Phosphatidylinositol 4,5-Bisphosphate Reverses Endothelin-1–Induced Insulin Resistance via an Actin-Dependent Mechanism

Strawbridge, Andrew B.; Elmendorf, Jeffrey S.

doi:10.2337/diabetes.54.6.1698

Cited by 44 publications

(42 citation statements)

References 52 publications

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“…In vascular smooth muscle cells and adipocytes, ET-1 causes insulin resistance by a PKCdependent mechanism (14,17). Endothelin has also been found to impair insulin action through interactions with downstream signaling events at the plasma membrane involving PIP 2 and actin cytoskeleton components of the insulin response (18), suggesting that ET-1 negatively impacts cytoskeletal structure important for insulin function. From this perspective, the question of effects of endothelin antagonism on glucose extraction as distinct from effects on blood flow is of interest.…”

Section: Discussionmentioning

confidence: 99%

“…In vitro, sustained exposure of insulin-responsive cells to endothelin 1 (ET-1) induces insulin resistance (14 -16). Molecular studies have shown that this effect is mediated by effects of endothelin on a number of components of the insulin signaling cascade, including heterologous desensitization of insulin signaling by a G ␣q/11 -mediated pathway (14), impaired stimulation of phosphoinositol-3 kinase by insulin receptor substrate (IRS)-1 and IRS-2 (14,17), and impairments in downstream plasma membrane phosphatidylinositol 4,5-bisphosphate (PIP 2 ) and actin cytoskeleton interactions (18).…”

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confidence: 99%

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Endothelin Limits Insulin Action in Obese/Insulin-Resistant Humans

et al. 2007

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The normal action of insulin to vasodilate and redistribute blood flow in support of skeletal muscle metabolism is impaired in insulin-resistant states. Increased endogenous endothelin contributes to endothelial dysfunction in obesity and diabetes. Here, we test the hypothesis that increased endogenous endothelin action also contributes to skeletal muscle insulin resistance via impairments in insulin-stimulated vasodilation. We studied nine lean and seven obese humans, measuring the metabolic and hemodynamic effects of insulin (300 mU ⅐ m ؊2 ⅐ min ؊1 ) alone and during femoral artery infusion of BQ123 (an antagonist of type A endothelin receptors, 1 mol/min). Endothelin antagonism augmented skeletal muscle responses to insulin in obese subjects through changes in both leg blood flow (LBF) and glucose extraction. Insulin-stimulated LBF was significantly increased in obese subjects only. These changes, combined with differential effects on glucose extraction, resulted in augmented insulin-stimulated leg glucose uptake in obese subjects (54.7 ؎ 5.7 vs. 107.4 ؎ 18.9 mg/min with BQ123), with no change in lean subjects (103.7 ؎ 11.4 vs. 88.9 ؎ 16.3, P ‫؍‬ 0.04 comparing BQ123 across groups). BQ123 allowed augmented leg glucose extraction in obese subjects even in the face of NOS antagonism. These findings suggest that increased endogenous endothelin action contributes to insulin resistance in skeletal muscle of obese humans, likely through both vascular and tissue effects. Diabetes 56:728 -734, 2007

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Endothelin Limits Insulin Action in Obese/Insulin-Resistant Humans

et al. 2007

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“…Furthermore, a very recent study demonstrated that chronic ET-1 treatment, which causes insulin resistance, results in dysregulation of cortical F-actin by diminishing the plasma membrane PI(4,5)P 2 level. Importantly, exogenous replenishment of PI(4,5)P 2 , but not PI(3,4,5)P 3 , restores the disrupted cortical F-actin structure and subsequently reverses the insulin resistance induced by chronic ET-1 treatment [226]. Thus, PI(4,5)P 2 and its dynamic turnover in response to extracellular stimuli including insulin are physiologically critical for maintaining proper membrane trafficking and actin dynamics, thereby directly affecting insulin-induced redistribution of GLUT4 .…”

Section: (4) Actin Dynamics Are Regulated By Both Phosphoinositimentioning

confidence: 99%

“…Recently, several studies have also demonstrated the importance of proper PI(4,5)P 2 metabolism in the regulation of GLUT4 recycling and its insulin responsiveness [194,[223][224][225][226]. The major pathway for PI(4,5)P 2 production is via sequential phosphorylation of PI by a PI 4-kinase to generate PI(4)P followed by phosphorylation with type I PIP 5-kinase.…”

