Natriuretic Peptides and Metabolic Risk in Obesity

Sponsor

Vanderbilt University Medical Center (Other)

Overall Status

Withdrawn

CT.gov ID

NCT02642523

Collaborator

(none)

Enrollment

Arms

Study Details

Study Description

Brief Summary

The investigators are examining:

the relationships of insulin levels and natriuretic peptide hormone levels, and
the effects of administering an infusion of natriuretic peptide hormone on the breakdown of fat

in healthy lean and otherwise healthy obese individuals.

Condition or Disease	Intervention/Treatment	Phase
Obesity Hyperinsulinemia	Drug: Nesiritide Drug: Insulin Other: Saline	Early Phase 1

Detailed Description

The cardiac natriuretic peptide hormonal system may protect against the development of cardiometabolic risk. Epidemiologic studies have shown that in relatively healthy individuals without heart failure, low natriuretic peptide levels are associated with unfavorable cardiometabolic phenotypes, including higher blood pressure, obesity, higher insulin levels, and diabetes mellitus. Understanding the mechanisms behind the "natriuretic peptide deficiency" of obesity would illuminate an important way in which obesity interacts with the cardiovascular system.

The investigators propose a prospective cross-over design in 40 healthy lean and otherwise healthy obese individuals. The investigators propose the following specific aims and hypotheses:

Aim 1: To study the effect of hyperinsulinemia on the response of the natriuretic peptide system to salt loading.

Hypothesis 1: Hyperinsulinemia will suppress natriuretic peptide levels in both obese and lean individuals.

Aim 2: To examine the effect of an intravenous infusion of natriuretic peptide on acute markers of lipolysis.

Hypothesis 2: An intravenous infusion of natriuretic peptide will raise acute markers of lipolysis in both obese and lean individuals.

Study Design

Study Type:

Interventional

Actual Enrollment :

0 participants

Allocation:

Non-Randomized

Intervention Model:

Crossover Assignment

Masking:

None (Open Label)

Primary Purpose:

Other

Official Title:

Natriuretic Peptides and Metabolic Risk in Obesity

Actual Primary Completion Date :

Feb 1, 2017

Actual Study Completion Date :

Feb 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Saline Infusion All subjects will undergo 3 interventions, performed at 3 separate outpatient study visits. The order of the 3 interventions will be randomly assigned. The interventions are: Saline Infusion, Insulin Clamp, and BNP Infusion (Nesiritide).	Other: Saline Subjects will receive an intravenous infusion of normal (0.9%) saline over 2 hours at a rate of 0.25 ml/kg/min. Subjects will receive a standardized high-salt diet for at least 6 days prior to this study visit. Other Names: Normal Saline
Experimental: Insulin Clamp All subjects will undergo 3 interventions, performed at 3 separate outpatient study visits. The order of the 3 interventions will be randomly assigned. The interventions are: Saline Infusion, Insulin Clamp, and BNP Infusion (Nesiritide).	Drug: Insulin The hyperinsulinemic-euglycemic insulin clamp, which will last between 2-2.5 hours, involves continuous intravenous infusions of human regular insulin and of dextrose solution. Simultaneously, subjects receive an intravenous infusion of normal (0.9%) saline over 2 hours. Subjects will receive a standardized high-salt diet for at least 6 days prior to this study visit. Other Names: Human Insulin
Experimental: BNP Infusion (Nesiritide) All subjects will undergo 3 interventions, performed at 3 separate outpatient study visits. The order of the 3 interventions will be randomly assigned. The interventions are: Saline Infusion, Insulin Clamp, and BNP Infusion (Nesiritide).	Drug: Nesiritide Subjects will receive an intravenous infusion of recombinant human b-type natriuretic peptide (BNP) (Nesiritide) over 2 hours at 2 doses: 0.003 ug/kg/min for 1 hour, followed by 0.01 ug/kg/min for 1 hour. Nesiritide (Johnson and Johnson) is FDA-approved for the treatment of heart failure. Study investigators received approval from the FDA for an IND exemption for nesiritide in this study. While receiving the BNP infusion, subjects will also receive an intravenous infusion of normal (0.9%) saline over 2 hours. Subjects will receive a standardized high-salt diet for at least 6 days prior to this study visit. Other Names: Recombinant human BNP

