Natriuretic Peptides and Metabolic Risk in Obesity

NCT ID: NCT02642523

Last Updated: 2017-11-06

Basic Information

• Recruitment Status: WITHDRAWN
• Clinical Phase: EARLY_PHASE1
• Study Classification: INTERVENTIONAL
• Study Completion Date: 2017-02-28

Brief Summary

The investigators are examining:

1. the relationships of insulin levels and natriuretic peptide hormone levels, and

2. the effects of administering an infusion of natriuretic peptide hormone on the breakdown of fat

in healthy lean and otherwise healthy obese individuals.

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.

Conditions

Obesity; Hyperinsulinemia

Keywords

natriuretic peptide; insulin; lipolysis; hormones; metabolism

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: OTHER
• Blinding Strategy: NONE

Study Groups

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).

Group Type: PLACEBO_COMPARATOR

Saline

Intervention Type: OTHER

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.

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).

Group Type: EXPERIMENTAL

Insulin

Intervention Type: DRUG

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.

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).

Group Type: EXPERIMENTAL

Nesiritide

Intervention Type: DRUG

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.

Interventions

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.

Intervention Type: 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.

Intervention Type: DRUG

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.

Intervention Type: OTHER

Other Intervention Names

Recombinant human BNP; Human Insulin; Normal Saline

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 50 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Vanderbilt University Medical Center

OTHER

Sponsor Role: lead

Responsible Party

Thomas Wang

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Katherine N Bachmann, MD

Role: STUDY_DIRECTOR

Vanderbilt Diabetes/Endocrinology

Thomas J Wang, MD

Role: PRINCIPAL_INVESTIGATOR

Vanderbilt Cardiovascular Medicine

Other Identifiers

151768

Identifier Type: -

Identifier Source: org_study_id