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Am J Physiol Heart Circ Physiol 286: H1597-H1602, 2004; doi:10.1152/ajpheart.00026.2004
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EDITORIAL

Insulin resistance and hypertension

James R. Sowers

Departments of Internal Medicine and Physiology/Pharmacology, University of Missouri-Columbia, H. S. Truman Veterans Affairs Medical Center, Columbia, Missouri 65212

Submitted 8 January 2004 ; accepted in final form 12 January 2004

ABSTRACT

Diminished insulin (Ins) sensitivity is a characteristic feature of various pathological conditions such as the cardiometabolic syndrome, Type 2 diabetes, and hypertension. Persons with essential hypertension are more prone than normotensive persons to develop diabetes, and this propensity may reflect decreased ability of Ins to promote relaxation and glucose transport in vascular and skeletal muscle tissue, respectively. There are increasing data suggesting that ANG II acting through its ANG type 1 receptor inhibits the actions of Ins in vascular and skeletal muscle tissue, in part, by interfering with Ins signally through phosphatidylinositol 3-kinase (PI3K) and its downstream protein kinase B (Akt) signaling pathways. This inhibitory action of ANG II is mediated, in part, through stimulation of RhoA activity and oxidative stress. Activated RhoA and increased reactive oxygen species inhibition of PI3K/Akt signaling results in decreased endothelial cell production of nitric oxide, increased myosin light chain activation with vasoconstriction, and reduced skeletal muscle glucose transport.

angiotensin II; blood pressure; glucose utilization

INSULIN (Ins) exerts important biological effects on cardiovascular tissue as well as conventional Ins tissues such as skeletal muscle and adipose tissue (17, 18, 21, 25–28, 37, 44–46, 65, 67, 73, 78, 79, 81, 82). For example, Ins and its homologous autocrine/paracrine peptide Ins-like growth factor (IGF-1) induce vasorelaxation by mechanisms that include stimulation of nitric oxide (NO) production and reductions in vascular smooth muscle cell (VSMC) intracellular Ca2+ concentration ([Ca2+]i) and Ca2+-myosin light chain (MLC) sensitization (1, 17, 18, 21, 25–28, 37, 44–46, 56, 65, 67, 73, 78, 79, 81, 82). IGF-1, unlike Ins, is produced by VSMC and cardiomyocytes in response to angiotensin II (ANG II) and other growth factors and mechanical forces such as stretch (79, 21, 46, 65). Many of the metabolic and vasomotor effects of Ins and IGF-1 are mediated by activation of the phosphatidylinositol 3-kinase (PI3K) and downstream signaling pathways, including protein kinase B (Akt) (82, 25, 27, 28, 31). The serine-threonine kinase Akt interacts with the phospholipids produced by PI3K, thereby undergoing phosphorylation of Thr308 and Ser473, which results in its activation (25, 27, 31). The activation of Akt is a necessary but not definitive requirement for Ins and IGF-1 to exert their metabolic and vascular effects.

Vascular relaxation in response to activation of PI3K/Akt signaling is mediated in part by endothelial cell production of NO (79, 81) (Fig. 1). Another effect of Ins/IGF-1 stimulation of the PI3K/Akt signaling pathway is a reduction in VSMC [Ca2+]i and Ca2+-MLC sensitization (56, 67) (Fig. 2). Ins and IGF-1 reduce VSMC [Ca2+]i by inhibiting agonist-induced inward Ca2+ currents and intracellular organelle release of Ca2+ (49, 66, 67). Ins and IGF-1 also reduce [Ca2+]i by stimulating the activity of the Na+-K+-ATPase pump in VSMC, a process that is dependent on PI3K/Akt signaling (18, 37, 73). Thus Ins and IGF-1 induce vascular relaxation by stimulation of endothelial cell production of NO and by reducing VSMC [Ca2+]i and Ca2+-MLC sensitization. These effects are mediated, in part, by activation of PI3K/Akt signaling pathways. This signaling pathway is also necessary for Ins and IGF-1 stimulation of glucose transport in vascular skeletal muscle and adipose tissue (31, 66, 68).



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  		Fig. 1. ANG II and insulin (Ins)/Ins-like growth factor-1 (IGF-1) counterregulatory actions in endothelial cells. NO, nitric oxide; eNOS, endothelial NO synthase; PI3K, phosphatidylinositol (PI) 3-kinase; IRS, Ins receptor substrate; PIP, PI production; T308, threonine 308; S473, serine 473; AT1-R, ANG type 1 receptor; PH, pleckstrin homology domain; ROK, Rho kinase.

 


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  		Fig. 2. ANG II and Ins/IGF-1 counterregulatory actions in vascular smooth muscle cells (VSMC). MLC, myosin light chain; MBS, myosin-bound serine.

