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Neural Mechanism of Aldosterone-induced Insulin Resistance

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ClinicalTrials.gov Identifier: NCT02102243
Recruitment Status : Recruiting
First Posted : April 2, 2014
Last Update Posted : March 22, 2021
Sponsor:
Information provided by (Responsible Party):
Wanpen Vongpatanasin, University of Texas Southwestern Medical Center

Tracking Information
First Submitted Date  ICMJE March 6, 2014
First Posted Date  ICMJE April 2, 2014
Last Update Posted Date March 22, 2021
Study Start Date  ICMJE November 2010
Estimated Primary Completion Date December 2025   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 26, 2015)
Increase in muscle sympathetic nerve activity during hyperinsulinemic euglycemic clamp [ Time Frame: 1 day ]
Original Primary Outcome Measures  ICMJE
 (submitted: March 28, 2014)
  • Increase in muscle sympathetic nerve activity during hyperinsulinemic euglycemic clamp [ Time Frame: 1 day ]
  • Change in endothelial cell protein expression after hyperinsulinemic euglycemic clamp [ Time Frame: 1 day ]
  • Change in forearm flow mediated dilation (FMD) after saline infusion [ Time Frame: 1 day ]
  • Change in forearm flow mediated dilation (FMD) after hyperinsulinemic euglycemic clamp [ Time Frame: 1 day ]
  • Increase in muscle sympathetic nerve activity during saline infusion [ Time Frame: 1 day ]
  • Change in endothelial cell protein expression after saline infusion [ Time Frame: 1 day ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: December 11, 2015)
  • Change in microvascular blood flow during hyperinsulinemic euglycemic clamp. [ Time Frame: 1 day ]
  • Change in microvascular blood flow during saline infusion. [ Time Frame: 1 day ]
  • Change in endothelial cell protein expression after hyperinsulinemic euglycemic clamp [ Time Frame: 1 day ]
  • Change in endothelial cell protein expression after saline infusion [ Time Frame: 1 day ]
  • Increase in muscle sympathetic nerve activity during saline infusion [ Time Frame: 1 day ]
Original Secondary Outcome Measures  ICMJE
 (submitted: March 28, 2014)
  • Change in microvascular blood flow during hyperinsulinemic euglycemic clamp. [ Time Frame: 1 day ]
  • Change in microvascular blood flow during saline infusion. [ Time Frame: 1 day ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Neural Mechanism of Aldosterone-induced Insulin Resistance
Official Title  ICMJE The Role of Aldosterone on Sympathetic Nerve Activity and Insulin Sensitivity
Brief Summary Patients with high aldosterone hormone have higher blood glucose than normal people. This study is being done to understand how aldosterone hormone affects the nerve activity that controls blood flow in the muscles and blood glucose. The information may be helpful in selecting blood pressure medications which can improve not only blood pressure but also improve blood sugar.
Detailed Description

Patients with primary aldosteronism are known to have impaired insulin sensitivity, which is improved after removal of aldosterone-producing adenoma. In patients with essential hypertension, plasma aldosterone levels have been also shown to positively correlate with indices of insulin resistance.

Mechanism underlying aldosterone-induced insulin resistance is unknown. Aldosterone has been shown to interfere with insulin signaling the vascular cells by increasing production of reactive oxygen species via activation of NADPH oxidase, resulting in decreased availability of nitric oxide (NO), the key mediator for insulin-mediated vasodilation. Treatment with mineralocorticoid receptor antagonists has been shown to improve insulin sensitivity in mice with obesity and metabolic syndrome. Aldosterone has also been shown to increase resting sympathetic vasoconstrictor activity to the peripheral circulation. However, effects of aldosterone and mineralocorticoid receptor antagonists on insulin-mediated skeletal muscle vasodilation, sympathetic activation, and vascular oxidative stress have not been assessed in humans.

