Hemodynamic Effects of Fenofibrate and Coenzyme Q10 in Type 2 Diabetic Subjects With Left Ventricular Diastolic Dysfunction

Chew, Gerard T.; Watts, Gerald F.; Davis, Timothy; Stuckey, Bronwyn; Beilin, Lawrence J.; Thompson, Peter L.; Burke, Valerie; Currie, Philip J.

doi:10.2337/dc08-0118

Cited by 64 publications

(63 citation statements)

References 25 publications

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“…Despite random allocation of subjects to treatment groups, the lower plasma ET-1 levels in the placebo group could be owing to sampling variation, and may account for why the between-group changes were less significant after adjustment for baseline values. Nevertheless, these observations provide a partial explanation for our finding that FF improves resistance vessel function and ambulatory blood pressure in diabetes mellitus 34,35 and could provide a contributing mechanism explaining the beneficial effects of FF on microvascular complications of diabetes mellitus in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) and Action to Control Cardiovascular Risk in Type 2 Diabetes (ACCORD) trials, including a significant reduction in the need for laser treatment of retinopathy, as well as a delay in the progression of nephropathy. [36][37][38] There is also a significant reduction in the risk of minor amputations in the absence of large-vessel disease, as observed in the FIELD study.…”

Section: Discussionmentioning

confidence: 44%

Fenofibrate Inhibits Endothelin-1 Expression by Peroxisome Proliferator–Activated Receptor α–Dependent and Independent Mechanisms in Human Endothelial Cells

Glineur

Gross

Neve

et al. 2013

ATVB

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Objective-Dyslipidemia contributes to endothelial dysfunction in type 2 diabetes mellitus. Fenofibrate (FF), a ligand of the peroxisome proliferator-activated receptor-α (PPARα), has beneficial effects on microvascular complications. FF may act on the endothelium by regulating vasoactive factors, including endothelin-1 (ET-1). In vitro, FF decreases ET-1 expression in human microvascular endothelial cells. We investigated the molecular mechanisms involved in the effect of FF treatment on plasma levels of ET-1 in type 2 diabetes mellitus patients. Methods and Results-FF impaired the capacity of transforming growth factor-β to induce ET-1 gene expression. PPARα activation by FF increased expression of the transcriptional repressor Krüppel-like factor 11 and its binding to the ET-1 gene promoter. Knockdown of Krüppel-like factor 11 expression potentiated basal and transforming growth factor-β-stimulated ET-1 expression, suggesting that Krüppel-like factor 11 downregulates ET-1 expression. FF, in a PPARα-independent manner, and insulin enhanced glycogen synthase kinase-3β phosphorylation thus reducing glycogen synthase kinase-3 activity that contributes to the FF-mediated reduction of ET-1 gene expression. In type 2 diabetes mellitus, improvement of flow-mediated dilatation of the brachial artery by FF was associated with a decrease in plasma ET-1. Key Words: endothelin-1 ◼ endothelium ◼ glycogen synthase kinase-3 ◼ peroxisome proliferator-activated receptor-α ◼ type 2 diabetes mellitus Conclusion-FF

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Section: Discussionmentioning

confidence: 44%

Fenofibrate Inhibits Endothelin-1 Expression by Peroxisome Proliferator–Activated Receptor α–Dependent and Independent Mechanisms in Human Endothelial Cells

Glineur

Gross

Neve

et al. 2013

ATVB

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“…In dyslipidemic T2D patients with ED, combination fenofibrate and CoQ 10 normalized forearm microcirculatory dysfunction [139]. Moreover, fenofibrate and CoQ 10 independently and interactively lowered 24-hour ambulatory blood pressure [140], consistent with their beneficial effects on endothelial function in resistance arterioles. This synergistic effect of fenofibrate and CoQ 10 may involve coactivation of peroxisome proliferatoractivated receptor alpha (PPAR-α) in endothelial and smooth muscle cells, improving the production and action of NO and decreasing the synthesis of endothelin-1.…”

Section: Combination Therapiesmentioning

confidence: 51%

“…However, fenofibrate alone did not significantly improve forearm microcirculatory function in T2D patients [139]. Moreover, fenofibrate and coenzyme Q 10 (CoQ 10 ) independently and interactively lowered 24-h ambulatory blood pressure consistent with their beneficial effects on endothelial function in resistance arterioles [140]. Ciprofibrate and gemfibrozil have been shown to improve brachial artery FMD in type 2 diabetic subjects in fasting and postprandial states [141,142].…”

