Acute effects of wortmannin on insulin's hemodynamic and metabolic actions in vivo

Bradley, EA; Clark, Michael G.; Rattigan, Stephen

doi:10.1152/ajpendo.00407.2006

Cited by 11 publications

(12 citation statements)

References 41 publications

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“…Clerk et al (20) described that fatty acid-induced insulin resistance in muscle is partially caused by impairment of insulin-mediated nutritive muscle blood flow (20), which is dependent on activation of phosphatidylinositol 3-kinase/Akt in muscle resistance arteries (19). These authors suggest a possible role for PKC in the impairment of insulin signaling in muscle resistance arteries (20).…”

Section: Discussionmentioning

confidence: 99%

“…PKC activation, induced by fatty acids, has been shown to impair insulin-mediated glucose uptake in skeletal muscle myocytes and in adipocytes by the inhibition of Akt in in vitro studies (16 -18). As outlined above, however, impaired glucose uptake in muscle is also caused by impaired nutritive blood flow, which is critically dependent on activation of Akt (19). It has been reported that fatty acids directly impair insulin-mediated nutritive muscle blood flow and cause insulin resistance (20).…”

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confidence: 98%

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Protein Kinase C θ Activation Induces Insulin-Mediated Constriction of Muscle Resistance Arteries

et al. 2008

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OBJECTIVE—Protein kinase C (PKC) θ activation is associated with insulin resistance and obesity, but the underlying mechanisms have not been fully elucidated. Impairment of insulin-mediated vasoreactivity in muscle contributes to insulin resistance, but it is unknown whether PKCθ is involved. In this study, we investigated whether PKCθ activation impairs insulin-mediated vasoreactivity and insulin signaling in muscle resistance arteries. RESEARCH DESIGN AND METHODS—Vasoreactivity of isolated resistance arteries of mouse gracilis muscles to insulin (0.02–20 nmol/l) was studied in a pressure myograph with or without PKCθ activation by palmitic acid (PA) (100 μmol/l). RESULTS—In the absence of PKCθ activation, insulin did not alter arterial diameter, which was caused by a balance of nitric oxide–dependent vasodilator and endothelin-dependent vasoconstrictor effects. Using three-dimensional microscopy and Western blotting of muscle resistance arteries, we found that PKCθ is abundantly expressed in endothelium of muscle resistance arteries of both mice and humans and is activated by pathophysiological levels of PA, as indicated by phosphorylation at Thr538 in mouse resistance arteries. In the presence of PA, insulin induced vasoconstriction (21 ± 6% at 2 nmol/l insulin), which was abolished by pharmacological or genetic inactivation of PKCθ. Analysis of intracellular signaling in muscle resistance arteries showed that PKCθ activation reduced insulin-mediated Akt phosphorylation (Ser473) and increased extracellular signal–related kinase (ERK) 1/2 phosphorylation. Inhibition of PKCθ restored insulin-mediated vasoreactivity and insulin-mediated activation of Akt and ERK1/2 in the presence of PA. CONCLUSIONS—PKCθ activation induces insulin-mediated vasoconstriction by inhibition of Akt and stimulation of ERK1/2 in muscle resistance arteries. This provides a new mechanism linking PKCθ activation to insulin resistance.

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Section: Discussionmentioning

confidence: 99%

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confidence: 98%

Protein Kinase C θ Activation Induces Insulin-Mediated Constriction of Muscle Resistance Arteries

et al. 2008

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“…Considering that inhibition of ACE or chronic blockade of AT1Rs is associated with increased levels of circulating ANG- (1)(2)(3)(4)(5)(6)(7), this hormone could be involved in the beneficial effects of antihypertensive therapy (15,26,44). The counterregulatory effects of ANG-(1-7) on the pressor and trophic actions of ANG II appear to be mediated by the Mas receptor (MasR), a G protein-coupled receptor present in several tissues, including heart and kidney (16,44).…”

mentioning

confidence: 99%

Angiotensin-(1–7) stimulates the phosphorylation of JAK2, IRS-1 and Akt in rat heart in vivo: role of the AT₁ and Mas receptors

Giani¹,

Gironacci²,

Muñoz³

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

110

101

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Angiotensin (ANG) II exerts a negative modulation on insulin signal transduction that might be involved in the pathogenesis of hypertension and insulin resistance. ANG-(1-7), an endogenous heptapeptide hormone formed by cleavage of ANG I and ANG II, counteracts many actions of ANG II. In the current study, we have explored the role of ANG-(1-7) in the signaling crosstalk that exists between ANG II and insulin. We demonstrated that ANG-(1-7) stimulates the phosphorylation of Janus kinase 2 (JAK2) and insulin receptor substrate (IRS)-1 in rat heart in vivo. This stimulating effect was blocked by administration of the selective ANG type 1 (AT(1)) receptor blocker losartan. In contrast to ANG II, ANG-(1-7) stimulated cardiac Akt phosphorylation, and this stimulation was blunted in presence of the receptor Mas antagonist A-779 or the phosphatidylinositol 3-kinase (PI3K) inhibitor wortmannin. The specific JAK2 inhibitor AG-490 blocked ANG-(1-7)-induced JAK2 and IRS-1 phosphorylation but had no effect on ANG-(1-7)-induced phosphorylation of Akt, indicating that activation of cardiac Akt by ANG-(1-7) appears not to involve the recruitment of JAK2 but proceeds through the receptor Mas and involves PI3K. Acute in vivo insulin-induced cardiac Akt phosphorylation was inhibited by ANG II. Interestingly, coadministration of insulin with an equimolar mixture of ANG II and ANG-(1-7) reverted this inhibitory effect. On the basis of our present results, we postulate that ANG-(1-7) could be a positive physiological contributor to the actions of insulin in heart and that the balance between ANG II and ANG-(1-7) could be relevant for the association among insulin resistance, hypertension, and cardiovascular disease.