The investigators will collect venous endothelial cells, and measure skeletal muscle microvascular perfusion using Octafluoropropane microbubble contrast agents, and measure sympathetic nerve activity in normotensive controls (NT), stage 1 essential hypertensive subjects (ET), and patients with primary aldosteronism (PA) during hyperinsulinemic euglycemic clamp.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Diagnostic
Condition  ICMJE Hypertension
Intervention  ICMJE
  • Drug: DEFINITY® infusion
    The DEFINITY® vial contains components that upon activation yield perflutren lipid microspheres, a diagnostic drug that is intended to be used for contrast enhancement during echocardiographic procedures. The vial contains a clear, colorless, sterile, non-pyrogenic, hypertonic liquid, which upon activation with agitation, provides a homogeneous, opaque, milky white injectable suspension of perflutren lipid microspheres. The suspension of activated DEFINITY® will be infused intravenously at a rate of 0.20 to 0.27 ml/min, not to exceed a maximum dose of 2 vials per study subject per day or visit.
    Other Name: (IND# 104397)
  • Drug: Human Recombinant Regular Insulin infusion
    The plasma insulin concentration will be acutely raised and maintained at at a steady state by a prime-continuous insulin infusion.
    Other Names:
    • Humulin R
    • National Drug Code # 0002-8501-01
  • Drug: Dextrose infusion
    The plasma glucose concentration will be held constant at 90 mg/dl by a variable glucose infusion during euglycemic hyperinsulinemic clamp
    Other Name: Dextrose 20%
  • Procedure: Flow mediated vasodilation
    Flow mediated vasodilation (FMD), which is a non-invasive assessment of endothelial function, will be performed on the brachial artery using ultrasound. After a clear picture of the artery has been obtained, the cuff on the same arm will be inflated until it is tight for five minutes. During and following this, the subject's arm will continue to be imaged to monitor maximal increase in the brachial artery diameter.
    Other Names:
    • FMD
    • Endothelial Dependent Vasodilation
  • Procedure: Endothelial cell collection
    We will collect endothelial cells from a superficial vein, usually in the arm. Following insertion of a peripheral intravenous (IV) catheter, we will collect cells from the inner lining of the vein using a thin, flexible J-tipped wire. The wire will be inserted through the IV into the vein and then removed, along with a sampling of endothelial cells. The cells collected will be processed and stained for several proteins involved in endothelial cell function, using immunofluorescent technique.
  • Procedure: Microvascular perfusion assessment using Definity
    Using high-resolution ultrasound, we will measure skeletal muscle blood flow during infusion of a solution containing the octafluoropropane microbubble contrast agent, Definity. The solution will be a dilution of 1 vial of Definity to 30 cc of normal saline. The ultrasound probe will be placed over the forearm to obtain images while octafluoropropane microbubbles (Definity) are infused intravenously at the rate of 0.20 to 0.27 ml/min, not to exceed a maximum dose of 2 vials per study subject per day or visit. The microvascular perfusion assessment using Definity be performed at rest as well as during slow and fast handgrip exercises.
  • Procedure: Microneurography
    Sympathetic nerve activity from the peroneal nerve measured by inserting a tiny needle directly into the nerve in the leg. Investigators will localize the nerve by electrical stimulation over the skin using a blunt probe. .The recording needle will remain in position throughout the study.
    Other Name: Assessment of sympathetic nerve activity (SNA)
Study Arms  ICMJE
  • Experimental: Hyperinsulinemic euglycemic clamp

    We will perform following procedures:

    DEFINITY® infusion Flow mediated vasodilation Endothelial cell collection Microvascular perfusion assessment using Definity Microneurography

    Interventions:
    • Drug: DEFINITY® infusion
    • Drug: Human Recombinant Regular Insulin infusion
    • Drug: Dextrose infusion
    • Procedure: Flow mediated vasodilation
    • Procedure: Endothelial cell collection
    • Procedure: Microvascular perfusion assessment using Definity
    • Procedure: Microneurography
  • Experimental: Initial Saline Infusion

    We will perform the following procedures:

    DEFINITY® infusion Human Recombinant Regular Insulin infusion Dextrose infusion Flow mediated vasodilation Endothelial cell collection Microvascular perfusion assessment using Definity Microneurography

    Interventions:
    • Drug: DEFINITY® infusion
    • Procedure: Flow mediated vasodilation
    • Procedure: Endothelial cell collection
    • Procedure: Microvascular perfusion assessment using Definity
    • Procedure: Microneurography
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: March 28, 2014)
2
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2025
Estimated Primary Completion Date December 2025   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Normotensive controls
  2. Stage I (140-159/90-99 mmHg) untreated subjects with essential hypertension
  3. Patients with PA and stage I (140-159/90-99 mmHg) hypertension

Exclusion Criteria:

  1. Congestive heart failure or coronary artery disease
  2. Blood pressure averaging > 159/99 mmHg
  3. Serum creatinine > 1.5 mg/dL
  4. Diabetes mellitus or other systemic illness
  5. Left ventricular hypertrophy by echocardiography or ECG
  6. Pregnancy
  7. Hypersensitivity to spironolactone, chlorthalidone, amlodipine, human recombinant insulin or Definity
  8. Any history of substance abuse (other than tobacco)
  9. History of gouty arthritis
  10. Patients with right-to-left, bi-directional, or transient right-to-left cardiac shunts
  11. Hypersensitivity to perflutren, blood, blood products or albumin
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 75 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE
Contact: Debbie Arbique, DNP (214)648-3188 debbie.arbique@utsouthwestern.edu
Contact: Alejandro Velasco, MD 2146483180 alejandro.velasco@utsouthwestern.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02102243
Other Study ID Numbers  ICMJE STU 102010-063
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Wanpen Vongpatanasin, University of Texas Southwestern Medical Center
Study Sponsor  ICMJE Wanpen Vongpatanasin
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Wanpen Vongpatanasin, MD UT Southwestern Medical Center
PRS Account University of Texas Southwestern Medical Center
Verification Date March 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP