Free Fatty Acids-Induced Hypertension, Endothelial Dysfunction, Inflammation, Insulin Resistance, and Autonomic Dysfunction in Lean and Obese Subjects

Condition(s) targeted: Diabetes; Hypertension; Obesity

Intervention: Intravenous Infusions with Intralipid 20%, normal saline and liquid fat (Drug); Intravenous Infusions with Intralipid 20%, normal saline and liquid fat (Drug)

Phase: N/A

Status: Not yet recruiting

Sponsored by: Emory University

Official(s) and/or principal investigator(s):
Guillermo Umpierrez, MD, Principal Investigator, Affiliation: Emory University

Overall contact:
Guillermo Umpierrez, MD, Phone: 404.778.1665, Email: geumpie@emory.edu

Our recent studies indicate that increased levels of a circulating fat (free fatty acids or FFAs) increases blood pressure, impairs endothelial (vascular) function, and increases inflammatory markers in subjects with and without diabetes. The effects of FFA on blood pressure and vasculature have not been fully investigated. We hypothesize that observed changes in blood pressure are the result of acute endothelial dysfunction, and/or increased activation of the autonomic nervous system. In addition, it is not known if increased FFAs by repeated oral fat load results in similar blood pressure than intravenous lipid infusion. Accordingly, we propose: 1) a systematic evaluation of the effects of increasing FFA levels on blood pressure and endothelial (vascular) function, and 2) determine the effects of comparable increases in FFA concentration via intravenous infusion of Intralipid or by repeated oral fat load on blood pressure, insulin resistance and endothelial dysfunction in obese subjects. This study has two parts.

In the first part of the study, a group of 12 obese and 12 lean nondiabetic, normotensive subjects will be admitted to the Grady Clinical Research Center (GCRC) on separate 3 occasions. Research subjects will receive, in random order, a 24-hour intravenous (IV) infusion of Intralipid 20ml/hr (a fat solution), 24-hour IV infusion of normal saline, or an oral liquid fat diet every 4 hours for 24-hours. The effect of increased FFAs on blood pressure and endothelial (vascular) function via intravenous infusion versus oral fat load therapy will be assessed. The fat load (IV vs. oral) that causes the largest effect on blood pressure and endothelial function will be used in the second portion of the protocol.

In the second part of the study, a group of 36 obese normotensive (diabetic and nondiabetic) subjects will be admitted to the GCRC on 2 separate occasions for a randomized control trial. Study subjects will first be admitted to receive a fat load and then they will be randomly placed on either salsalate, carvedilol, or placebo for 6 weeks. After the 6-week intervention period, the subjects will be re-admitted to the GCRC to see if the intervention has any effect on improving blood pressure or endothelial function.

Official title: Free Fatty Acids-Induced Hypertension, Endothelial Dysfunction, Inflammation, Insulin Resistance, and Autonomic Dysfunction in Lean and Obese Subjects

Study design: Treatment, Randomized, Single Blind (Subject), Placebo Control, Parallel Assignment, Safety/Efficacy Study

Primary outcome: To determine the effects of increasing FFA on BP, endothelial function, vascular inflammatory markers, oxidative stress, and sympathetic nervous system activity in obese normotensive subjects.

Secondary outcome: To determine in mechanistic studies whether the FFA-induced "acute MetS" can be modulated by pathways involving NF-B-mediated inflammation, or autonomic activation.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

Inclusion Criteria:

- Males or females, obese subjects (BMI ≥ 30 kg/m2), between the ages of 18 and 65

years

- Diabetic subjects must have a known history of T2DM < 3 years, an HbA1c of < 8%,

- On diet alone or receiving as their only anti-diabetic therapy stable doses of

sulfonylureas for 2 months.

- A BP < 140/80 mm Hg and no prior history of hypertension.

Exclusion Criteria:

- History of hypertension, fasting triglyceride levels > 250 mg/dL, liver disease (ALT

2. 5x > upper limit of normal),

- Serum creatinine ≥1. 5 mg/dL,

- Smokers,

- Drug or alcohol abuse,

- Mental condition rendering the subject unable to understand the scope and possible

consequences of the study,

- Female subjects who are pregnant or breast feeding.

Guillermo Umpierrez, MD, Phone: 404.778.1665, Email: geumpie@emory.edu

Grady Memorial Hospital, Atlanta, Georgia 30303, United States

Starting date: October 2008
Ending date: June 2011
Last updated: October 7, 2008