Exploring Pathophysiology and Treatment Approaches in Mild Autonomous Cortisol Secretion

Ut Southwestern Medical Center, Dallas TX

Investigators

Linked publications, trials & patents

Abstract

PROJECT SUMMARY / ABSTRACT TITLE: Exploring Pathophysiology and Treatment Approaches in Mild Autonomous Cortisol Secretion Adrenal tumors are found in ~5% of the adult population and up to 20% of patients with obesity, diabetes, and hypertension. Most of these comprise adrenal cortical adenoma. Mild Autonomous Cortisol Secretion (MACS) is a prevalent condition, defined as failure to suppress cortisol ≤1.8 mcg/dL after a 1-mg dexamethasone suppression test. MACS is usually discovered during biochemical workup of incidental adrenal tumor. MACS is linked with weight gain, hypertension, impaired glucose metabolism, insulin resistance (IR), nearly 3-fold increase in cardiovascular events, and more than 10-fold increase in mortality. MACS has a well-established association with IR. However, the pathophysiologic link between MACS and IR remains incompletely characterized. Some studies show that IR, hyperinsulinemia, and the anabolic effects on adrenal tissue, which has insulin-like growth factor (IGF)-1, IGF-2, and insulin receptors, offer possible pathophysiological links. Other studies conclude the inverse pathway – that dysregulated cortisol secretion in MACS elicits excess adiposity and IR. Adrenalectomy is the only available treatment option for MACS, but it leads to inconsistent outcomes. To date, there is no prospective data comparing adrenalectomy to pharmacological weight loss and its effects on IR and dysregulated cortisol secretion in MACS. Further investigation into the relationship of the “adrenal-insulin axis”, and how cortisol and IR relate to one another, is urgently needed. Tirzepatide, a novel dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, is the most effective FDA-approved agent for treatment of obesity (with or without diabetes). We hypothesize that weight loss with tirzepatide will improve IR, but weight loss will not normalize dysregulated cortisol secretion. To directly test this, we will conduct a pilot randomized trial to compare the effect of adrenalectomy vs weight loss with tirzepatide on IR, steroid profile, body composition, muscle strength, and cardiometabolic profile in patients with MACS. We will also perform a prospective interventional case-control study to compare the effect of tirzepatide on weight loss, body composition, and cardiometabolic changes in patients with MACS vs matched controls following 6-month treatment. The studies proposed in this K23 proposal will provide valuable insights into the pathophysiology of MACS, and in turn identify better treatment strategies. In parallel, the proposal will allow me to get in-depth training in assessing cardiometabolic and adrenal metabolome outcomes in patients with MACS, skills necessary to achieve my long-term career goal of becoming an independent clinical investigator and leader in adrenal disorders. This proposal builds on my prior clinical and research experience and leverages a strong mentorship team that is invested in my professional development. My 5-year training and mentoring plan includes formal coursework, professional development, and mentored research, with defined milestones to ensure productivity, progress, and successful transition to investigational independence.