Endogenous Renin-Angiotensin-Aldosterone System and Glucose Metabolism

Study Overview
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Brief Summary
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Aim 1.Test the hypothesis that activation of the endogenous renin-angiotensin-aldosterone system impairs glycemic control via effects on insulin sensitivity and insulin secretion. Aim 2. Test the hypothesis that activation of the endogenous renin-angiotensin-aldosterone system impairs insulin secretion and insulin sensitivity via an mineralocorticoid-receptor dependent mechanism.

Detailed Description
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In aim 1 subjects are randomized to cross over between an 8 day high salt and 8 day low salt diet and assessments are made. In aim 2, subjects are randomized to a 2x2 cross over study with an 8 day low salt diet and either eplerenone 50mg or amlodipine 5mg.

Official Title
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Endogenous Renin-Angiotensin-Aldosterone System and Glucose Metabolism

Conditions
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Metabolic Syndrome

Intervention / Treatment
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* Other: Low Salt diet plus Placebo tablet
* Other: Low Sodium diet plus Salt tablet
* Drug: Epleronone
* Drug: Amlodipine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ambulatory subjects, 18 to 70 years of age, inclusive For female subjects, the following conditions must be met: postmenopausal status for at least 1 year, or status-post surgical sterilization, or if of childbearing potential, utilization of adequate birth control and willingness to undergo urine beta-hcg testing prior to drug treatment and on every study day. Metabolic Syndrome as defined by the presence of > 3 of the following: Systolic Blood Pressure > 130 mm Hg OR Diastolic Blood Pressure > 85 mm Hg. Glucose Intolerance (Fasting Plasma Glucose ≥ 100 mg/dL) Increased triglyceride level > 150mg/dL (1.7mmol/L) Decreased levels of HDL cholesterol (For males, less than 40 mg/dL; For females, less than 50 mg/dL) Waist circumference (For males, greater than 40 inches; For females, greater than 35 inches) Exclusion Criteria: type 1 Diabetes Type II Diabetes Impaired renal function Prior allergies to medications used in the study protocol Screening plasma potassium >5.5 mmol/L or sodium <135 mmol/L Cardiovascular disease Use of hormone replacement therapy Breast-feeding Treatment with anticoagulants History of serious neurologic disease History or presence of immunological or hematological disorders Diagnosis of asthma requiring use of inhaled beta agonist Clinically significant gastrointestinal impairment Impaired hepatic function Hematocrit <35% Any underlying or acute disease requiring regular medication which could possibly pose a threat to the subject or make implementation of the protocol or interpretation of the study results difficult, such as arthritis treated with non-steroidal antiinflammatory drugs Treatment with chronic systemic glucocorticoid therapy Treatment with lithium salts History of alcohol or drug abuse Treatment with any investigational drug in the 1 month preceding Mental conditions rendering the subject unable to understand the nature, scope and possible consequences of the study Inability to comply with the protocol, e.g., uncooperative attitude, inability to return for follow-up visits, and unlikelihood of completing the study

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Aim1-Low Sodium then High Sodium<br>Subjects will be provided with a low sodium diet from the Vanderbilt Clinical Research Center that will be controlled for salt content. Participants will be given low sodium diet (50mEq/d) and Placebo tablets for 8 days and assessments will be made, washout and then cross over to a low sodium diet (50mEq/d) plus Salt tables (150mEq) for 8days and assessments will be made. | Other: Low Salt diet plus Placebo tablet<br> <br> Other: Low Sodium diet plus Salt tablet<br> <br> |
| Active Comparator: Aim 1-high salt diet then low salt diet<br>Subjects will be provided with a diet from the Vanderbilt Clinical Research Center that will be controlled for salt content. Participants will be given low sodium diet (50mEq/d) and Salt tables (150mEq) for 8 days and assessments will be made, washout and then cross over to a low sodium diet (50mEq/d) plus Placebo tablets for 8days and assessments will be made. | Other: Low Salt diet plus Placebo tablet<br> <br> Other: Low Sodium diet plus Salt tablet<br> <br> |
| Active Comparator: Aim2- low salt diet and epleronone then amlodipine<br>Subjects on a low salt diet will receive Epleronone 50mg for 8 days and assessments will be made, then cross over to a low salt diet with Amlodipine 5mg for 8days and assessments will be made. | Other: Low Salt diet plus Placebo tablet<br> <br> Drug: Epleronone<br>* 50mg daily<br>* Other names: Inspra;Drug: Amlodipine<br>* 5mg daily<br>* Other names: Norvasc;|
| Active Comparator: aim2- low salt diet and amlodipine then epleronone<br>Subjects on a low salt diet will receive Amlodipine 5mg for 8 days and assessments will be made, then cross over to a low salt diet with Epleronone 50mg for 8days and assessments will be made. | Other: Low Salt diet plus Placebo tablet<br> <br> Drug: Epleronone<br>* 50mg daily<br>* Other names: Inspra;Drug: Amlodipine<br>* 5mg daily<br>* Other names: Norvasc;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Insulin Secretion | Hyperglycemic clamp- acute insulin response (AIR) during time 0-10 minutes | After 8 days of diet or drug | 
| Insulin Sensitivity | Hyperinsulinemic clamp- glucose infusion rate during insulin administration | after 8 days of diet or medication |