Type 2 Diabetes, Hypertension
Conditions
Keywords
diabetes,, hypertension,, free-fatty acids
Brief 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.
Detailed description
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.
Interventions
DRUGRosiglitazone
Diabetic subjects will be receive rosiglitazone for 6 weeks
DRUGNormal saline 0.9%
Normal saline 0.9% intravenous infusion at 40ml/hr for 48 hours
DRUGIntralipid 20%
Intralipid 20% at 40ml/hr intravenously for 48 hours
Sponsors
GlaxoSmithKline
Emory University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Changes in Systolic Blood Pressure During Initial Intralipid Infusion | Baseline, 48 hours | Systolic blood pressure change from baseline during an 48-hour intralipid infusion |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Changes in Systolic Blood Pressure During Saline Infusions | 48 hours | Systolic blood pressure change from baseline during an 48-hour normal saline infusion in obese diabetic subjects |
| Changes in Systolic Blood Pressure During Intralipid Infusion Post-rosiglitazone Intervention | 48 hours | Systolic blood pressure change from baseline during an 48-hour intralipid infusion after taking rosiglitazone for 6 weeks in obese diabetic subjects |
Countries
United States
Participant flow
Pre-assignment details
Four subjects were withdrawn due to exclusion criteria prior to randomization. Non-diabetic arm did not continue after the first intralipid infusion (period 1).
Participants by arm
| Arm | Count |
|---|---|
| Diabetics Obese, normotensive African-Americans with diabetes received Intralipid 20% at 40ml/hr intravenously for 48 hours, normal saline 0.9% at 40 ml/hr intravenously for 48 hours, and rosiglitazone for 6 weeks followed by Intralipid 20% at 40ml/hr intravenously for 48 hours | 19 |
| Non-Diabetic Obese, normotensive African-Americans without diabetes received Intralipid 20% at 40ml/hr intravenously for 48 hours and normal saline 0.9% at 40 ml/hr intravenously for 48 hours | 13 |
| Total | 32 |
Baseline characteristics
| Characteristic | Diabetics | Non-Diabetic | Total |
|---|---|---|---|
| Age, Continuous | 41 years STANDARD_DEVIATION 2 | 42 years STANDARD_DEVIATION 1 | 41.5 years STANDARD_DEVIATION 0.7 |
| Sex: Female, Male Female | 7 Participants | 9 Participants | 16 Participants |
| Sex: Female, Male Male | 12 Participants | 4 Participants | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 2 / 19 | 1 / 13 |
| serious Total, serious adverse events | 0 / 19 | 0 / 13 |
Outcome results
Primary
Changes in Systolic Blood Pressure During Initial Intralipid Infusion
Systolic blood pressure change from baseline during an 48-hour intralipid infusion
Time frame: Baseline, 48 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Diabetics | Changes in Systolic Blood Pressure During Initial Intralipid Infusion | 23 mmHg | Standard Error 9 |
| Non-Diabetic | Changes in Systolic Blood Pressure During Initial Intralipid Infusion | 13 mmHg | Standard Error 12 |
Secondary
Changes in Systolic Blood Pressure During Intralipid Infusion Post-rosiglitazone Intervention
Systolic blood pressure change from baseline during an 48-hour intralipid infusion after taking rosiglitazone for 6 weeks in obese diabetic subjects
Time frame: 48 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Diabetics | Changes in Systolic Blood Pressure During Intralipid Infusion Post-rosiglitazone Intervention | 1 mmHg | Standard Error 6 |
Secondary
Changes in Systolic Blood Pressure During Saline Infusions
Systolic blood pressure change from baseline during an 48-hour normal saline infusion in obese diabetic subjects
Time frame: 48 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Diabetics | Changes in Systolic Blood Pressure During Saline Infusions | 0 mmHg | Standard Error 4 |