The goal of this study is to learn how two treatments-adrenalectomy (surgical removal of an adrenal gland) and semaglutide (a medication used for weight management)-affect insulin resistance and cortisol regulation in adults with mild autonomous cortisol secretion (MACS). The study will also learn how these treatments impact body composition, blood pressure, cholesterol, inflammation, muscle strength, and quality of life.
The main questions the study aims to answer are:
1. Does adrenalectomy or semaglutide improve insulin resistance more in people with MACS? 2. How do these treatments change cortisol patterns and other cardiometabolic risk factors? 3. Do people with MACS respond differently to semaglutide compared to matched adults without MACS?
Participants will:
1. Receive either adrenalectomy or semaglutide if they have MACS, or semaglutide if they are matched controls 2. Complete clinic visits and phone visits over about 26-30 weeks 3. Undergo metabolic testing such as blood tests, urine steroid profiling, body composition scans, blood pressure monitoring, muscle strength testing, and questionnaires about health and well-being
Adults ≥18 years
MACS groups: adrenal adenoma + DST cortisol >1.8 µg/dL + no overt Cushing + eligible for adrenalectomy
Willingness to postpone surgery 6 months if randomized
Controls: no adrenal abnormalities + normal DST + BMI ≥27 + ≥2 cardiometabolic conditions
Prior GLP-1 RA within 90 days
Weight change >5 kg in past 90 days
Prior obesity/diabetes surgery
Type 1 diabetes or other diabetes types
Parallel
Intervention 1: Adrenalectomy
Procedure/SurgerySurgical removal of one adrenal gland performed by an endocrine surgeon following institutional standard-of-care practices. Includes postoperative monitoring for adrenal insufficiency and routine clinical follow-up.
Intervention 2: Semaglutide
DrugOnce-weekly subcutaneous semaglutide administered according to FDA-approved titration for chronic weight management (0.25 mg to 2.4 mg weekly as tolerated). Participants receive training on injection technique, dose escalation, and safety monitoring.
Change in Insulin Sensitivity (M-value), mg/kg/min
Hyperinsulinemic-euglycemic clamp
Change in fasting plasma glucose, mg/dL
Change in hemoglobin A1C, %
fasting blood test
Change in fasting insulin, µU/mL
Fasting blood test
Change in glucagon, pg/mL
Fasting blood test
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University of Texas Southwestern Medical Center
Lead sponsor
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Collaborator
