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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.
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The investigators are examining:
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Saline Infusion | Placebo Comparator | 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). |
|
| Insulin Clamp | Experimental | 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). |
|
| BNP Infusion (Nesiritide) | Experimental | 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). |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Nesiritide | 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. |
| 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 |
| 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 |
| Measure | Description | 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) |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Katherine N Bachmann, MD | Vanderbilt Diabetes/Endocrinology | Study Director |
| Thomas J Wang, MD | Vanderbilt Cardiovascular Medicine | Principal Investigator |
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| ID | Term |
|---|---|
| D009765 | Obesity |
| D006946 | Hyperinsulinism |
| D007333 | Insulin Resistance |
| ID | Term |
|---|---|
| D050177 | Overweight |
| D044343 | Overnutrition |
| D009748 | Nutrition Disorders |
| D009750 | Nutritional and Metabolic Diseases |
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| ID | Term |
|---|---|
| D020097 | Natriuretic Peptide, Brain |
| D007328 | Insulin |
| D012965 | Sodium Chloride |
| D000077330 | Saline Solution |
| ID | Term |
|---|---|
| D045265 | Natriuretic Peptides |
| D036361 | Peptide Hormones |
| D006728 | Hormones |
| D006730 | Hormones, Hormone Substitutes, and Hormone Antagonists |
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|
|
| Insulin | 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. |
|
|
| Saline | 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. |
|
|
| 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 |
| D001835 |
| Body Weight |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D010455 | Peptides |
| D000602 | Amino Acids, Peptides, and Proteins |
| D009419 | Nerve Tissue Proteins |
| D011506 | Proteins |
| D011384 | Proinsulin |
| D061385 | Insulins |
| D010187 | Pancreatic Hormones |
| D002712 | Chlorides |
| D006851 | Hydrochloric Acid |
| D017606 | Chlorine Compounds |
| D007287 | Inorganic Chemicals |
| D017670 | Sodium Compounds |
| D000077324 | Crystalloid Solutions |
| D007552 | Isotonic Solutions |
| D012996 | Solutions |
| D004364 | Pharmaceutical Preparations |