 

Vascular actions of Ins and IGF-1. Both Ins and IGF-1 exert their effects on vascular tone via metabolic actions exerted on endothelial cells (18, 79, 81). Both peptides stimulate NO production (21, 26, 28, 45, 78). The effect of these peptides on endothelial NO is mediated via PI3K-dependent Akt activation, involving phosphorylation of endothelial NO synthase at Ser1179 (26, 28, 45, 78) (Fig. 1). Ins and IGF-1 exert their metabolic effects by binding to their cell surface heterotetrameric receptors, thus stimulating receptor autophosphorylation and activation of several cytosolic docking proteins termed insulin receptor substrates (IRSs) (45). Tyrosine phosphorylation of IRS-1 and IRS-2 induces their binding to Src homology 2-domain containing molecules, including PI3K. The interaction between the IRSs and PI3K increases the catalytic activity of the p110 subunit of this enzyme. Activated PI3K, in turn, activates the Ser/Thr kinase Akt by binding phosphatidylinositol-3,4,5-triphosphate to its pleckstrin domain and consequent Ser/Thr phosphorylation (45): the two major positive regulatory phosphorylation sites in Akt are Thr308 and Ser473.

Ins resistance in essential hypertension. There is impaired Ins signaling in essential hypertension (Table 1) (10, 41, 58, 63, 64, 69, 76). For example, untreated patients with essential hypertension have higher fasting and postprandial insulin levels than age- and sex-matched normotensive persons regardless of body mass; a direct correlation between plasma Ins levels and blood pressure exists (58, 63). Ins resistance and hypertension coexist in rodents with genetic hypertension such as Zucker obese and Goto-Kakizaki rats (6, 49, 58, 66, 68). Furthermore, the relationship between plasma Ins levels and hypertension does not occur with secondary hypertension (58). Thus Ins resistance and hyperinsulinemia are not consequences of hypertension, but rather a genetic predisposition, which may contribute to both disorders. This notion is supported by the observation that there is abnormal glucose metabolism in the offspring of hypertensive parents (58, 63).


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  		Table 1. Mechanisms of insulin resistance in hypertension

 

Endothelial dysfunction, Ins resistance, and essential hypertension. In studies of Ins resistance using the euglycemic hyperinsulinemic clamp technique, skeletal muscle tissue accounts for the majority of whole body glucose uptake (Table 1) (41, 63, 64, 69, 76). Normally, there is a close relationship between Ins-mediated glucose disposal and incremental blood flow in response to Ins. This normal response is lost in Ins-resistant/obese persons, suggesting resistance to the action of Ins to induce vascular NO production (69). Accumulating data suggest that Ins sensitivity in skeletal muscle, fat, and vascular tissue is impaired in persons who are predisposed to develop hypertension (64). In keeping with this notion, there exists a strong clustering of markers of endothelial damage and Ins resistance in persons predisposed to salt-sensitive hypertension (10).

Ins/IGF-1 and ANG II counterregulatory actions. There is increasing evidence that ANG II inhibits Ins and IGF-1 signaling through the PI3K/Akt pathway resulting in inhibition of mechanisms involved in the vasodilator and glucose transport properties of Ins and IGF-1 (1, 10, 11, 21, 25–28, 37, 44, 45, 64, 69, 78, 82). The mechanisms involved in these effects of ANG II include increases in the generation of reactive oxygen species (ROS) and the activation of low-molecular-weight G proteins such as RhoA (4, 7, 9, 11, 12, 14, 16, 29, 33–36, 40, 42, 43, 50, 52, 57, 59, 61, 71, 74, 80). The consequent generation of ROS and RhoA inhibit actions mediated through PI3K/Akt signaling including activation of endothelial NO synthase activity, Na+ pump activation, and Ca2+-MLC desensitization. These observations may explain, in part, the beneficial effects of angiotensin-converting enzyme inhibitors and angiotensin receptor blocking agents in improving Ins sensitivity as well as reducing cardiovascular disease in patients with the cardiometabolic syndrome, which is composed of a constellation of clinical findings such as central obesity, insulin resistance, diabetic dyslipidemia, and other abnormalities (58, 63).

