Neural Mechanism of Aldosterone-induced Insulin Resistance

NCT02102243 | Withdrawn Phase 4 DMC

• 1 other identifier: STU 102010-063
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

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.

Conditions

Hypertension

Keywords

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

Outcome Measures

Primary Outcomes (1)

• Increase in muscle sympathetic nerve activity during hyperinsulinemic euglycemic clamp

  1 day

Secondary Outcomes (5)

• Change in microvascular blood flow during hyperinsulinemic euglycemic clamp.

  1 day

• Change in microvascular blood flow during saline infusion.

  1 day

• Change in endothelial cell protein expression after hyperinsulinemic euglycemic clamp

  1 day

• Change in endothelial cell protein expression after saline infusion

  1 day

• Increase in muscle sympathetic nerve activity during saline infusion

  1 day

Study Arms (2)

Hyperinsulinemic euglycemic clamp

EXPERIMENTAL

We will perform following procedures: DEFINITY® infusion Flow mediated vasodilation Endothelial cell collection Microvascular perfusion assessment using Definity Microneurography

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

Initial Saline Infusion

EXPERIMENTAL

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; Procedure: Flow mediated vasodilation; Procedure: Endothelial cell collection; Procedure: Microvascular perfusion assessment using Definity; Procedure: Microneurography

Interventions

DEFINITY® infusion DRUG

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.

Also known as: (IND# 104397)

Hyperinsulinemic euglycemic clamp; Initial Saline Infusion

Human Recombinant Regular Insulin infusion DRUG

The plasma insulin concentration will be acutely raised and maintained at at a steady state by a prime-continuous insulin infusion.

Also known as: Humulin R, National Drug Code # 0002-8501-01

Hyperinsulinemic euglycemic clamp

Dextrose infusion DRUG

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

Also known as: Dextrose 20%

Hyperinsulinemic euglycemic clamp

Flow mediated vasodilation PROCEDURE

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.

Also known as: FMD, Endothelial Dependent Vasodilation

Hyperinsulinemic euglycemic clamp; Initial Saline Infusion

Endothelial cell collection PROCEDURE

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.

Hyperinsulinemic euglycemic clamp; Initial Saline Infusion

Microvascular perfusion assessment using Definity PROCEDURE

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.

Hyperinsulinemic euglycemic clamp; Initial Saline Infusion

Microneurography PROCEDURE

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.

Also known as: Assessment of sympathetic nerve activity (SNA)

Hyperinsulinemic euglycemic clamp; Initial Saline Infusion

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Wanpen Vongpatanasin: lead

Study Sites (1)

UT Southwestern Medical Center

Dallas, Texas, 75390, United States

Location

Related 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.

  PMID: 16822818 BACKGROUND

• 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.

  PMID: 19465546 BACKGROUND

• 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.

  PMID: 17575088 BACKGROUND

• 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.

  PMID: 20660053 BACKGROUND

MeSH Terms

Conditions

Hypertension

Interventions

Insulin

Condition Hierarchy (Ancestors)

Vascular Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Proinsulin; Insulins; Pancreatic Hormones; Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Peptides; Amino Acids, Peptides, and Proteins

Study Officials

• Wanpen Vongpatanasin, MD

  University of Texas Southwestern Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: DIAGNOSTIC
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: PROFESSOR

Study Record Dates

• First Submitted: March 6, 2014
• First Posted: April 2, 2014
• Study Start: November 1, 2010
• Primary Completion: December 1, 2025
• Study Completion: December 1, 2025
• Last Updated: March 15, 2023

Record last verified: 2023-03

Locations

US (1)