Free Fatty Acid-Induced Hypertension in Obese Subjects With Type 2 Diabetes
Condition: Type 2 Diabetes; Hypertension
MeSH terms: Hypertension; Diabetes Mellitus; Diabetes Mellitus, Type 2
Intervention: Rosiglitazone; Normal saline 0.9%; Intralipid 20%
Intervention description: Diabetic subjects will be receive rosiglitazone for 6 weeks; Normal saline 0.9% intravenous infusion at 40ml/hr for 48 hours; Intralipid 20% at 40ml/hr intravenously for 48 hours
Intervention MeSH terms: Rosiglitazone; Soybean oil, phospholipid emulsion
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 36.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: diabetes,; hypertension,; free-fatty acids

Summary:

      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.
    

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.