Free Fatty Acid-Induced Hypertension in Obese Subjects With Type 2 Diabetes

Insulin resistance has been implicated as the central pathogenetic feature of cardiovascular risk factor cluster that includes hypertension, impaired glucose tolerance, diabetes, dyslipidemia, and hemostatic disorders. Recent evidence suggests that increased levels of free fatty acids (FFA) in obese subjects is a leading candidate in the pathogenesis of insulin resistance (1-4). In our preliminary studies on the effect of FFA on insulin secretion and action (lipotoxicity), we have observed that the infusion of Intralipid/heparin to increase FFA \~ four-fold-baseline levels for 48 hours results in a significant and reproducible raise in systolic and diastolic blood pressure (BP) in obese African American subjects with and without diabetes. The increase in blood pressure is apparent after 12 hours of infusion, reaching a peak increment of 32 mm Hg in systolic and 14 mm Hg in diastolic pressure at 24 hours. These preliminary findings indicate that, in addition to the well-known effect on insulin resistance, sustained elevation of FFA results in the development of an acute metabolic syndrome.

The FFA-induced hypertension constitutes a useful model with which to examine disease mechanisms and test new therapeutic interventions to correct the different disorders associated with insulin resistance and metabolic syndrome. The effect of FFA on insulin action is well established (4-6); however, the pressor effect of FFA infusion in obese subjects has not been investigated. We hypothesize that observed changes in blood pressure is the result of acute endothelial dysfunction due to increased FFA concentration; and that rosiglitazone, a PPAR gamma receptor agonist, will protect against FFA-induced elevation in blood pressure and endothelial dysfunction in obese subjects.

Eligibility Criteria:
Inclusion Criteria:

* Males or females between the ages of 18 and 70 years.
* Subjects must have a BMI of ≥ 30 kg/m2.
* Subjects must have a BP \< 130/80 mm Hg and no prior history of hypertension.
* A known history of type 2 diabetes mellitus \< 3 years (now 5 years).
* Subjects must have an HbA1c of \< 9%.
* Diabetic subjects must have been receiving as their only current anti-diabetic therapy stable doses of sulfonylureas for the last 2 months.
* Subjects must be able to understand and willing to adhere to the study protocol.

Exclusion Criteria:

* Subjects with history of hypertension (BP \> 140/90 mm HG) or who have received antihypertensive drug therapy prior to the study.
* Obese nondiabetic controls with impaired glucose tolerance (2-hour glucose between 140 - 199 mg/dl) during a 75-g OGTT.
* Diabetic subjects who require insulin therapy or have received an insulin sensitizer agent (metformin, rosiglitazone, pioglitazone) within 3 months of entering the study (at SV1, week-2).
* Subjects with fasting triglyceride levels \> 250 mg/dL prior to the study (at SV1, week-2).
* Clinically relevant hepatic disease (ALT 2.5x \> upper limit of normal), or other significant medical or surgical illness.
* Renal failure, as shown by a serum creatinine ≥1.5 mg/dL for males, or ≥ 1.4 mg/dL for females.
* Mental condition rendering the subject unable to understand the nature, scope, and possible consequences of the study.
* Female subjects are pregnant or breast feeding at time of enrollment into the study.