Arm

Intervention/Treatment

Placebo Comparator: Saline Infusion

All subjects will undergo 3 interventions, performed at 3 separate outpatient study visits. The order of the 3 interventions will be randomly assigned. The interventions are: Saline Infusion, Insulin Clamp, and BNP Infusion (Nesiritide).

Other: Saline

Subjects will receive an intravenous infusion of normal (0.9%) saline over 2 hours at a rate of 0.25 ml/kg/min. Subjects will receive a standardized high-salt diet for at least 6 days prior to this study visit.

Other Names:

Normal Saline

Experimental: Insulin Clamp

Drug: Insulin

The hyperinsulinemic-euglycemic insulin clamp, which will last between 2-2.5 hours, involves continuous intravenous infusions of human regular insulin and of dextrose solution. Simultaneously, subjects receive an intravenous infusion of normal (0.9%) saline over 2 hours. Subjects will receive a standardized high-salt diet for at least 6 days prior to this study visit.

Other Names:

Human Insulin

Experimental: BNP Infusion (Nesiritide)

Drug: Nesiritide

Subjects will receive an intravenous infusion of recombinant human b-type natriuretic peptide (BNP) (Nesiritide) over 2 hours at 2 doses: 0.003 ug/kg/min for 1 hour, followed by 0.01 ug/kg/min for 1 hour. Nesiritide (Johnson and Johnson) is FDA-approved for the treatment of heart failure. Study investigators received approval from the FDA for an IND exemption for nesiritide in this study. While receiving the BNP infusion, subjects will also receive an intravenous infusion of normal (0.9%) saline over 2 hours. Subjects will receive a standardized high-salt diet for at least 6 days prior to this study visit.

Other Names:

Recombinant human BNP

Outcome Measures

Primary Outcome Measures

Change in natriuretic peptide levels [4 hours (during 2-hour study infusions and for 2 hours after study infusions)]
Change in glycerol levels [1 hour]
Change during 1-hour of low-dose BNP infusion, 1-hour of high-dose BNP infusion, and 1-hour of normal saline infusion

Secondary Outcome Measures

Change in free fatty acid levels [1 hour]
Change during 1-hour of low-dose BNP infusion, 1-hour of high-dose BNP infusion, and 1-hour of normal saline infusion
Change in triglyceride levels [1 hour]
Change during 1-hour of low-dose BNP infusion, 1-hour of high-dose BNP infusion, and 1-hour of normal saline infusion
Change in energy expenditure assessed by indirect calorimetry [1 hour]
Change during 1-hour of low-dose BNP infusion, 1-hour of high-dose BNP infusion, and 1-hour of normal saline infusion

Other Outcome Measures

Change in plasma renin activity [4 hours (during 2-hour study infusions and for 2 hours after study infusions)]
Change in aldosterone [4 hours (during 2-hour study infusions and for 2 hours after study infusions)]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 50 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

Men and women ages 18-50 years
BMI 18 to <25 kg/m2 (lean group, N=20) or BMI 30 to <40 kg/m2 (obese group, N=20)

Exclusion Criteria:

Current use of antihypertensive medications
Current use of glucocorticoids, metformin, or any antidiabetes medications
Prior or current cardiovascular disease, renal disease, or liver disease
Diabetes mellitus (taking insulin, other anti-diabetic agents, or diet-controlled)
Atrial fibrillation
Bleeding disorder or anemia
Elevated LFTs
estimuated GFR < 60 ml/min
Abnormal sodium or potassium level
Positive pregnancy test, women of child-bearing age not practicing birth control, women who are breastfeeding