Overview
The overall purpose of this study is to learn more about the metabolic effects of angiotensin-(1-7) in the insulin resistant state associated with obesity. Pharmacologic approaches to increase angiotensin-(1-7) levels or its actions are currently in development for treatment of metabolic-related diseases such as obesity and type II diabetes, based on findings from animal studies. It is unclear if this peptide contributes to the regulation of metabolism in humans. The investigators will test if angiotensin-(1-7) infusion can improve insulin sensitivity measured by hyperinsulinemic-euglycemic clamp methods in individuals with obesity and insulin resistance. The investigators will also examine for changes in blood pressure and related hemodynamic and hormonal changes following angiotensin-(1-7) infusion.
Description
This is an outpatient study that requires a screening visit and two study days in the Vanderbilt Clinical Research Center. Subjects will be asked to stop taking any medications for high blood pressure for at least 2 weeks prior to the study. Subjects will receive intravenous angiotensin-(1-7) or saline infusion on two separate study days, with each study day lasting approximately four hours. There will be at least one week of washout between study days. On each study day, subjects will be instrumented with two intravenous catheters (one for blood sampling and one for drug infusion), arm and finger blood pressure cuffs, and sticky patches to measure heart rate throughout the study. The investigators will take baseline measurements of blood pressure and heart rate and collect blood samples. The investigators will also perform a rebreathing test to measure the heart's pumping capacity. After baseline measurements, the investigators will infuse angiotensin-(1-7) or saline for 30 minutes, with blood pressure and heart rate measured every 10 minutes. At the end of 30 minutes, blood samples will be collected and the rebreathing test will be repeated. The investigators will continue the angiotensin-(1-7) or saline infusion for an additional 2 hours while performing a hyperinsulinemic-euglycemic clamp to measure insulin sensitivity.
Eligibility
Inclusion Criteria:
- Males and females of all races between 18 and 60 years of age
- Obesity defined as body mass index between 30-40 kg/m2
- Insulin resistance defined as homeostasis model assessment 2 insulin resistance (HOMA2-IR) score >2.2
- Hypertension defined by two or more properly measured seated blood pressure readings >130/85 mmHg, or by use of anti-hypertensive medications. This blood pressure cutoff will allow us to include subjects with pre-hypertension.
- Able and willing to provide informed consent
Exclusion Criteria:
- Pregnancy or breast-feeding
- Current smokers or history of heavy smoking (>2 packs/day)
- History of alcohol or drug abuse
- Morbid obesity (BMI > 40 kg/m2)
- Previous allergic reaction to study medications
- Evidence of type I or type II diabetes (i.e. fasting glucose >126 mg/dl, use of anti-diabetic medications)
- Cardiovascular disease other than hypertension such as myocardial infarction within 6 months prior to enrollment, presence of angina pectoris, significant arrhythmia, congestive heart failure (LV hypertrophy acceptable), deep vein thrombosis, pulmonary embolism, second or third degree heart block, mitral valve stenosis, aortic stenosis, or hypertrophic cardiomyopathy
- History of serious cerebrovascular disease such as cerebral hemorrhage, stroke, or transient ischemic attack
- History or presence of immunological or hematological disorders
- Impaired hepatic function [aspartate amino transaminase (AST) and/or alanine amino transaminase (ALT) > 2.0 x upper limit of normal range]
- Impaired renal function (serum creatinine >1.5 mg/dl)
- Anemia (hemoglobin <13.5 g/dl in males or <12.5 g/dl in females)
- Treatment with serotonin-norepinephrine reuptake inhibitors (SNRIs) or norepinephrine transporter (NET) inhibitors
- Treatment with phosphodiesterase 5 inhibitors
- Treatment with anticoagulants
- Treatment with chronic systemic glucocorticoid therapy (more than 7 consecutive days in 1 month)
- Treatment with any investigational drug in the 1 month preceding the study
- Inability to give, or withdraw, informed consent
- Other factors which in the investigator's opinion would prevent the subject from completing the protocol (i.e., clinically significant abnormalities on clinical, mental examination or laboratory testing or inability to comply with protocol)