Section: (4) Actin Dynamics Are Regulated By Both Phosphoinositimentioning

confidence: 99%

Insulin Receptor Signals Regulating GLUT4 Translocation and Actin Dynamics

Kanzaki

2006

Endocr J

131

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Abstract. In skeletal muscle and adipose tissue, insulin-stimulated glucose uptake is dependent upon translocation of the insulin-responsive glucose transporter GLUT4 from intracellular storage compartments to the plasma membrane. This insulin-induced redistribution of GLUT4 protein is achieved through a series of highly organized membrane trafficking events, orchestrated by insulin receptor signals. Recently, several key molecules linking insulin receptor signals and membrane trafficking have been identified, and emerging evidence supports the importance of subcellular compartmentalization of signaling components at the right time and in the right place. In addition, the translocation of GLUT4 in adipocytes requires insulin stimulation of dynamic actin remodeling at the inner surface of the plasma membrane (cortical actin) and in the perinuclear region. This results from at least two independent insulin receptor signals, one leading to the activation of phosphatidylinositol (PI) 3-kinase and the other to the activation of the Rho family small GTP-binding protein TC10. Thus, both spatial and temporal regulations of actin dynamics, both beneath the plasma membrane and around endomembranes, by insulin receptor signals are also involved in the process of GLUT4 translocation.

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“…153 This same mechanism may also be operative in metabolic tissues, inasmuch as ET-1 impairs insulinstimulated translocation of GLUT4 in adipocytes. 154,155 …”

Section: Pathophysiological Cross-talk Between Metabolic and Vascularmentioning

confidence: 99%

Reciprocal Relationships Between Insulin Resistance and Endothelial Dysfunction

Kim

Montagnani²,

Koh³

et al. 2006

Circulation

1,445

1,257

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Abstract-Endothelial dysfunction contributes to cardiovascular diseases, including hypertension, atherosclerosis, and coronary artery disease, which are also characterized by insulin resistance. Insulin resistance is a hallmark of metabolic disorders, including type 2 diabetes mellitus and obesity, which are also characterized by endothelial dysfunction. Metabolic actions of insulin to promote glucose disposal are augmented by vascular actions of insulin in endothelium to stimulate production of the vasodilator nitric oxide (NO). Indeed, NO-dependent increases in blood flow to skeletal muscle account for 25% to 40% of the increase in glucose uptake in response to insulin stimulation. Phosphatidylinositol 3-kinase-dependent insulin-signaling pathways in endothelium related to production of NO share striking similarities with metabolic pathways in skeletal muscle that promote glucose uptake. Other distinct nonmetabolic branches of insulin-signaling pathways regulate secretion of the vasoconstrictor endothelin-1 in endothelium. Metabolic insulin resistance is characterized by pathway-specific impairment in phosphatidylinositol 3-kinase-dependent signaling, which in endothelium may cause imbalance between production of NO and secretion of endothelin-1, leading to decreased blood flow, which worsens insulin resistance. Therapeutic interventions in animal models and human studies have demonstrated that improving endothelial function ameliorates insulin resistance, whereas improving insulin sensitivity ameliorates endothelial dysfunction. Taken together, cellular, physiological, clinical, and epidemiological studies strongly support a reciprocal relationship between endothelial dysfunction and insulin resistance that helps to link cardiovascular and metabolic diseases. In the present review, we discuss pathophysiological mechanisms, including inflammatory processes, that couple endothelial dysfunction with insulin resistance and emphasize important therapeutic implications. Key Words: diabetes mellitus Ⅲ endothelium Ⅲ hypertension Ⅲ insulin I nsulin resistance is typically defined as decreased sensitivity and/or responsiveness to metabolic actions of insulin that promote glucose disposal. This important feature of diabetes, obesity, glucose intolerance, and dyslipidemia is also a prominent component of cardiovascular disorders, including hypertension, coronary artery disease, and atherosclerosis, which are characterized by endothelial dysfunction. 1 Conversely, endothelial dysfunction is present in diabetes, obesity, and dyslipidemias. 2 Moreover, it is firmly established that these metabolic disorders are major risk factors for cardiovascular diseases. 3 In addition to its essential metabolic actions, insulin has important vascular actions that involve stimulation of the production of nitric oxide (NO) from endothelium, leading to vasodilation, increased blood flow, and augmentation of glucose disposal in skeletal muscle. 4 Elucidation of insulin-signaling pathways regulating endothelial production of NO reveals strik...

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Phosphatidylinositol 4,5-Bisphosphate Reverses Endothelin-1–Induced Insulin Resistance via an Actin-Dependent Mechanism

Cited by 44 publications

References 52 publications

Endothelin Limits Insulin Action in Obese/Insulin-Resistant Humans

Endothelin Limits Insulin Action in Obese/Insulin-Resistant Humans

Insulin Receptor Signals Regulating GLUT4 Translocation and Actin Dynamics

Reciprocal Relationships Between Insulin Resistance and Endothelial Dysfunction

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