Section: Lipid-regulating Therapymentioning

confidence: 99%

Endothelial Dysfunction in Diabetes: Pathogenesis, Significance, and Treatment

2013

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■ AbstractType 2 diabetes (T2D) markedly increases the risk of cardiovascular disease. Endothelial dysfunction (ED), an early indicator of diabetic vascular disease, is common in T2D and independently predicts cardiovascular risk. Although the precise pathogenic mechanisms for ED in T2D remain unclear, at inception they probably involve uncoupling of both endothelial nitric oxide synthase activity and mitochondrial oxidative phosphorylation, as well as the activation of vascular nicotinamide adenine dinucleotide phosphate oxidase. The major contributing factors include dyslipoproteinemia, oxidative stress, and inflammation. Therapeutic interventions are designed to target these pathophysiological factors that underlie ED. Therapeutic interventions, including lifestyle changes, antiglycemic agents and lipid-regulating therapies, aim to correct hyperglycemia and atherogenic dyslipidemia and to improve ED. However, high residual cardiovascular risk is seen in both research and clinical practice settings. Well-designed studies of endothelial function in appropriately selected volunteers afford a good opportunity to test new therapeutic interventions, paving the way for clinical trials and utilization in the care of the diabetic patient. However, based on the results from a recent clinical trial, niacin should not be added to a statin in individuals with low high-density lipoprotein cholesterol and very well controlled low-density lipoprotein cholesterol.

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“…69 In humans, the PPAR␣ ligand fenofibrate only lowers blood pressure during sleep. 70 Moreover, dexamethasone, a glucocorticoid receptor ligand, potently induces a phase shift in fibroblasts in vitro and in peripheral mouse tissues in vivo. 71 Glucocorticoids inhibit the phase adjustment of the peripheral clock in response to restricted feeding in the light phase.…”

Section: Modulation Of the Circadian Control Of Metabolismmentioning

confidence: 99%

Nuclear Receptors Linking Circadian Rhythms and Cardiometabolic Control

Duez

Staels

2010

ATVB

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Abstract-Many behavioral and physiological processes, including locomotor activity, blood pressure, body temperature, sleep (fasting)/wake (feeding) cycles, and metabolic regulation display diurnal rhythms. Circadian Rhythms in PhysiologyCircadian rhythms are variations that occur with a period of approximately 1 day ("circa diem") and allow the organism to anticipate and optimize its metabolic, hormonal, and locomotor activity to predictable environmental daily changes. 1 In mammals, a central clock resides in the suprachiasmatic nuclei of the hypothalamus and synchronizes physiology to day/night cycles. In metabolic organs, output signals from the suprachiasmatic nuclei clock, conveyed by peripheral oscillators, are combined to additional circadian cues, such as food availability, information concerning local fuel availability, and the hormonal milieu to drive circadian rhythms in intermediary metabolites (eg, AMP/ATP or oxidized nicotinamide-adenosine dinucleotide (NAD ϩ )/reduced nicotinamide adenine dinucleotide ratios) and enzymes involved in local physiology. Consequently, many metabolic functions, including lipid and carbohydrate metabolism, and hormone secretion follow circadian variations. 2 The circadian clock also synchronizes the cardiovascular system. The heart and vasculature have an autonomous circadian pacemaker to anticipate physiological demand in heart fuel use and contractile function. 3 For instance, blood pressure displays marked circadian variations, increasing in the morning and decreasing at night. Heart beat and blood flow, vascular tone, fibrinolytic activity, and endothelial function are all naturally subjected to diurnal variations. 4 Interestingly, the incidence of acute myocardial infarction, sudden cardiac death, and ischemic stroke is highest early in the morning. Adverse Cardiometabolic Consequences of Altered Circadian Rhythms: Clinical EvidenceThe metabolic syndrome comprises a constellation of abnormalities, including dyslipidemia, high fasting blood glucose level, and hypertension. 5 It is precipitated by central obesity and increases the risk for type 2 diabetes mellitus and cardiovascular complications. In addition to genetic risk factors, numerous environmental factors (eg, increased food intake and physical inactivity) contribute to the etiology of the metabolic syndrome. Chronic circadian derangement, experienced by shift workers, also increases the risk of developing features of the metabolic syndrome (Figure 1). 6,7 Interestingly, in humans subjected to a progressive forced desynchrony, circadian misalignment increased blood glucose despite increased insulin, suggestive of decreased insulin sensitivity and increased blood pressure, with a maximal disturbance during maximal misalignment (ie, 180°phase shift). 8 A decrease in sleep duration and poor-quality sleep, although not circadian disorders per se, are often seen in nightshift workers, travelers, and patients with obstructive sleep apnea. Sleep curtailment results in reduced glucose tolerance and

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Hemodynamic Effects of Fenofibrate and Coenzyme Q10 in Type 2 Diabetic Subjects With Left Ventricular Diastolic Dysfunction

Cited by 64 publications

References 25 publications

Fenofibrate Inhibits Endothelin-1 Expression by Peroxisome Proliferator–Activated Receptor α–Dependent and Independent Mechanisms in Human Endothelial Cells

Fenofibrate Inhibits Endothelin-1 Expression by Peroxisome Proliferator–Activated Receptor α–Dependent and Independent Mechanisms in Human Endothelial Cells

Endothelial Dysfunction in Diabetes: Pathogenesis, Significance, and Treatment

Nuclear Receptors Linking Circadian Rhythms and Cardiometabolic Control

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