Neural Mechanism of Aldosterone-induced Insulin Resistance

Phase 4

Withdrawn

• Conditions: Hypertension
• Interventions: Drug: DEFINITY® infusion; Drug: Human Recombinant Regular Insulin infusion; Procedure: Flow mediated vasodilation; Drug: Dextrose infusion; Procedure: Endothelial cell collection; Procedure: Microvascular perfusion assessment using Definity; Procedure: Microneurography

• Registration Number: NCT02102243
• Lead Sponsor: Wanpen Vongpatanasin

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 Timeline

• Study Start: 2010-11
• Study First Submitted: 2014-03-06
• Study First Submitted QC: 2014-03-28
• Study First Posted: 2014-04-02
• Status Verified: 2023-03
• Last Update Submitted: 2023-03-12
• Last Update Posted: 2023-03-15
• Primary Completion: 2025-12
• Study Completion: 2025-12

Recruitment & Eligibility

• Status: WITHDRAWN
• Sex: All
• Target Recruitment: Not specified

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Hyperinsulinemic euglycemic clamp	DEFINITY® infusion	We will perform following procedures: DEFINITY® infusion Flow mediated vasodilation Endothelial cell collection Microvascular perfusion assessment using Definity Microneurography
Initial Saline Infusion	DEFINITY® 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
Hyperinsulinemic euglycemic clamp	Human Recombinant Regular Insulin infusion	We will perform following procedures: DEFINITY® infusion Flow mediated vasodilation Endothelial cell collection Microvascular perfusion assessment using Definity Microneurography
Hyperinsulinemic euglycemic clamp	Microneurography	We will perform following procedures: DEFINITY® infusion Flow mediated vasodilation Endothelial cell collection Microvascular perfusion assessment using Definity Microneurography
Hyperinsulinemic euglycemic clamp	Dextrose infusion	We will perform following procedures: DEFINITY® infusion Flow mediated vasodilation Endothelial cell collection Microvascular perfusion assessment using Definity Microneurography
Initial Saline Infusion	Microneurography	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
Initial Saline Infusion	Flow mediated vasodilation	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
Hyperinsulinemic euglycemic clamp	Endothelial cell collection	We will perform following procedures: DEFINITY® infusion Flow mediated vasodilation Endothelial cell collection Microvascular perfusion assessment using Definity Microneurography
Initial Saline Infusion	Endothelial cell collection	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
Hyperinsulinemic euglycemic clamp	Flow mediated vasodilation	We will perform following procedures: DEFINITY® infusion Flow mediated vasodilation Endothelial cell collection Microvascular perfusion assessment using Definity Microneurography
Hyperinsulinemic euglycemic clamp	Microvascular perfusion assessment using Definity	We will perform following procedures: DEFINITY® infusion Flow mediated vasodilation Endothelial cell collection Microvascular perfusion assessment using Definity Microneurography
Initial Saline Infusion	Microvascular perfusion assessment using Definity	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

Primary Outcome Measures

Name	Time	Method
Increase in muscle sympathetic nerve activity during hyperinsulinemic euglycemic clamp	1 day

Secondary Outcome Measures

Name	Time	Method
Change in microvascular blood flow during saline infusion.	1 day
Change in endothelial cell protein expression after saline infusion	1 day
Change in microvascular blood flow during hyperinsulinemic euglycemic clamp.	1 day
Change in endothelial cell protein expression after hyperinsulinemic euglycemic clamp	1 day
Increase in muscle sympathetic nerve activity during saline infusion	1 day

Trial Locations

Locations (1)

UT Southwestern Medical Center; 🇺🇸 Dallas, Texas, United States