SAT-550 A Hidden Culprit: Insulinoma Masquerading as GLP-1 Agonist-Induced Hypoglycemia

Abstract Disclosure: A.K. Jain: None. T. Amin: None. K. Chalasani: None. S.W. Holland: None. Introduction: Hypoglycemia in non-diabetic individuals is a diagnostic challenge that needs thorough evaluation to distinguish between endogenous and exogenous causes. Dual GIP/GLP-1 (glucose-dependent insulinotropic peptide / glucagon-like peptide-1) receptor co-agonists like tirzepatide have been associated with hypoglycemia, particularly in patients on concomitant insulin or sulfonylureas. However, in the absence of these agents, persistent hypoglycemia warrants further investigation. Insulinoma, a rare neuroendocrine tumor, is a critical consideration in cases of endogenous hyperinsulinism. Here we present a case of recurrent hypoglycemia initiated by tirzepatide use that was ultimately diagnosed to be an insulinoma. Case Presentation: A 56-year-old female with seizure disorder on daily lacosamide and levetiracetam presents for recurrent hypoglycemia throughout the day detected on continuous glucose monitoring (CGM). She has no history of diabetes. Her PCP prescribed tirzepatide for weight loss (starting at 2.5 mg weekly, increased to 5 mg). Within five weeks, she was admitted for severe hypoglycemia (28 mg/dL) following confusion at work. Initial thyroid, cortisol, and levetiracetam levels were normal. Hypoglycemia resolved with IV dextrose. Given no other changes, hypoglycemia was attributed to tirzepatide use and was discontinued. Severe recurrent hypoglycemia, especially fasting levels in the morning, prompted admission for a 72-hour fast. Within 12 hours, patient experienced symptomatic hypoglycemia at 45 mg/dL, with insulin 4.5 µU/mL, proinsulin 5.8 pmol/L, and β-hydroxybutyrate 0.23 mmol/L, indicating inappropriate insulin secretion. CT imaging showed a 1.1 cm lesion in the pancreatic tail, and further evaluation (PET-CT, endoscopic ultrasound) is planned, with surgery as the next step. Discussion: Tirzepatide, a dual GIP/GLP-1 receptor co-agonist, is used for type 2 diabetes and obesity due to its ability to enhance insulin secretion, promote satiety, and improve glycemic control. If a patient is unknowingly already harboring an insulinoma, the added insulinotropic effects of the GIP/GLP-1 agonist might intensify hypoglycemic episodes. This effect is thought to result from GIP/GLP-1 agonists stimulating insulin release from pancreatic beta cells, potentially causing excessive insulin production and overwhelming the body’s compensatory mechanisms. Conclusion: This case highlights how GLP-1 agonists can unmask insulinoma-related hypoglycemia and underscores the importance of considering insulinoma in the differential diagnosis during GLP-1 therapy. Early recognition and careful evaluation of unexplained hypoglycemia are key to preventing life-threatening complications. Presentation: Saturday, July 12, 2025