Endothelin Limits Insulin Action in Obese/Insulin-Resistant Humans

Lteif, Amale; Vaishnava, Prashant; Baron, Alain; Mather, Kieren J.

doi:10.2337/db06-1406

Cited by 106 publications

(91 citation statements)

References 54 publications

(67 reference statements)

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“…We further demonstrated that the vasodilatory effects of insulin were mediated by the release of endothelial nitric oxide, and we and others demonstrated that blocking nitric oxide production in vivo could induce insulin resistance and inhibit glucose uptake by preventing insulin-mediated vasodilation in skeletal muscle (3). Finally, we demonstrated that endothelial dysfunction, characterized by reduced nitric oxide production and exaggerated release of endothelin, was a key feature of human insulin-resistant states (4). The link between insulin resistance and endothelial dysfunction is now widely accepted, and there is broad recognition that insulin's action to enhance its own vascular delivery (and that of its substrates) is integral to its overall action.…”

mentioning

confidence: 78%

Insulin resistance in the vasculature

Mather¹,

Steinberg²,

Baron³

2013

J. Clin. Invest.

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104

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mentioning

confidence: 78%

Insulin resistance in the vasculature

Mather¹,

Steinberg²,

Baron³

2013

J. Clin. Invest.

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104

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“…Vasoconstrictor effects of insulin are critically dependent on the activation of extracellular signal-related kinase (ERK) 1/2, which controls ET-1 release by the endothelium (7)(8)(9). Increased ET-1 activity, as observed in insulin-resistant states, has been shown to impair blood flow and glucose uptake (10). In microvessels of insulin-resistant animals, it has been observed that insulin-mediated Akt activation is selectively impaired, whereas ERK1/2 activation is not altered (11).…”

mentioning

confidence: 99%

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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“…In health, insulin's vasodilatory effect dominates. With endothelial dysfunction, as occurs with obesity and type 2 diabetes, the PI3K pathway appears to be selectively inhibited by low-grade inflammation, FFA, oxidative stress, and reduced perivascular adiponectin release (55,61,75,79,123). In these circumstances, a reduced vasodilatory response or even paradoxical vasoconstriction can be seen with hyperinsulinemia (23,55).…”

Section: E381mentioning

confidence: 99%

Muscle microvasculature's structural and functional specializations facilitate muscle metabolism

Kusters

Barrett

2016

American Journal of Physiology-Endocrinology and Metabolism

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Kusters YH, Barrett EJ. Muscle microvasculature's structural and functional specializations facilitate muscle metabolism. Am J Physiol Endocrinol Metab 310: E379-E387, 2016. First published December 29, 2015; doi:10.1152/ajpendo.00443.2015.-We review the evolving findings from studies that examine the relationship between the structural and functional properties of skeletal muscle's vasculature and muscle metabolism. Unique aspects of the organization of the muscle microvasculature are highlighted. We discuss the role of vasomotion at the microscopic level and of flowmotion at the tissue level as modulators of perfusion distribution in muscle. We then consider in some detail how insulin and exercise each modulate muscle perfusion at both the microvascular and whole tissue level. The central role of the vascular endothelial cell in modulating both perfusion and transendothelial insulin and nutrient transport is also reviewed. The relationship between muscle metabolic insulin resistance and the vascular action of insulin in muscle continues to indicate an important role for the microvasculature as a target for insulin action and that impairing insulin's microvascular action significantly affects body glucose metabolism. muscle microvasculature; vasomotion; flowmotion; endothelium; insulin resistance MUSCLE'S MICROVASCULATURE IS THE FINAL INTERFACE through which circulating nutrients, hormones, gases, and electrolytes must pass in journeying to and from the systemic circulation. It has evolved multiple structural and functional adaptations to flexibly and efficiently fulfill its role in optimizing muscle function. Here, we examine how the minute-to-minute metabolic activity of skeletal muscle is coupled to the function of muscle's vasculature. We will discuss how bulk blood flow and flow distribution can regulate nutrient delivery to muscle microvasculature as well as how transendothelial transport processes can modulate the exchange of hormones and metabolites between plasma and the myocytes. We focus on acute regulatory relationships and defer discussion of chronic vascular or myocyte adaptation to environmental, nutritional, and most pathological processes.Muscle blood flow has been measured in numerous classical limb balance and metabolic tracer studies of the acute effects of fasting, feeding, exercise, and hormonal manipulation on muscle nutrient exchange. These methods, however, treat muscle's vasculature as a "black box." Here, we consider muscle microvasculature's specialized architecture and how that architecture might impact nutrient fluxes into and out of the muscle. We will discuss the role of vasomotion and flowmotion in the regulation of microvascular perfusion. We recognize that factors acting on the endothelial cell (EC), the vascular smooth muscle cell (SMC), or pericytes may affect muscle perfusion.We will consider in more detail the effect insulin and exercise have on the endothelium and directly or indirectly on the vascular SMC to influence nutrient delivery.Beyond muscle perfusion, we will co...

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Endothelin Limits Insulin Action in Obese/Insulin-Resistant Humans

Cited by 106 publications

References 54 publications

Insulin resistance in the vasculature

Insulin resistance in the vasculature

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

Muscle microvasculature's structural and functional specializations facilitate muscle metabolism

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