The Impact of Reducing Inflammation on Vascular Function in the Metabolic Syndrome
The purpose of the study is to test whether salsalate,an aspirin-like drug, can improve blood vessel function by reducing inflammation caused by insulin resistance, making the development of blockages less common.
We also want to see if salsalate will
- Change the way blood vessels expand and/or
- Improve the ability of cells to use blood sugar for energy.
|Study Design:||Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Basic Science
|Official Title:||The Impact of Reducing Inflammation on Vascular Function in the Metabolic Syndrome|
- The purpose of the study is to test whether salsalate can improve blood vessel function by reducing inflammation caused by insulin resistance, making the development of blockages less common. [ Time Frame: once every 8 weeks ] [ Designated as safety issue: No ]
- We also want to see if salsalate will change the way blood vessels expand and/or improve the ability of cells to use blood sugar for energy [ Time Frame: once every 8 weeks ] [ Designated as safety issue: No ]
|Study Start Date:||November 2005|
|Study Completion Date:||June 2011|
|Primary Completion Date:||June 2011 (Final data collection date for primary outcome measure)|
Active Comparator: 1
4 grams daily for 28 days
Placebo Comparator: 2
To test the hypothesis that reductions in intracellular inflammation will restore insulin-mediated and endothelium-dependent vasodilation in subjects with the metabolic syndrome.
Recent demographic trends indicate a dramatic growth in the incidence of obesity and insulin resistance in the United States, highlighting a population at increased risk for the complications of atherosclerosis. The metabolic syndrome, identified as through a collection of risk factors, is associated with increases in adiposity and insulin resistance. Insulin resistance, typically characterized by impaired skeletal muscle glucose uptake, affects tissues other than skeletal muscle, including liver, adipose, and blood vessels. In experimental animal models and humans with insulin resistance, disturbances in insulin signaling consistently lead to decreased bioavailability of endothelium-derived nitric oxide and impaired endothelium-dependent vasodilation. The impact of abnormal insulin signaling on vascular endothelium has not been well characterized in humans in vivo.
Basic studies suggest that insulin receptor medicated activation of the PI 3-kinase pathway is important for normal endothelial nitric oxide synthase function. Abnormalities demonstrated in the metabolic syndrome alter signaling at multiple sites within this pathway, particularly phosphorylation of the serine residue of the insulin receptor substrate. Excess free fatty acid liberation by adipose tissue impairs insulin signaling and activates protein kinase C beta and Inhibitor kappa B kinase beta. Each of these pathobiological disturbances, including excess FFA, heightened PKC-beta activation, and increased inflammatory transcription factor activation serine phosphorylate IRS, cause endothelial dysfunction in humans, and are potential therapeutic targets. Data defining the pathophysiology of endothelial insulin resistance and the importance of these candidate mechanisms in patients is lacking.
The applicants will determine whether inhibition of IKKbeta by salsalate improves endothelium-dependent vasodilation as a consequence of restored endothelial insulin signaling and serine 1177 phosphorylation of eNOS in patients with metabolic syndrome.
|United States, Massachusetts|
|Brigham and Women's Hospital|
|Boston, Massachusetts, United States, 02115|
|Principal Investigator:||Joshua A Beckman, MD||Brigham and Women's Hospital|