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“…Tissues were prepared as described in Ref. 6, with the exception that protease inhibitor cocktail (Sigma) was added to the solubilization buffer. Protein (25 g) was then heated with 125 mM Tris·HCl, pH 6.8, 20% glycerol, 4% ␤-mercaptoethanol, 0.2% bromophenol blue, and 4% SDS for 10 min at 90°C.…”

Section: Methodsmentioning

confidence: 99%

cGMP phosphodiesterase inhibition improves the vascular and metabolic actions of insulin in skeletal muscle

Genders

Bradley

Rattigan

et al. 2011

American Journal of Physiology-Endocrinology and Metabolism

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Genders AJ, Bradley EA, Rattigan S, Richards SM. cGMP phosphodiesterase inhibition improves the vascular and metabolic actions of insulin in skeletal muscle. Am J Physiol Endocrinol Metab 301: E342-E350, 2011. First published June 7, 2011; doi:10.1152/ajpendo.00691.2010.-There is considerable support for the concept that insulin-mediated increases in microvascular blood flow to muscle impact significantly on muscle glucose uptake. Since the microvascular blood flow increases with insulin have been shown to be nitric oxide-dependent inhibition of cGMP-degrading phosphodiesterases (cGMP PDEs) is predicted to enhance insulinmediated increases in microvascular perfusion and muscle glucose uptake. Therefore, we studied the effects of the pan-cGMP PDE inhibitor zaprinast on the metabolic and vascular actions of insulin in muscle. Hyperinsulinemic euglycemic clamps (3 mU·min Ϫ1 ·kg Ϫ1 ) were performed in anesthetized rats and changes in microvascular blood flow assessed from rates of 1-methylxanthine metabolism across the muscle bed by capillary xanthine oxidase in response to insulin and zaprinast. We also characterized cGMP PDE isoform expression in muscle by real-time PCR and immunostaining of frozen muscle sections. Zaprinast enhanced insulin-mediated microvascular perfusion by 29% and muscle glucose uptake by 89%, while whole body glucose infusion rate during insulin infusion was increased by 33% at 2 h. PDE2, -9, and -10 were the major isoforms expressed at the mRNA level in muscle, while PDE1B, -9A, -10A, and -11A proteins were expressed in blood vessels. Acute administration of the cGMP PDE inhibitor zaprinast enhances muscle microvascular blood flow and glucose uptake response to insulin. The expression of a number of cGMP PDE isoforms in skeletal muscle suggests that targeting specific cGMP PDE isoforms may provide a promising avenue for development of a novel class of therapeutics for enhancing muscle insulin sensitivity. cyclic guanosine monophosphate; blood flow; insulin and glucose delivery to muscle; microvascular blood flow ENDOTHELIAL DYSFUNCTION ARISING from impaired nitric oxide (NO) signaling underlies a range of cardiovascular conditions including erectile dysfunction, heart failure, and vascular disease in diabetes. Agents such as cinaciguat and sildenfil enhance NO signaling by increasing the formation of cyclic guanosine monophosphate (cGMP) by the NO-sensitive enzyme soluble guanylate cyclase or by reducing its hydrolysis by cGMP-degrading phosphodiesterases (cGMP PDEs), respectively. Cinaciguat, or BAY 58-2667, improves cardiovascular function in patients with acute decompensated heart failure (19) and preferentially vasodilates blood vessels containing a form of soluble guanylate cyclase affected by oxidative stress from human type 2 diabetics (36). In addition to its use for erectile dysfunction, sildenafil treatment has been shown to improve flow-mediated dilatation in brachial arteries of type 2 diabetics (14), and its chronic administration enhances the metabolic actions of insulin in hig...

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Acute effects of wortmannin on insulin's hemodynamic and metabolic actions in vivo

Abstract: Bradley EA, Clark MG, Rattigan S. Acute effects of wortmannin on insulin's hemodynamic and metabolic actions in vivo.

Cited by 11 publications

References 41 publications

Protein Kinase C θ Activation Induces Insulin-Mediated Constriction of Muscle Resistance Arteries

Protein Kinase C θ Activation Induces Insulin-Mediated Constriction of Muscle Resistance Arteries

Angiotensin-(1–7) stimulates the phosphorylation of JAK2, IRS-1 and Akt in rat heart in vivo: role of the AT₁ and Mas receptors

cGMP phosphodiesterase inhibition improves the vascular and metabolic actions of insulin in skeletal muscle

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Acute effects of wortmannin on insulin's hemodynamic and metabolic actions in vivo

Abstract: Bradley EA, Clark MG, Rattigan S. Acute effects of wortmannin on insulin's hemodynamic and metabolic actions in vivo.

Cited by 11 publications

References 41 publications

Protein Kinase C θ Activation Induces Insulin-Mediated Constriction of Muscle Resistance Arteries

Protein Kinase C θ Activation Induces Insulin-Mediated Constriction of Muscle Resistance Arteries

Angiotensin-(1–7) stimulates the phosphorylation of JAK2, IRS-1 and Akt in rat heart in vivo: role of the AT1 and Mas receptors

cGMP phosphodiesterase inhibition improves the vascular and metabolic actions of insulin in skeletal muscle

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Angiotensin-(1–7) stimulates the phosphorylation of JAK2, IRS-1 and Akt in rat heart in vivo: role of the AT₁ and Mas receptors