Signaling Crosstalk Angiotensin II Receptor Subtypes and Insulin
Masatsugu HORIUCHI, Masaki MOGI, Masaru IWAI
2006
Endocrine journal
ANGIOTENSIN II (Ang II) seems to be involved in the pathogenesis of both hypertension and insulin resistance, though few studies have examined the direct relationship between the two. Crosstalk between insulin and Ang II signaling has received great attention, since hypertension and insulin resistance often coexist and are leading risk factors for cardiovascular disease. Recent studies have suggested that Ang II might negatively modulate insulin-mediated actions by regulating multiple levels of
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... the insulin signaling cascade such as the insulin receptor, IRS and PI3K [1, 2]. The major cardiovascular actions of Ang II have been reported to be mediated by a seven transmembranespanning, G-protein-coupled receptor (GPCR) which is termed the AT 1 receptor, and a second receptor subtype known as AT 2 receptor. Based on the restricted expression of AT 2 receptor in fetal tissues as well as in disease states such as myocardial infarction and vascular injury, this receptor is thought to be involved in growth, development and/or differentiation, while both AT 1 and AT 2 receptor belong to the seven-transmembrane, GPCR family and share 32% primary sequence homology [3] . Evidence has revealed that the functions of the AT 1 and AT 2 receptors are mutually antagonistic. The effect of AT 1 receptor blockers (ARB) may not be entirely due to blockade of the AT 1 receptor. When the AT 1 receptor is blocked and unbound Ang II can act on the AT 2 receptor, stimulation of the AT 2 receptor might be involved in the effects of ARB. However, the detailed mechanism of direct cross-talk of insulin and Ang II-mediated signaling via the AT 1 and AT 2 receptor subtypes in glucose metabolism and vascular remodeling is still unclear. Here, we reviewed the potential crosstalk of Ang II receptor subtypes and insulin especially focusing on glucose metabolism. Insulin sensitivity and angiotensin II Recent large clinical trials revealed that new-onset diabetes arose in significantly fewer hypertensive patients on an ARB, valsartan, than in those on calcium channel blocker [4] . Moreover it has been reported that treatment with an ARB, losartan, was associated with less peripheral vascular hypertrophy/rarefaction and higher insulin sensitivity in hypertensive patients with a lower incidence of new-onset diabetes compared to those on b-blocker [5] . In animal studies, the insulin sensitivity of fructose-fed rats has been reported to be improved by treatment with an ARB, due to changes in muscle fiber composition and a decrease in TNF-a expression in skeletal muscle [6] . An ARB has been reported to improve glucose tolerance in the obese Zucker rat, at least in part through enhancement of skeletal muscle glucose transport, with an increase in GLUT4 protein expression [7] . These results suggest that Ang II might regulate insulin sensitivity at multiple sites in various diabetic animal models. However, it remains unclear whether Ang II has a direct effect on the insulin-mediated pathway of glucose metabolism in addition to changes in local blood flow in insulin-sensitive organs such as skeletal mus-Correspondence to: Masatsugu HORIUCHI, M.D.,
doi:10.1507/endocrj.53.1
pmid:16543666
fatcat:e566xt22nzfmxkvwnvcvv62fje