Tetrahydrobiopterin increases insulin sensitivity in patients with type 2 diabetes and coronary heart disease

Nyström, Thomas; Nygren, Arne; Sjöholm, Åke

doi:10.1152/ajpendo.00046.2004

Cited by 51 publications

(34 citation statements)

References 40 publications

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“…130 eNOS, although classically described as being atheroprotective, can significantly contribute to ROS production if electron transfer within the enzyme becomes uncoupled secondary to loss of either the cofactor 5,6,7, 8,-tetrahydrobiopterin (BH 4 ) or the substrate Larginine, resulting in the transfer of electrons to O 2 , forming superoxide. 127 Interestingly, hypercholesterolemia, 134 diabetes 135 and hypertension 136 have all been associated with eNOS uncoupling, potentially through ROS production, further potentiating the creation of superoxide.…”

Section: Reactive Oxygen Speciesmentioning

confidence: 99%

The role of shear stress in the pathogenesis of atherosclerosis

Cunningham

Gotlieb

2005

Laboratory Investigation

912

654

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Although the pathobiology of atherosclerosis is a complex multifactorial process, blood flow-induced shear stress has emerged as an essential feature of atherogenesis. This fluid drag force acting on the vessel wall is mechanotransduced into a biochemical signal that results in changes in vascular behavior. Maintenance of a physiologic, laminar shear stress is known to be crucial for normal vascular functioning, which includes the regulation of vascular caliber as well as inhibition of proliferation, thrombosis and inflammation of the vessel wall. Thus, shear stress is atheroprotective. It is also recognized that disturbed or oscillatory flows near arterial bifurcations, branch ostia and curvatures are associated with atheroma formation. Additionally, vascular endothelium has been shown to have different behavioral responses to altered flow patterns both at the molecular and cellular levels and these reactions are proposed to promote atherosclerosis in synergy with other well-defined systemic risk factors. Nonlaminar flow promotes changes to endothelial gene expression, cytoskeletal arrangement, wound repair, leukocyte adhesion as well as to the vasoreactive, oxidative and inflammatory states of the artery wall. Disturbed shear stress also influences the site selectivity of atherosclerotic plaque formation as well as its associated vessel wall remodeling, which can affect plaque vulnerability, stent restenosis and smooth muscle cell intimal hyperplasia in venous bypass grafts. Thus, shear stress is critically important in regulating the atheroprotective, normal physiology as well as the pathobiology and dysfunction of the vessel wall through complex molecular mechanisms that promote atherogenesis. Laboratory Investigation (2005) 85, 9-23, advance online publication, 29 November 2004; doi:10.1038/labinvest.3700215Keywords: shear stress; atherosclerosis; endothelium; smooth muscle cells; nitric oxide; cytoskeleton; mechanotransductionThe parallel frictional drag force of shear stress is one of the important blood flow-induced mechanical stresses acting on the vessel wall, which also includes the perpendicular force of blood pressure and the cyclic stretch of pulsatile flow. Shear stress is a biomechanical force that is determined by blood flow, vessel geometry and fluid viscosity that is computationally estimated using fluid dynamics models and is expressed in units of dynes/cm 2 .

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Section: Reactive Oxygen Speciesmentioning

confidence: 99%

The role of shear stress in the pathogenesis of atherosclerosis

Cunningham

Gotlieb

2005

Laboratory Investigation

912

654

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“…The rate-limiting enzyme in BH4 biosynthesis is GTP-cyclohydrolase (GTPCH)-1; there is evidence that supports a role for insulin in upregulation of GTPCH-1, stimulating BH4 synthesis. In insulin resistant states these effects are impaired [62]. Furthermore, BH4 itself is rapidly degraded by reactive oxygen species (ROS) such as superoxide, so that a vicious cycle can ensue, whereby oxidative stress worsens BH4 deficiency [60].…”

Section: Relationship Of Endothelial Dysfunction and Low-grade Chronimentioning

confidence: 99%

Vascular abnormalities and low-grade chronic inflammation in women with polycystic ovary syndrome: Relationships with insulin resistance, obesity and hyperandrogenemia

