Targeting Vascular Endothelial Cell Insulin Resistance in Type 2 Diabetes Mellitus

Pierce, Gary L.

doi:10.1161/circulationaha.112.150813

Cited by 5 publications

(2 citation statements)

References 21 publications

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“…Due to decreased activity and expression of eNOS, diabetic patients displayed a decreased conversion of l -arginine to NO•, and ET of human diabetic vessels cannot generate enough NO• to regulate blood flow [ 10 , 100 ]. Decreased vascular eNOS activity/expression in T2D is due to (A) increased dimethylarginine dimethylaminohydrolase (DDAH) activity, which increases asymmetric dimethyl arginine (ADMA) [ 117 ], (B) increased AEGs, which decreases eNOS mRNA stability and eNOS phosphorylation [ 118 ], (C) increased NOX, which uncouples eNOS and oxidizes BH 4 [ 121 ], (D) impaired insulin signaling [ 122 ], (F) increased arginase activity [ 120 ], and (G) decreased NOS sensitivity to ACh [ 120 ].…”

Section: Vascular No• Production In T2dmentioning

confidence: 99%

“…T2D also initiates a cascade of events in the vessel wall, including NOX-induced ROS over-production, oxidation of BH 4 , and uncoupling of eNOS in vascular ET, leading to decreased NO• availability [ 121 ]. In addition, T2D impairs phosphatidylinositol 3-kinase (PI3K)-protein kinase B (PKB/Akt) insulin signaling pathway in the vascular ET; this pathway stimulates eNOS and thus NO production; therefore, its impairment decreases NO• production in T2D vessels [ 122 ].…”

Section: Vascular No• Production In T2dmentioning

confidence: 99%

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Vascular nitric oxide resistance in type 2 diabetes

et al. 2023

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Vascular nitric oxide (NO•) resistance, manifested by an impaired vasodilator function of NO• in both the macro- and microvessels, is a common state in type 2 diabetes (T2D) associated with developing cardiovascular events and death. Here, we summarize experimental and human evidence of vascular NO• resistance in T2D and discuss its underlying mechanisms. Human studies indicate a ~ 13-94% decrease in the endothelium (ET)-dependent vascular smooth muscle (VSM) relaxation and a 6-42% reduced response to NO• donors, i.e., sodium nitroprusside (SNP) and glyceryl trinitrate (GTN), in patients with T2D. A decreased vascular NO• production, NO• inactivation, and impaired responsiveness of VSM to NO• [occurred due to quenching NO• activity, desensitization of its receptor soluble guanylate cyclase (sGC), and/or impairment of its downstream pathway, cyclic guanosine monophosphate (cGMP)-protein kinase G (PKG)] are the known mechanisms underlying the vascular NO• resistance in T2D. Hyperglycemia-induced overproduction of reactive oxygen species (ROS) and vascular insulin resistance are key players in this state. Therefore, upregulating vascular NO• availability, re-sensitizing or bypassing the non-responsive pathways to NO•, and targeting key vascular sources of ROS production may be clinically relevant pharmacological approaches to circumvent T2D-induced vascular NO• resistance.

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