ANG II effects on endothelial function. ANG II, acting through its AT1 receptor (AT1R), increases generation of ROS in the vasculature, primarily through activation of membrane-bound NAD(P)H oxidase (4, 9, 16, 34, 43, 61, 74, 80). Generated ROS react with bioavailable NO to form peroxynitrate in endothelial cells, and AT1R blockade inhibits this effect of ANG II (14, 50, 52) (Fig. 1). Infusion of ANG II impairs endothelial-dependent relaxation (9), and this impairment is corrected by coadministration of superoxide dismutase (3, 36), indicating that ROS are involved in ANG II-mediated endothelial dysfunction. The membrane-bound NADH and NADPH are present in VSMC, fibroblasts, and phagocytic mononuclear cells (4, 9, 16, 34, 43, 61, 74, 80). An increase in vascular activity of NADH and NADPH oxidase enhances the production of ROS by several pathways, including the activation of xanthine oxidase, the autooxidation of NADH, and the inactivation of superoxide dismutase (61). Thus there is increasing evidence that it is NO degradation or NO inactivation by ROS, rather than reduced NO production itself, that plays the principal role in the impairment of endothelium-dependent vasodilation in diabetes and related cardiovascular disease (61) (Fig. 1).

Counterregulatory VSMC actions of ANG II and Ins/IGF-1. Vascular relaxation responses to Ins/IGF-1 are mediated by reductions in VSMC [Ca2+]i and Ca2+-MLC sensitization (1, 17, 18, 21, 25–28, 37, 44–46, 56, 65, 67, 73, 78, 79, 81, 82) as well as increased endothelial cell production of NO (Fig. 2). The increased NO, in response to Ins and IGF-1, results in inhibition of MLC phosphorylation/activation (2) through stimulation of the myosin-bound Ser/Thr phosphatase (MBP) (1, 38, 70). Thus Ins/IGF-1 attenuates the increase in Ca2+-MLC sensitization mediated by vasoconstrictive agonists, such as ANG II (1). ANG II, in contrast, antagonizes the vasodilatory actions of Ins/IGF-1 via activation of low-molecular-weight G proteins such as Rho A, and generation of ROS (3, 4, 7, 8, 9, 12, 14, 16, 29, 33–36, 38, 40, 42, 43, 50, 52, 57, 59–61, 70, 71, 74, 80). RhoA, a member of the Ras superfamily of monomeric GTPases, plays a key role in Ca2+-MLC sensitization and associated vasoconstriction elicited by ANG II (33). The downstream signaling protein of RhoA, Rho kinase (ROK), increases Ca2+-MLC sensitization. On the other hand, Ins/IGF-1 directly reduces ROK-mediated site-specific phosphorylation of MBP and indirectly by increasing endothelial cell production of NO, which also stimulates MBP (8, 57). Furthermore, NO, produced by stimulation of endothelial NO synthase by Ins/IGF-1, diffuses to VSMC and directly inhibits ROK activity and thus Ca2+-MLC sensitization. Thus Ins/ IGF-1 exerts counterregulatory actions to those of ANG II on Ca2+-MLC sensitization and vascular contractility. In keeping with this notion, increases in ROK and Ca2+-MLC sensitization have been observed in ANG II-related (8, 75) and Ins/IGF-1-resistant (2, 55) hypertensive rodent models.

Counterregulatory roles of Ins and ANG II in glucose utilization: role of oxidative stress. There is increasing evidence of a strong association between hypertension, Ins resistance, and the development of Type 2 diabetes mellitus (6, 41, 58, 62, 64, 68, 76) (Fig. 3). Increased autocrine/paracrine activity of tissue ANG II, diminished PI3K-Akt signaling, and enhanced generation of ROS may explain impaired glucose utilization (2, 24, 32, 54, 72) as well as hypertension (5, 15, 19, 22, 23, 30, 47, 48, 60, 62) associated with Ins resistance and Type 2 diabetes mellitus. In this regard, both AT1R blocking agents (22, 23, 47) and other strategies that reduce ROS in vivo (5, 19, 30, 48) improve Ins-mediated glucose utilization in Ins-resistant rodents (22, 23, 30, 47) and humans (13, 20, 39, 63, 64). Accumulating data indicate that ANG II overexpression (24, 32, 51) and Ins resistance (22, 31) are associated impaired glucose transporter-4 expression/translocation, an abnormality corrected by AT1 receptor blockade (22, 23), AT1 receptor antisense gene therapy (30), or attenuation of oxidative stress (53, 77) (Fig. 3). This is potentially a very fertile area for research on Ins resistance in the future.



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  		Fig. 3. ANG II and Ins/IGF-1 counterregulatory actions in skeletal muscle. GLUT, glucose transporter.

 

ACKNOWLEDGMENTS

The author thanks Paddy McGowan for excellent work in helping to prepare this manuscript.

GRANTS

This work was supported by National Heart, Lung, and Blood Institute Grant RO1 HL-63904-01 and a Department of Veterans Affairs Merit Review.

FOOTNOTES


Address for reprint requests and other correspondence: J. R. Sowers, Prof. of Medicine and Physiology/Pharmacology, Univ. of Missouri-Columbia, Dept. of Internal Medicine, MA410 Health Science Center, One Hospital Dr., Columbia, MO 65212 (E-mail: sowersj{at}health.missouri.edu).

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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