Effects of the Renin Angiotensin System on Insulin Signaling

The effects of RAS inhibition on insulin action have been attributed to changes in both the inhibition of Ang II/ ATI receptor signaling and enhancement of bradykinin/B2 receptor action. ACE, also called kininase II, degrades bradykinin 1-9 and thereby reduces bradykinin B2 receptor activation (Fig. 2). Several reports have shown that bradykinin B2-receptor antagonism blocks the decreases in insulin resistance and enhanced glucose uptake associated with ACE inhibition (148,149,157) and is mimicked by chronic bradykinin administration (158). Moreover, bradykinin B2 receptor deficient mice are insulin-resistant (159). Although the mechanisms responsible for the amelioration of insulin resistance by bradykinin are not fully understood, bradykinin has been shown to enhance insulin-stimulated insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation and its subsequent association with Phosphatidylinositol 3'-kinase (PI3K) in skeletal muscle and liver (160,161), possibly by inhibiting insulin receptor dephosphorylation (162). Bradykinin has also been shown to increase GLUT-4 translocation to the plasma membrane, which may contribute to insulin-independent glucose uptake in the heart and skeletal muscle (163,164).

Although bradykinin appears to contribute to the effects of ACE inhibition on insulin sensitivity, there is also considerable evidence that Ang II can inhibit insulin signaling and induce insulin resistance. Infusion of Ang II during a hyperinsulinemic euglycemic clamp in anesthetized dogs results in increases in both plasma and interstitial insulin without a concomitant increase in glucose utilization, suggesting that Ang II induced insulin resistance at the cellular level (165). Increased Ang II production induced by transgenic over expression of renin in TG(mREN2)27 rats induces insulin-resistance compared with nontransgenic control rats (166). Infusion of Ang II in rats inhibits insulin-stimulated PI3K activation in the heart by reducing insulin-stimulated PI3K activity associated with IRS-1 without significantly impairing IRS-1 tyrosine phosphorylation or IRS-1/p85 P13K docking (132).

Angiotensin Ati Signalization

Fig. 2. Modulation of insulin signaling by the renin-angiotensin system. Angiotensin-converting enzyme (ACE) catalyses the conversion of Ang I to Ang II and degrades bradykinin 1-9 (BK2 receptor agonist). The Ang II/AT1 pathway stimulates serine phosphorylation of IRS-1, which reducing its tyrosine phosphorylation by activated insulin receptor thereby inhibiting insulin signaling. The Bradykinin BK2 receptor pathway increases insulin receptor phosphorylation resulting in enhanced insulin action. Both activated insulin receptor and BK2 receptor increase glucose transport and NO synthesis. JNK, Jun N-terminal kinase; IRS-1, insulin receptor sub-strate-1; PI3K, Phosphatidylinositol 3'-kinase; P-Ser, phosphoserine.

Fig. 2. Modulation of insulin signaling by the renin-angiotensin system. Angiotensin-converting enzyme (ACE) catalyses the conversion of Ang I to Ang II and degrades bradykinin 1-9 (BK2 receptor agonist). The Ang II/AT1 pathway stimulates serine phosphorylation of IRS-1, which reducing its tyrosine phosphorylation by activated insulin receptor thereby inhibiting insulin signaling. The Bradykinin BK2 receptor pathway increases insulin receptor phosphorylation resulting in enhanced insulin action. Both activated insulin receptor and BK2 receptor increase glucose transport and NO synthesis. JNK, Jun N-terminal kinase; IRS-1, insulin receptor sub-strate-1; PI3K, Phosphatidylinositol 3'-kinase; P-Ser, phosphoserine.

Our laboratory and others have shown that Ang II inhibits insulin stimulation of PI3K in both vascular cells and tissues. In cultured VSMCs, Ang II inhibits insulin-stimulated IRS-1 tyrosine phosphorylation, and its subsequent docking with the regulatory p85 subunit of PI3K (131). Because Ang II did not alter insulin receptor autophosphorylation, the inhibitory effects of Ang II appear to occur subsequent to insulin receptor activation. Ang II-induced serine phosphorylation of IRS-1 correlated with impaired IRS-1 binding to activated insulin receptor, suggesting that Ang II-induced serine phosphorylation of IRS-1 prevents its ability to bind and become tyrosine phosphorylated by the insulin receptor (Fig. 2). Recent studies have shown that Ang II, via the AT1 receptor, increases IRS-1 phosphorylation at Ser312 and Ser616 via Jun NH(2)-terminal kinase (JNK) and ERK1/2, respectively, in human umbilical vein endothelial cells (167). Additionally, activation of JNK has been shown to stimulate IRS-1 phosphorylation at Ser307 and inhibit insulin-stimulated tyrosine phosphorylation of IRS-1 (168). These reports have begun to provide a biochemical basis for Ang II/insulin "crosstalk" at the signal transduc-tion level in vascular cells. Although chronic AT1 antagonism has been associated with a 20% increase in GLUT-4 expression and increased glucose uptake in skeletal muscle (151,152), the mechanisms that mediate these effects of AT1 receptor antagonists on insulin action in skeletal muscle have not yet been elucidated.

summary and conclusions

The RAS has emerged as a network of angiotensin peptides and receptors, whose production and activities are regulated at multiple levels. A growing number of clinical trials and experimental studies using diabetic animal models have shown that both ACE1 and the ATI receptor contribute to cardiovascular dysfunctions and disease in diabetes. The cardiovascular effects of the RAS are results of a combination of its systemic and local/intravascular actions. The systemic actions of the RAS include BP control, and effects on insulin sensitivity, metabolic control, and circulating CVD risk factors, such as PAI-1. The intravascular RAS exerts additional effects on vascular remodeling, inflammation, oxidation, thrombosis, fibrosis, and endothelial functions including permeability and vasorelaxation. Although the RAS has emerged as a leading therapeutic target for diabetic microvascular and cardiovascular complications, additional factors associated with insulin resistance, metabolic control, and inflammation also play major roles in the excessive cardiovascular risk associated with diabetes. Further understanding of the interactions between RAS and diabetic vascular complications will provide new insight into the role of RAS inhibition in the treatment and management of CVD in diabetes.


This work was supported in part by National Institutes of Health grant DK 48358.


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