Glucose Metabolism in Subjects With Aldosterone-Producing Adenomas

This observational study tests the hypothesis that endogenous aldosterone impairs insulin secretion and insulin sensitivity in subjects with primary aldosteronism.

Study Overview

• Status: Completed
• Conditions: Primary Aldosteronism
• Intervention / Treatment: Other: Adrenalectomy; Drug: mineralocorticoid receptor antagonist

Detailed Description

The week of each study period, subjects will be provided a standard 160mmol/d sodium diet for 6-8 days to control for inter-individual sodium intake.

In period 1, subjects will report after 5 days of controlled sodium diet for a hyperglycemic clamp study (to measure insulin secretion). Subjects will continue the study diet, and then return for a hyperinsulinemic-euglycemic clamp study (to measure insulin sensitivity).

After completion of period 1 assessment, subjects will undergo adrenalectomy by our endocrine surgeons or initiate medical treatment, according to routine clinical care.

In period 2, the investigators will repeat the studies in the same manner as period 1, 3 to 12 months after adrenalectomy or initiation of medical treatment.

• Study Type: Observational
• Enrollment (Actual): 10

Contacts and Locations

Study Locations

• United States
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

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

2. 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 on every study day.

3. Primary aldosteronism determined by both:

   • Biochemical hyperaldosteronism defined as either:

     1. Plasma aldosterone ≥15 ng/dL
     2. or aldosterone-to-renin ratio of ≥30 if on ACE inhibitor
     3. or aldosterone-to-renin ratio of ≥40 in absence of an ACE inhibitor

   • Positive suppression test defined as either:

     1. failure to suppress aldosterone to <7ng/dL after intravenous 0.9% saline infusion over 2 hours
     2. failure to suppress 24-hour urinary aldosterone excretion to <12 µcg with simultaneously documented urine sodium excretion >200 mmol.

Exclusion Criteria:

- Subjects presenting with any of the following will not be included in the study:

1. Previously diagnosed type 1 Diabetes

2. Type II Diabetes, as defined by ADA criteria:

   • Hemoglobin A1C ≥6.5%
   • Fasting plasma glucose ≥126mg/dl (7.0mmol/l)
   • 2-hour 75g oral glucose tolerance test (OGTT) plasma glucose ≥200mg/dl (11.1 mmol/l) d. Current treatment with anti-diabetic medication(s)
3. Impaired renal function [estimated glomerular filtration rate (eGFR) of <30ml/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.
4. Prior allergies to medications used in the study protocol (e.g. L-arginine, potassium chloride, insulin), or to drugs within the same class.
5. Screening plasma potassium >5.5 mmol/L or sodium <135 mmol/L
6. Cardiovascular disease such as recent (<6 months) 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
7. Breast-feeding
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. Hematocrit <35%
15. 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
16. Treatment with chronic systemic glucocorticoid therapy (more than 7 consecutive days in 1 month)
17. Treatment with lithium salts
18. History of alcohol or drug abuse
19. Treatment with any investigational drug in the 1 month preceding the study
20. Mental conditions rendering the subject unable to understand the nature, scope and possible consequences of the study
21. Inability to comply with the protocol, e.g., uncooperative attitude, inability to return for follow-up visits, and unlikelihood of completing the study

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Adrenalectomy; Subjects will undergo assessment before and after adrenalectomy for treatment of primary aldosteronism	Other: Adrenalectomy; Adrenalectomy for treatment of primary aldosteronism, according to standard of care
Medical Therapy; Subjects will undergo assessment before and after medical treatment of primary aldosteronism	Drug: mineralocorticoid receptor antagonist; Subjects will be treated with a mineralocorticoid receptor antagonist according to standard of care; Other Names: spironolactone; eplerenone

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Acute Glucose-stimulated Insulin Secretion	measured by hyperglycemic clamp	Change from Baseline vs. 3-12 months after intervention
Change in Insulin Sensitivity Index	measured by hyperinsulinemic-euglycemic clamp	Change from Baseline vs. 3-12 months after intervention
Change in Disposition Index (product of Insulin sensitivity index and acute insulin secretion)	Product of insulin sensitivity and insulin secretion	Change from Baseline vs. 3-12 months after intervention

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Suppression of Hepatic glucose production	suppression of hepatic glucose production during hyperinsulinemic clamp, determined using glucose tracer	Change from Baseline vs. 3-12 months after intervention

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Urinary exosomal biomarkers	Urinary biomarkers of renal sodium channels and sodium transporters	Change from Baseline vs. 3-12 months after intervention
Associative learning Memory testing	Associative learning task matching images and words	Change from Baseline vs. 3-12 months after intervention

Collaborators and Investigators

• Sponsor: Vanderbilt University
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); Brigham and Women's Hospital

Publications and helpful links

General Publications

• Luther JM, Wei DS, Ghoshal K, Peng D, Adler GK, Turcu AF, Nian H, Yu C, Solorzano CC, Pozzi A, Brown NJ. Treatment of Primary Aldosteronism Increases Plasma Epoxyeicosatrienoic Acids. Hypertension. 2021 Apr;77(4):1323-1331. doi: 10.1161/HYPERTENSIONAHA.120.14808. Epub 2021 Feb 15.
• Adler GK, Murray GR, Turcu AF, Nian H, Yu C, Solorzano CC, Manning R, Peng D, Luther JM. Primary Aldosteronism Decreases Insulin Secretion and Increases Insulin Clearance in Humans. Hypertension. 2020 May;75(5):1251-1259. doi: 10.1161/HYPERTENSIONAHA.119.13922. Epub 2020 Mar 16.

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2015
• Primary Completion (Actual): January 1, 2020
• Study Completion (Actual): January 1, 2020

Study Registration Dates

• First Submitted: February 5, 2015
• First Submitted That Met QC Criteria: February 11, 2015
• First Posted (Estimate): February 12, 2015

Study Record Updates

• Last Update Posted (Actual): May 4, 2021
• Last Update Submitted That Met QC Criteria: April 28, 2021
• Last Verified: April 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Endocrine System Diseases; Adrenocortical Hyperfunction; Adrenal Gland Diseases; Adenoma; Hyperaldosteronism; Physiological Effects of Drugs; Antihypertensive Agents; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Natriuretic Agents; Diuretics; Hormone Antagonists; Diuretics, Potassium Sparing; Spironolactone; Mineralocorticoid Receptor Antagonists; Eplerenone; Mineralocorticoids
• Other Study ID Numbers: 141553; R01DK096994 (U.S. NIH Grant/Contract)