Vascular Function, Endothelin, and Inflammation in Pre-diabetic Obesity Versus Lean Healthy Controls

Study Overview
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Brief Summary
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Aims: Does inflammation contribute importantly to concurrent defects in vascular and metabolic dysfunction in human pre-diabetic obesity? Are there benefits of anti-inflammatory treatment strategies in pre-diabetic obesity in the context of existing treatment with metformin? Are there benefits of anti-inflammatory treatment strategies in pre-diabetic obesity in the context of existing treatment with lisinopril?

Detailed Description
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We set out to pursue the following Aims: Does inflammation contribute importantly to concurrent defects in vascular and metabolic dysfunction in human pre-diabetic obesity? Pilot studies were performed exploring the acute actions of salsalate on vascular function, the chronic actions of salasate in obese individuals, and actions of chronic salsalate to prevent vascular dysfunction induced by fatty acids in lean individuals. Are there benefits of anti-inflammatory treatment strategies in pre-diabetic obesity in the context of existing treatment with metformin? No studies were performed Are there benefits of anti-inflammatory treatment strategies in pre-diabetic obesity in the context of existing treatment with lisinopril? No studies were performed The intent of the current project is to efficiently and at low cost generate preliminary data along each of these lines of questioning, studying the minimum number of subjects required to assess the viability of the question using the current measurement approaches.

Official Title
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Vascular Function, Endothelin, and Inflammation in Pre-diabetic Obesity Versus Lean Healthy Controls

Conditions
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Pre-diabetes, Obesity

Intervention / Treatment
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* Drug: Chronic salsalate
* Drug: Acute Salsalate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: healthy normotensive (BP<140/95 mmHg) lean and obese 18 and 55 years women must be premenopausal Exclusion Criteria: use of pharmacologic agents or recreational drugs, with the exception of occasional use of non-narcotic pain medications blood pressure (>140/90 mmHg) elevated cholesterol (LDL >130 mg/dL) diabetes mellitus (by ADA criteria) evidence of coronary and/or peripheral vascular disease by history and physical exam >5 kg change in weight in the preceding 3 months chronic systemic illness with recognized metabolic effects hepatitis C and HIV recognized systemic inflammatory or autoimmune processes such as rheumatoid arthritis or systemic lupus erythematosis Raynaud's phenomenon or other abnormalities of hand or finger perfusion regular participation in endurance or high-performance athletic activity history of aspirin or salsalate sensitivity including aspirin-induced asthma prior treatment with salsalate, pentoxyfilline, or monoclonal anti-TNFalpha antibodies pregnancy liver transaminase levels >3 times the upper limit of normal creatinine >1.5 mg/dL history of a cellular immunodeficiency-related opportunistic infections, such as an endemic mycosis (eg. histoplasmosis) or mycobacterial infection (eg tuberculosis) reactive tuberculin skin test history of malignancy except for basal cell carcinoma of the skin

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Acute Salsalate<br>Nondiabetic lean and obese subjects will be studied in this arm. Subjects will be studied at baseline and after a single dose of oral salsalate. | Drug: Acute Salsalate<br>* Subjects will receive a single oral dose of 2 gram of oral salsalate<br>|
| Experimental: Chronic Salsalate - Obese<br>Obese subjects will be studied in this arm. Subjects will be studied at baseline and after 2 months' treatment with oral salsalate. | Drug: Chronic salsalate<br>* Subjects will receive 2 months of treatment with 4 gram/day of oral salsalate divided into 3 doses.<br>|
| Experimental: Chronic Salsalate - Lean<br>Lean subjects will be studied in this arm. Subjects will be studied at baseline and after 2 months' treatment with oral salsalate. The effects of an acute fatty acid infusion on vascular function will be measured on both occasions. | Drug: Chronic salsalate<br>* Subjects will receive 2 months of treatment with 4 gram/day of oral salsalate divided into 3 doses.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Vascular Function | The primary endpoints of interest is flow-mediated vasodilation | Measured at baseline and after a single oral dose of salsalate (Acute) or 2 months' treatment with salsalate (Chronic) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Vascular function, Glucose tolerance, Obesity, Pre-diabetes