Endogenous Renin-Angiotensin-Aldosterone System and Glucose Metabolism

Endogenous Renin-Angiotensin-Aldosterone System and Glucose Metabolism

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.

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.

Inclusion Criteria:

1. Ambulatory subjects, 18 to 70 years of age, inclusive

2. For female subjects, the following conditions must be met:

   1. postmenopausal status for at least 1 year, or
   2. status-post surgical sterilization, or
   3. 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.

3. Metabolic Syndrome as defined by the presence of > 3 of the following:

   1. Systolic Blood Pressure > 130 mm Hg OR Diastolic Blood Pressure > 85 mm Hg.
   2. Glucose Intolerance (Fasting Plasma Glucose ≥ 100 mg/dL)
   3. Increased triglyceride level > 150mg/dL (1.7mmol/L)
   4. Decreased levels of HDL cholesterol (For males, less than 40 mg/dL; For females, less than 50 mg/dL)
   5. Waist circumference (For males, greater than 40 inches; For females, greater than 35 inches)

Exclusion Criteria:

1. type 1 Diabetes
2. Type II Diabetes
3. Impaired renal function
4. Prior allergies to medications used in the study protocol
5. Screening plasma potassium >5.5 mmol/L or sodium <135 mmol/L
6. Cardiovascular disease
7. Use of hormone replacement therapy
8. Breast-feeding
9. Treatment with anticoagulants
10. History of serious neurologic disease
11. History or presence of immunological or hematological disorders
12. Diagnosis of asthma requiring use of inhaled beta agonist
13. Clinically significant gastrointestinal impairment
14. Impaired hepatic function
15. Hematocrit <35%
16. 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
17. Treatment with chronic systemic glucocorticoid therapy
18. Treatment with lithium salts
19. History of alcohol or drug abuse
20. Treatment with any investigational drug in the 1 month preceding
21. Mental conditions rendering the subject unable to understand the nature, scope and possible consequences of the study
22. Inability to comply with the protocol, e.g., uncooperative attitude, inability to return for follow-up visits, and unlikelihood of completing the study