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Metabolic Effects of Angiotensin-(1-7)

Primary Purpose

Obesity, Insulin Resistance, Hypertension

Status
Recruiting
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Angiotensin-(1-7)
Saline
Sponsored by
Vanderbilt University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional other trial for Obesity focused on measuring renin-angiotensin system, angiotensin, insulin resistance, blood pressure

Eligibility Criteria

18 Years - 60 Years (Adult)All SexesDoes not accept healthy volunteers

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)

Sites / Locations

  • Vanderbilt University School of MedicineRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Angiotensin-(1-7)

Saline

Arm Description

Subjects will receive intravenous infusion of three ascending doses of Angiotensin-(1-7). The doses are 4, 8, and 16 ng/kg/min. Each dose will be maintained for 10 minutes. The highest dose of Angiotensin-(1-7) will be maintained for an additional 120 minutes during the hyperinsulinemic-euglycemic clamp, for a total of 150 minutes of infusion.

Subjects will receive an intravenous infusion of saline that is matched in volume to the Angiotensin-(1-7) study day. The saline infusion will also be maintained for a total of 150 minutes.

Outcomes

Primary Outcome Measures

Whole-Body Insulin Sensitivity
Whole-body insulin sensitivity will be defined as the glucose infusion rate needed to maintain euglycemia during steady state (time=90 to 120 minutes) of the hyperinsulinemic-euglycemic clamp following angiotensin-(1-7) versus saline infusion. The insulin sensitivity will be corrected by body weight, lean body mass, and steady-state plasma insulin concentrations.

Secondary Outcome Measures

Blood Pressure
The change in blood pressure following angiotensin-(1-7) versus saline infusion.
Heart Rate
The change in heart rate following angiotensin-(1-7) versus saline infusion.
Cardiac Output
The change in cardiac output following angiotensin-(1-7) versus saline infusion.
Stroke Volume
The change in stroke volume following angiotensin-(1-7) versus saline infusion.
Systemic Vascular Resistance
The change in systemic vascular resistance following angiotensin-(1-7) versus saline infusion.

Full Information

First Posted
December 31, 2015
Last Updated
January 26, 2023
Sponsor
Vanderbilt University
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1. Study Identification

Unique Protocol Identification Number
NCT02646475
Brief Title
Metabolic Effects of Angiotensin-(1-7)
Official Title
Metabolic Effects of Angiotensin-(1-7)
Study Type
Interventional

2. Study Status

Record Verification Date
January 2023
Overall Recruitment Status
Recruiting
Study Start Date
February 2016 (Actual)
Primary Completion Date
December 2023 (Anticipated)
Study Completion Date
December 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Vanderbilt University

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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.
Detailed 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Obesity, Insulin Resistance, Hypertension, Metabolic Cardiovascular Syndrome
Keywords
renin-angiotensin system, angiotensin, insulin resistance, blood pressure

7. Study Design

Primary Purpose
Other
Study Phase
Phase 1
Interventional Study Model
Crossover Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
19 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Angiotensin-(1-7)
Arm Type
Experimental
Arm Description
Subjects will receive intravenous infusion of three ascending doses of Angiotensin-(1-7). The doses are 4, 8, and 16 ng/kg/min. Each dose will be maintained for 10 minutes. The highest dose of Angiotensin-(1-7) will be maintained for an additional 120 minutes during the hyperinsulinemic-euglycemic clamp, for a total of 150 minutes of infusion.
Arm Title
Saline
Arm Type
Placebo Comparator
Arm Description
Subjects will receive an intravenous infusion of saline that is matched in volume to the Angiotensin-(1-7) study day. The saline infusion will also be maintained for a total of 150 minutes.
Intervention Type
Drug
Intervention Name(s)
Angiotensin-(1-7)
Other Intervention Name(s)
Angiotensin I (1-7), Angiotensin I/II (1-7) Acetate
Intervention Description
This is a biologically active endogenous angiotensin peptide. It may play an important role in the regulation of blood pressure by dilating blood vessels as well as a role in the regulation of insulin action.
Intervention Type
Drug
Intervention Name(s)
Saline
Other Intervention Name(s)
normal saline, 0.9% sodium chloride
Intervention Description
Normal saline will be used as a placebo comparator.
Primary Outcome Measure Information:
Title
Whole-Body Insulin Sensitivity
Description
Whole-body insulin sensitivity will be defined as the glucose infusion rate needed to maintain euglycemia during steady state (time=90 to 120 minutes) of the hyperinsulinemic-euglycemic clamp following angiotensin-(1-7) versus saline infusion. The insulin sensitivity will be corrected by body weight, lean body mass, and steady-state plasma insulin concentrations.
Time Frame
steady-state (time 90 to 120 minutes) during hyperinsulinemic-euglycemic clamp
Secondary Outcome Measure Information:
Title
Blood Pressure
Description
The change in blood pressure following angiotensin-(1-7) versus saline infusion.
Time Frame
150 minutes
Title
Heart Rate
Description
The change in heart rate following angiotensin-(1-7) versus saline infusion.
Time Frame
150 minutes
Title
Cardiac Output
Description
The change in cardiac output following angiotensin-(1-7) versus saline infusion.
Time Frame
150 minutes
Title
Stroke Volume
Description
The change in stroke volume following angiotensin-(1-7) versus saline infusion.
Time Frame
150 minutes
Title
Systemic Vascular Resistance
Description
The change in systemic vascular resistance following angiotensin-(1-7) versus saline infusion.
Time Frame
150 minutes
Other Pre-specified Outcome Measures:
Title
Renin Activity
Description
The change in plasma renin activity following angiotensin-(1-7) versus saline infusion.
Time Frame
150 minutes
Title
Angiotensin Peptides
Description
The change in plasma angiotensin peptides following angiotensin-(1-7) versus saline infusion.
Time Frame
150 minutes
Title
Aldosterone
Description
The change in plasma aldosterone following angiotensin-(1-7) versus saline infusion.
Time Frame
150 minutes
Title
Adipokines
Description
The change in circulating adipokines following angiotensin-(1-7) versus saline infusion.
Time Frame
150 minutes

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
60 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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)
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Kaleigh Rae, MPH
Phone
615-875-7421
Email
kaleigh.rae@vanderbilt.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Italo Biaggioni, MD
Organizational Affiliation
Vanderbilt University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Vanderbilt University School of Medicine
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37232
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Kaleigh Rae, MPH
Phone
615-875-7421
Email
kaleigh.rae@vanderbilt.edu

12. IPD Sharing Statement

Plan to Share IPD
No

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Metabolic Effects of Angiotensin-(1-7)

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