Obesity-Associated Insulin Resistance
Conditions
Brief summary
The purpose of this study is to study the role of sympathetic mechanisms involved in chronic regulation of cardiovascular and metabolic abnormalities seen in obesity. The investigators will study the effects chronic sympathetic inhibition on insulin sensitivity, inflammation and endothelial function in obese hypertensive human subjects.
Detailed description
Continuing Review (CR, 2021/08/04) Update: Removal of the angiotensin receptor blockade arm of the study The presence of obesity increases the risk for hypertension and diabetes, in part due to the development of insulin resistance. Obesity is also associated with sympathetic activation and the overarching hypothesis is that sympathetic activation contributes to insulin resistance with impairment of its vascular and metabolic actions. Preliminary studies suggest that 1) Blood pressure can be normalized by autonomic blockade in obese hypertensives, 2) Sympathetic activation provides no metabolic benefit because the increase in resting energy expenditure associated with obesity is due to an increase in fat free mass rather than sympathetic activation. On the contrary, autonomic blockade: 3) Improves insulin sensitivity in obese hypertensives, 4) Reverses their impaired NO-mediated dilation, and 5) Reduces plasma isoprostanes, a measure of oxidative stress. Furthermore, these abnormalities are interrelated in negative feedback loops, whereby inflammation/oxidative stress impairs nitric oxide mechanisms, which in turn reduces insulin-mediated vasodilation important for substrate delivery, thus contributing to insulin resistance; insulin resistance leads to compensatory increases in insulin levels, which contributes to further sympathetic activation. Current treatment guidelines do not specifically address the treatment of obesity hypertension, and do not target sympathetic activation as a first line approach. It is important, therefore, to determine whether or not targeting sympathetic activation offers unique advantages in the treatment of obesity hypertension over current approaches. The investigators propose a proof-of-concept mechanistic study comparing the metabolic, vascular, and anti-inflammatory effects of sympathetic inhibition, calcium channel blockade and angiotensin receptor blockade in obesity hypertension. The investigators will test the hypotheses that sympathetic activation contributes to 1) metabolic insulin resistance, which impairs the suppression of endogenous glucose production and the stimulation of glucose uptake normally provided by insulin, 2) vascular insulin resistance, which impairs insulin-mediated vasodilation and microvascular recruitment that normally promote glucose uptake, and 3) inflammation and oxidative stress, which contribute to insulin resistance and hypertension. The proposed studies will gauge the contribution of sympathetic activation to the cardiovascular and metabolic complications of obesity and provide the mechanistic insight to determine whether or not it should foster the efforts currently under way to develop novel therapies targeting sympathetic activation for hypertension.
Interventions
Moxonidine 0.2 MG twice daily
DRUGAmlodipine 5 MG
Amlodipine 5 MG twice daily
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Italo Biaggioni
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Males and females of all races between 18 and 60 years of age * Hypertension defined by two or more properly measured seated blood pressure readings \>130/85 mmHg or currently on antihypertensive medication. * Obesity will be defined as having a body mass index (BMI) ≥ 30 kg/m2. * Able and willing to provide informed consent.
Exclusion criteria
* Pregnancy or breast feeding * Current smokers or history of heavy smoking (\>2 packs/day) * History of alcohol or drug abuse * Previous allergic reaction to study medications * Evidence of type I diabetes * Cardiovascular disease other than hypertension * History of serious cerebrovascular disease * History or presence of immunological or hematological disorders * Impaired renal function * Treatment with any investigational drug in the 1 month preceding the study * Inability to give, or withdraw, informed consent * Other factors which in the investigator's opinion would prevent the subject from completing the protocol
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Insulin Sensitivity | 6 hours | Dose response curve to insulin (measure as glucose infusion rate, mg/kg/min) |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Moxonidine Moxonidine to be administered at a dose to produce a decrease in BP of at least 20% of baseline for 9 weeks
Moxonidine 0.2 MG: Moxonidine 0.2 MG twice daily | 5 |
| Amlodipine Amlodipine to be administered at a dose to produce a decrease in BP of at least 20% of baseline for 9 weeks
Amlodipine 5 MG: Amlodipine 5 MG twice daily | 5 |
| Total | 10 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Physician Decision | 3 | 4 |
Baseline characteristics
| Characteristic | Moxonidine | Amlodipine | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 5 Participants | 5 Participants | 10 Participants |
| Age, Continuous | 43 years STANDARD_DEVIATION 5 | 41 years STANDARD_DEVIATION 6 | 42 years STANDARD_DEVIATION 6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants | 5 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment United States | 5 participants | 5 participants | 10 participants |
| Sex: Female, Male Female | 4 Participants | 3 Participants | 7 Participants |
| Sex: Female, Male Male | 1 Participants | 2 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 5 | 0 / 5 |
| other Total, other adverse events | 0 / 5 | 0 / 5 |
| serious Total, serious adverse events | 0 / 5 | 0 / 5 |
Outcome results
Primary
Insulin Sensitivity
Dose response curve to insulin (measure as glucose infusion rate, mg/kg/min)
Time frame: 6 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Moxonidine | Insulin Sensitivity | 4.3 mg/kg/min | Standard Deviation 3.1 |
| Amlodipine | Insulin Sensitivity | 3.6 mg/kg/min | Standard Deviation 3.3 |