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 23, 2022

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Sponsor:

Information provided by (Responsible Party):

Wanpen Vongpatanasin, University of Texas Southwestern Medical Center

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Hypertension	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	Phase 4

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 Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	2 participants
Allocation:	Randomized
Intervention Model:	Crossover Assignment
Masking:	None (Open Label)
Primary Purpose:	Diagnostic
Official Title:	The Role of Aldosterone on Sympathetic Nerve Activity and Insulin Sensitivity
Study Start Date :	November 2010
Estimated Primary Completion Date :	December 2025
Estimated Study Completion Date :	December 2025

Resource links provided by the National Library of Medicine

MedlinePlus Genetics related topics: Hypertension

Drug Information available for: Insulin Insulin human

U.S. FDA Resources

Arms and Interventions

Arm	Intervention/treatment
Experimental: Hyperinsulinemic euglycemic clamp We will perform following procedures: DEFINITY® infusion Flow mediated vasodilation Endothelial cell collection Microvascular perfusion assessment using Definity Microneurography	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)
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	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) 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)

Arm

Intervention/treatment

Experimental: Hyperinsulinemic euglycemic clamp

We will perform following procedures:

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

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)

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

Drug: DEFINITY® infusion

Other Name: (IND# 104397)

Procedure: Flow mediated vasodilation

Other Names:

FMD
Endothelial Dependent Vasodilation

Procedure: Endothelial cell collection

Procedure: Microvascular perfusion assessment using Definity

Procedure: Microneurography

Other Name: Assessment of sympathetic nerve activity (SNA)

Outcome Measures

Primary Outcome Measures :

Increase in muscle sympathetic nerve activity during hyperinsulinemic euglycemic clamp [ Time Frame: 1 day ]

Secondary Outcome Measures :

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 ]

Eligibility Criteria

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Ages Eligible for Study:	18 Years to 75 Years (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	Yes

Criteria

Inclusion Criteria:

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

Exclusion Criteria:

Congestive heart failure or coronary artery disease
Blood pressure averaging > 159/99 mmHg
Serum creatinine > 1.5 mg/dL
Diabetes mellitus or other systemic illness
Left ventricular hypertrophy by echocardiography or ECG
Pregnancy
Hypersensitivity to spironolactone, chlorthalidone, amlodipine, human recombinant insulin or Definity
Any history of substance abuse (other than tobacco)
History of gouty arthritis
Patients with right-to-left, bi-directional, or transient right-to-left cardiac shunts
Hypersensitivity to perflutren, blood, blood products or albumin

Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02102243

Contacts

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Contact: Debbie Arbique, DNP	(214)648-3188	debbie.arbique@utsouthwestern.edu
Contact: Alejandro Velasco, MD	2146483180	alejandro.velasco@utsouthwestern.edu

Locations

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United States, Texas
UT Southwestern Medical Center	Recruiting
Dallas, Texas, United States, 75390
Contact: Debbie Arbique, DNP 214-648-3188 debbie.arbique@utsouthwestern.edu

Sponsors and Collaborators

Wanpen Vongpatanasin

Investigators

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Principal Investigator:	Wanpen Vongpatanasin, MD	UT Southwestern Medical Center

More Information

Publications:

Catena C, Lapenna R, Baroselli S, Nadalini E, Colussi G, Novello M, Favret G, Melis A, Cavarape A, Sechi LA. Insulin sensitivity in patients with primary aldosteronism: a follow-up study. J Clin Endocrinol Metab. 2006 Sep;91(9):3457-63. Epub 2006 Jul 5.

Donato AJ, Gano LB, Eskurza I, Silver AE, Gates PE, Jablonski K, Seals DR. Vascular endothelial dysfunction with aging: endothelin-1 and endothelial nitric oxide synthase. Am J Physiol Heart Circ Physiol. 2009 Jul;297(1):H425-32. doi: 10.1152/ajpheart.00689.2008. Epub 2009 May 22.

Colussi G, Catena C, Lapenna R, Nadalini E, Chiuch A, Sechi LA. Insulin resistance and hyperinsulinemia are related to plasma aldosterone levels in hypertensive patients. Diabetes Care. 2007 Sep;30(9):2349-54. Epub 2007 Jun 15.

Kontak AC, Wang Z, Arbique D, Adams-Huet B, Auchus RJ, Nesbitt SD, Victor RG, Vongpatanasin W. Reversible sympathetic overactivity in hypertensive patients with primary aldosteronism. J Clin Endocrinol Metab. 2010 Oct;95(10):4756-61. doi: 10.1210/jc.2010-0823. Epub 2010 Jul 21.

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Responsible Party:	Wanpen Vongpatanasin, PROFESSOR, University of Texas Southwestern Medical Center
ClinicalTrials.gov Identifier:	NCT02102243
Other Study ID Numbers:	STU 102010-063
First Posted:	April 2, 2014 Key Record Dates
Last Update Posted:	March 23, 2022
Last Verified:	March 2022

Keywords provided by Wanpen Vongpatanasin, University of Texas Southwestern Medical Center:


hypertension blood pressure sympathetic nerve activity vascular oxidative stress nitric oxide nitric oxide synthase (eNOS) endothelium	endothelial dysfunction endothelial cell protein expression microvascular blood flow flow mediated dilation endothelial cell collection microbubbles Definity

Additional relevant MeSH terms:

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Hypertension Vascular Diseases Cardiovascular Diseases Insulin	Insulin, Globin Zinc Hypoglycemic Agents Physiological Effects of Drugs

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