Aldosterone and Glucose Homeostasis

• ClinicalTrials.gov Identifier: NCT00732160
• Recruitment Status: Completed
• First Posted: August 11, 2008
• Results First Posted: April 6, 2017
• Last Update Posted: April 6, 2017
• Sponsor: Vanderbilt University
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI); National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Information provided by (Responsible Party): James Matt Luther, Vanderbilt University

Study Description

Brief Summary:

Determine the effect of aldosterone on how the body handles glucose (sugar).

Condition or disease	Intervention/treatment	Phase
Diabetes Mellitus	Drug: Aldosterone infusion (A); Drug: Vehicle Infusion (V); Other: High Sodium Diet (HS); Other: Low Sodium Diet (LS)	Not Applicable

Detailed Description:

Determine the effect of aldosterone on glucose metabolism in humans.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 34 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Basic Science
• Official Title: Aldosterone and Glucose Homeostasis
• Study Start Date: September 2008
• Actual Primary Completion Date: September 2012
• Actual Study Completion Date: December 2013

Arms and Interventions

Arm	Intervention/treatment
Experimental: HS-V/A; LS-V/A; High Sodium diet- Vehicle infusion then Aldosterone infusion Low Sodium diet- Vehicle infusion then Aldosterone infusion	Drug: Aldosterone infusion (A); Infusion of exogenous aldosterone (0.7 mcg/kg/hr for 12.5 hrs); Other Name: placebo; Drug: Vehicle Infusion (V); Vehicle infusion for 12.5 hours; Other: High Sodium Diet (HS); 160 mmol/d sodium diet for 7 days; Other: Low Sodium Diet (LS); 20 mmol/d sodium diet for 9 days
Experimental: HS-A/V; LS-A/V; High Sodium diet- Aldosterone infusion then Vehicle infusion Low Sodium diet- Aldosterone infusion then Vehicle infusion	Drug: Aldosterone infusion (A); Infusion of exogenous aldosterone (0.7 mcg/kg/hr for 12.5 hrs); Other Name: placebo; Drug: Vehicle Infusion (V); Vehicle infusion for 12.5 hours; Other: High Sodium Diet (HS); 160 mmol/d sodium diet for 7 days; Other: Low Sodium Diet (LS); 20 mmol/d sodium diet for 9 days
Experimental: LS-V/A; HS-V/A; Low Sodium diet- Vehicle infusion then Aldosterone infusion High Sodium diet- Vehicle infusion then Aldosterone infusion	Drug: Aldosterone infusion (A); Infusion of exogenous aldosterone (0.7 mcg/kg/hr for 12.5 hrs); Other Name: placebo; Drug: Vehicle Infusion (V); Vehicle infusion for 12.5 hours; Other: High Sodium Diet (HS); 160 mmol/d sodium diet for 7 days; Other: Low Sodium Diet (LS); 20 mmol/d sodium diet for 9 days
Experimental: LS-A/V; HS-A/V; Low Sodium diet- Aldosterone infusion then Vehicle infusion High Sodium diet- Aldosterone infusion then Vehicle infusion	Drug: Aldosterone infusion (A); Infusion of exogenous aldosterone (0.7 mcg/kg/hr for 12.5 hrs); Other Name: placebo; Drug: Vehicle Infusion (V); Vehicle infusion for 12.5 hours; Other: High Sodium Diet (HS); 160 mmol/d sodium diet for 7 days; Other: Low Sodium Diet (LS); 20 mmol/d sodium diet for 9 days

Outcome Measures

Primary Outcome Measures :

1. Insulin Secretion [ Time Frame: 3 hours ]
   Acute Insulin response during Hyperglycemic clamp (delta insulin uU/mL, t=0-10)

Secondary Outcome Measures :

1. Insulin Sensitivity [ Time Frame: 3 hours ]
   Insulin sensitivity index (ISI) was calculated by dividing the average glucose infusion rate (mg glucose infusion/kg body weight/min) by the average insulin concentration (uU/mL) from 90 to 120 minutes. This was multiplied by 100 (thus, x100 in units description), per reporting convention in literature.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 70 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

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

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

   a postmenopausal status for at least 1 year, or b status-post surgical sterilization, or c 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:

a Systolic Blood Pressure > 130 mm Hg OR Diastolic Blood Pressure > 85 mm Hg. b Glucose Intolerance (Fasting Plasma Glucose > 100 mg/dL) c Increased triglyceride level > 150mg/dL (1.7mmol/L) d Decreased levels of HDL cholesterol For males, less than 40 mg/dL For females, less than 50 mg/dL e Waist circumference For males, greater than 40 inches (102 cm) For females, greater than 35 inches (89 cm).

