Metabolic Syndrome
Conditions
Brief summary
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
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.
Interventions
OTHERLow Salt diet plus Placebo tablet
OTHERLow Sodium diet plus Salt tablet
DRUGEpleronone
50mg daily
DRUGAmlodipine
5mg daily
Sponsors
Vanderbilt University Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Insulin Secretion | After 8 days of diet or drug | Hyperglycemic clamp- acute insulin response (AIR) during time 0-10 minutes |
| Insulin Sensitivity | after 8 days of diet or medication | Hyperinsulinemic clamp- glucose infusion rate during insulin administration |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Aim 1 Low Sodium and High Sodium diet crossover | 28 |
| Aim 2 Eplerenone and Amlodipine crossover | 16 |
| Total | 44 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Illness | 0 | 2 | 0 | 0 |
| Overall Study | Inadequate IV access | 1 | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Aim 1 | Total | Aim 2 |
|---|---|---|---|
| Age, Continuous | 45 years | 45 years | 46 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 28 Participants | 44 Participants | 16 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 4 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 24 Participants | 39 Participants | 15 Participants |
| Region of Enrollment United States | 28 participants | 44 participants | 16 participants |
| Sex: Female, Male Female | 15 Participants | 21 Participants | 6 Participants |
| Sex: Female, Male Male | 13 Participants | 23 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 28 | 0 / 28 | 0 / 16 | 0 / 16 |
| other Total, other adverse events | 7 / 28 | 10 / 28 | 3 / 16 | 3 / 16 |
| serious Total, serious adverse events | 0 / 28 | 0 / 28 | 0 / 16 | 0 / 16 |
Outcome results
Primary
Insulin Secretion
Hyperglycemic clamp- acute insulin response (AIR) during time 0-10 minutes
Time frame: After 8 days of diet or drug
Population: Participants with metabolic syndrome
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Aim 1- Low Sodium | Insulin Secretion | 293.1 uU/mL*10min |
| Aim 1- High Sodium | Insulin Secretion | 234.7 uU/mL*10min |
| Aim 2- Eplerenone | Insulin Secretion | 330.8 uU/mL*10min |
| Aim 2- Amlodipine | Insulin Secretion | 300.4 uU/mL*10min |
Primary
Insulin Sensitivity
Hyperinsulinemic clamp- glucose infusion rate during insulin administration
Time frame: after 8 days of diet or medication
Population: Participants with metabolic syndrome
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Aim 1- Low Sodium | Insulin Sensitivity | 6.6 mg/kg/min |
| Aim 1- High Sodium | Insulin Sensitivity | 6.9 mg/kg/min |
| Aim 2- Eplerenone | Insulin Sensitivity | 6.4 mg/kg/min |
| Aim 2- Amlodipine | Insulin Sensitivity | 6.3 mg/kg/min |