Natriuretic Peptides and Metabolic Risk in Obesity

Preliminary data run on rat samples showed that this study question and design would not produce conclusive results. The PI decided not to carry out the study.

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.

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.

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).

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).

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).

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.

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.

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.

Change during 1-hour of low-dose BNP infusion, 1-hour of high-dose BNP infusion, and 1-hour of normal saline infusion

Change during 1-hour of low-dose BNP infusion, 1-hour of high-dose BNP infusion, and 1-hour of normal saline infusion

Change during 1-hour of low-dose BNP infusion, 1-hour of high-dose BNP infusion, and 1-hour of normal saline infusion

Change during 1-hour of low-dose BNP infusion, 1-hour of high-dose BNP infusion, and 1-hour of normal saline infusion

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