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

Phase 1

Terminated

Brief Summary: 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?

Detailed Description: 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.

Recruitment & Eligibility

Inclusion Criteria

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

Arm && Interventions

Group	Intervention	Description
Acute Salsalate	Acute Salsalate	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.
Chronic Salsalate - Lean	Chronic salsalate	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.
Chronic Salsalate - Obese	Chronic salsalate	Obese subjects will be studied in this arm. Subjects will be studied at baseline and after 2 months' treatment with oral salsalate.

Primary Outcome Measures

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

Secondary Outcome Measures