Hyperinsulinemia, Obesity
Conditions
Keywords
natriuretic peptide, insulin, lipolysis, hormones, metabolism
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.
Interventions
DRUGNesiritide
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.
DRUGInsulin
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.
OTHERSaline
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.
Sponsors
Vanderbilt University Medical Center
Study design
Allocation
NON_RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| 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 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 |
Other
| 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) |
Outcome results
None listed