Natriuretic Peptides and Metabolic Risk in Obesity

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.

Study Overview

• Status: Withdrawn
• Conditions: Obesity; Hyperinsulinemia
• Intervention / Treatment: Other: Saline; Drug: Insulin; Drug: Nesiritide

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 Type: Interventional
• Phase: Early Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Non-Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in free fatty acid levels	Change during 1-hour of low-dose BNP infusion, 1-hour of high-dose BNP infusion, and 1-hour of normal saline infusion	1 hour
Change in triglyceride levels	Change during 1-hour of low-dose BNP infusion, 1-hour of high-dose BNP infusion, and 1-hour of normal saline infusion	1 hour
Change in energy expenditure assessed by indirect calorimetry	Change during 1-hour of low-dose BNP infusion, 1-hour of high-dose BNP infusion, and 1-hour of normal saline infusion	1 hour

Other Outcome Measures

Outcome Measure	Time Frame
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)

Collaborators and Investigators

• Sponsor: Vanderbilt University Medical Center
• Investigators: Study Director: Katherine N Bachmann, MD, Vanderbilt Diabetes/Endocrinology; Principal Investigator: Thomas J Wang, MD, Vanderbilt Cardiovascular Medicine

Study record dates

Study Major Dates

• Primary Completion (Actual): February 1, 2017
• Study Completion (Actual): February 1, 2017

Study Registration Dates

• First Submitted: November 24, 2015
• First Submitted That Met QC Criteria: December 24, 2015
• First Posted (Estimate): December 30, 2015

Study Record Updates

• Last Update Posted (Actual): November 6, 2017
• Last Update Submitted That Met QC Criteria: October 31, 2017
• Last Verified: October 1, 2017

More Information

Terms related to this study

• Keywords: insulin; metabolism; hormones; lipolysis; natriuretic peptide
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Overnutrition; Nutrition Disorders; Overweight; Body Weight; Obesity; Hyperinsulinism; Hypoglycemic Agents; Physiological Effects of Drugs; Natriuretic Agents; Insulin; Insulin, Globin Zinc; Natriuretic Peptide, Brain
• Other Study ID Numbers: 151768