Exclusion Criteria:

1. Previously diagnosed Type I Diabetes , or the use of anti-diabetic medication. Subjects with type II diabetes not on medication will be allowed to participate if fasting blood glucose is <200mg/dL.
2. Prior allergies to medications used in the study protocol (e.g. L-arginine, potassium chloride).
3. Screening plasma potassium <3.5 mmol/L or use of chronic potassium supplements for the treatment of hypokalemia
4. Use of hormone replacement therapy
5. If on statin therapy for hypercholesterolemia, a change in dose within the past 6 months.
6. Breast-feeding
7. Cardiovascular disease such as prior myocardial infarction, presence of angina pectoris, significant arrhythmia, congestive heart failure (LV hypertrophy acceptable), deep vein thrombosis, pulmonary embolism, second or third degree heart block, mitral valve stenosis, aortic stenosis or hypertrophic cardiomyopathy
8. Treatment with anticoagulants
9. History of serious neurologic disease such as cerebral hemorrhage, stroke, seizure, or transient ischemic attack
10. History or presence of immunological or hematological disorders
11. Diagnosis of asthma requiring use of inhaled beta agonist >1 time per week
12. Clinically significant gastrointestinal impairment that could interfere with drug absorption
13. Impaired hepatic function [aspartate amino transaminase (AST) and/or alanine amino transaminase (ALT) >2.0 x upper limit of normal range]
14. Impaired renal function [estimated glomerular filtration rate (eGFR) of <60ml/min] as determined by the four-variable Modification of Diet in Renal Disease (MDRD) equation, where serum creatinine (Scr) is expressed in mg/dl and age in years:
15. eGFR <60 ml/min
16. Hematocrit <35%
17. 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
18. Treatment with chronic systemic glucocorticoid therapy (more than 7 consecutive days in 1 month)
19. Treatment with lithium salts
20. History of alcohol or drug abuse
21. Treatment with any investigational drug in the 1 month preceding the study
22. Mental conditions rendering the subject unable to understand the nature, scope and possible consequences of the study
23. Inability to comply with the protocol, e.g., uncooperative attitude, inability to return for follow-up visits, and unlikelihood of completing the study

Contacts and Locations

Locations

United States, Tennessee

Vanderbilt University Medical Center

Nashville, Tennessee, United States, 37232

Sponsors and Collaborators

Vanderbilt University

National Heart, Lung, and Blood Institute (NHLBI)

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Investigators

• Principal Investigator: James M Luther, MD; Vanderbilt University Medical Center

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Ramirez CE, Shuey MM, Milne GL, Gilbert K, Hui N, Yu C, Luther JM, Brown NJ. Arg287Gln variant of EPHX2 and epoxyeicosatrienoic acids are associated with insulin sensitivity in humans. Prostaglandins Other Lipid Mediat. 2014 Oct;113-115:38-44. doi: 10.1016/j.prostaglandins.2014.08.001. Epub 2014 Aug 28.

Luther JM, Byrne LM, Yu C, Wang TJ, Brown NJ. Dietary sodium restriction decreases insulin secretion without affecting insulin sensitivity in humans. J Clin Endocrinol Metab. 2014 Oct;99(10):E1895-902. doi: 10.1210/jc.2014-2122. Epub 2014 Jul 16.

Brown JM, Williams JS, Luther JM, Garg R, Garza AE, Pojoga LH, Ruan DT, Williams GH, Adler GK, Vaidya A. Human interventions to characterize novel relationships between the renin-angiotensin-aldosterone system and parathyroid hormone. Hypertension. 2014 Feb;63(2):273-80. doi: 10.1161/HYPERTENSIONAHA.113.01910. Epub 2013 Nov 4.

• Responsible Party: James Matt Luther, Assistant Professor of Medicine, Vanderbilt University
• ClinicalTrials.gov Identifier: NCT00732160
• Other Study ID Numbers: 080248
• First Posted: August 11, 2008
• Results First Posted: April 6, 2017
• Last Update Posted: April 6, 2017
• Last Verified: February 2017

Keywords provided by James Matt Luther, Vanderbilt University:

Glucose; Insulin