-kinase
(PI3K) and the serine/threonine protein kinase
Akt. Akt has several targets in endothelial cells, one of which is
endothelial
nitric oxide (NO) synthase (eNOS).
Insulin-induced activation of the PI3K-Akt-eNOS pathway causes increased
production of
NO, vasorelaxation,3 and suppressed expression of vascular cell adhesion …
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