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

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

Aims:

1. Does inflammation contribute importantly to concurrent defects in vascular and metabolic dysfunction in human pre-diabetic obesity?
2. Are there benefits of anti-inflammatory treatment strategies in pre-diabetic obesity in the context of existing treatment with metformin?
3. Are there benefits of anti-inflammatory treatment strategies in pre-diabetic obesity in the context of existing treatment with lisinopril?

We set out to pursue the following Aims:

1. 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.
2. Are there benefits of anti-inflammatory treatment strategies in pre-diabetic obesity in the context of existing treatment with metformin? No studies were performed
3. 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.

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