Neural Mechanism of Aldosterone-induced Insulin Resistance

Wanpen Vongpatanasin

Status and phase: Withdrawn; Phase 4

Conditions: Hypertension

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

Study type: Interventional

Funder types: Other

Identifiers

NCT02102243

STU 102010-063

Details and patient eligibility

About

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.

Full 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.

Sex: All

Ages: 18 to 75 years old

Volunteers: Accepts Healthy Volunteers

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

Trial design

Primary purpose: Diagnostic

Allocation: Randomized

Interventional model: Crossover Assignment

Masking: None (Open label)

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0 participants in 2 patient groups

Hyperinsulinemic euglycemic clamp

Experimental group

Description:

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

Treatment:

Procedure: Flow mediated vasodilation

Procedure: Microneurography

Drug: Human Recombinant Regular Insulin infusion

Procedure: Endothelial cell collection

Drug: Dextrose infusion

Procedure: Microvascular perfusion assessment using Definity

Drug: DEFINITY® infusion

Initial Saline Infusion

Experimental group

Description:

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

Treatment:

Procedure: Flow mediated vasodilation

Procedure: Microneurography

Procedure: Endothelial cell collection

Procedure: Microvascular perfusion assessment using Definity

Drug: DEFINITY® infusion