Neural Mechanism of Aldosterone-induced Insulin Resistance

Hypertension Clinical Trial

Official title:

The Role of Aldosterone on Sympathetic Nerve Activity and Insulin Sensitivity

Clinical Trial Details — Status: Withdrawn

Administrative data

• NCT number: NCT02102243
• Other study ID #: STU 102010-063
• Status: Withdrawn
• Phase: Phase 4
• Start date: November 2010
• Est. completion date: December 2025

Study information

• Verified date: March 2023
• Source: University of Texas Southwestern Medical Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Withdrawn
• Enrollment: 0
• Est. completion date: December 2025
• Est. primary completion date: December 2025
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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

Related Conditions & MeSH terms

• Hypertension

Intervention

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.
• 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.
• Dextrose infusion
The plasma glucose concentration will be held constant at 90 mg/dl by a variable glucose infusion during euglycemic hyperinsulinemic clamp

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.
• 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.
• 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.
• 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.

Locations

Country	Name	City	State
United States	UT Southwestern Medical Center	Dallas	Texas

Sponsors (1)

Lead Sponsor	Collaborator
Wanpen Vongpatanasin

Country where clinical trial is conducted

United States, 

References & Publications (4)

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. doi: 10.1210/jc.2006-0736. Epub 2006 Jul 5. — View Citation

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. doi: 10.2337/dc07-0525. Epub 2007 Jun 15. — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Increase in muscle sympathetic nerve activity during hyperinsulinemic euglycemic clamp		1 day
Secondary	Change in microvascular blood flow during hyperinsulinemic euglycemic clamp.		1 day
Secondary	Change in microvascular blood flow during saline infusion.		1 day
Secondary	Change in endothelial cell protein expression after hyperinsulinemic euglycemic clamp		1 day
Secondary	Change in endothelial cell protein expression after saline infusion		1 day
Secondary	Increase in muscle sympathetic nerve activity during saline infusion		1 day