et al. 2008

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AbstractPolycystic ovary syndrome (PCOS) is possibly the most common endocrinopathy of reproductive age, characterized by hyperandrogenism and oligomenorrhea. Additionally, approximately one-third to one-half of all women and adolescent girls with PCOS tend to fulfill many of the metabolic syndrome criteria, and many view PCOS as a premetabolic syndrome condition, predisposing to a high risk for cardiovascular disease. Endothelial dysfunction, impaired arterial structure, or proinflammatory markers are early features of atherosclerosis, and can be used as surrogate indicators of future coronary artery disease in women with PCOS. However, as the latest studies show, these symptoms are the result of deleterious effects that cardiovascular risk factors, in particular insulin resistance and obesity, produce on the vascular wall, rather than to the presence of PCOS per se. The relationship between hyperandrogenemia and the risk of cardiovascular disease is controversial and needs to be clarified. Further research is warranted to understand the pathogenesis of cardiovascular disease in PCOS, and to identify subtypes of PCOS in which the presence of cardiovascular risk factors may result in increased cardiovascular events, leading to high morbidity or mortality rates caused by cardiovascular disease.

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“…where D i is the absolute difference between two measurements, and n is the number of measurements] based on 32 individuals 1 week apart was 7.2 for FMD and 10.7 for NTG [10].…”

Section: Fmd (Flow-mediated Dilation) and Ntg (Nitroglycerine)-inducementioning

confidence: 99%

“…The hyperinsulinaemic clamp was performed as described by DeFronzo et al [11], and has been reported in detail previously [10]. The glucose clamp-derived index of S I [insulin sensitivity; units are 10 −4 dl · kg −1 of body weight · min −1 · (µ-units/ml) −1 ] was calculated from the GIR (glucose infusion rate), corrected for body weight, during the final 30 min as follows:…”

Section: Isoglycaemic-hyperinsulinaemic Clampmentioning

confidence: 99%

Increased levels of tumour necrosis factor-α (TNF-α) in patients with Type II diabetes mellitus after myocardial infarction are related to endothelial dysfunction

2006

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The pathophysiology of insulin resistance and atherosclerosis may share a common inflammatory basis, maintaining endothelial dysfunction, suggesting why patients with T2DM (Type II diabetes mellitus) have an impaired prognosis after an MI (myocardial infarction), but it remains unclear how these parameters are inter-related. Forty patients with an MI (20 patients with and 20 patients without T2DM) took part in this cross-sectional study. Endothelium-dependent [FMD (flow-mediated dilation)] and -independent [NTG (nitroglycerine)] vasodilatation (determined by ultrasound), S(I) (insulin sensitivity index; determined by isoglycaemic-hyperinsulinaemic clamp) and serum levels of CRP (C-reactive protein), TNF-alpha (tumour necrosis factor-alpha), IL-6 (interleukin 6), resistin and adiponectin (determined by ELISA) were measured. Associations between FMD/NTG and S(I), and CRP, TNF-alpha, IL-6, adiponectin, resistin, lipids, blood pressure, BMI (body mass index) and brachial artery diameter were then assessed. FMD (2.1 compared with 4.7%; P<0.05), NTG (14.9 compared with 21.2%; P<0.05) and S(I) [4.3 compared with 6.6 10(-4) dl.kg(-1) of body weight.min(-1).(mu-units/ml)(-1); P<0.05], and adiponectin levels (3.1 compared with 6.4 microg/ml; P<0.01) were all lower in patients with T2DM. TNF-alpha (6.9 compared with 1.8 pg/ml; P<0.01) and IL-6 (2.3 compared with 1.2 pg/ml; P<0.01) levels were higher in patients with T2DM, whereas differences in CRP and resistin levels did not attain statistical significance between the two groups. TNF-alpha concentrations and brachial artery diameter were negatively, whereas S(I) was positively, correlated with FMD. Adjustment for age weakened the association for S(I), whereas TNF-alpha and brachial artery diameter remained significantly associated with FMD after adjustment for group, age and BMI. Endothelial dysfunction and low-grade inflammation co-exist in T2DM after MI. These results suggest that the endothelium is negatively impacted in multiple ways by the diabetic state after an MI.

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Tetrahydrobiopterin increases insulin sensitivity in patients with type 2 diabetes and coronary heart disease

Abstract: Nyström, Thomas, Arne Nygren, and Å ke Sjöholm. Tetrahydrobiopterin increases insulin sensitivity in patients with type 2 diabetes and coronary heart disease.

Cited by 51 publications

References 40 publications

The role of shear stress in the pathogenesis of atherosclerosis

The role of shear stress in the pathogenesis of atherosclerosis

Vascular abnormalities and low-grade chronic inflammation in women with polycystic ovary syndrome: Relationships with insulin resistance, obesity and hyperandrogenemia

Increased levels of tumour necrosis factor-α (TNF-α) in patients with Type II diabetes mellitus after myocardial infarction are related to endothelial dysfunction

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