Immune Checkpoint Inhibitor-Associated Insulin-Deficient Diabetes Presenting With Severe Diabetic Ketoacidosis During Pembrolizumab Therapy: A Case Report

Immune checkpoint inhibitor-associated diabetes mellitus (ICI-DM) is a rare but potentially life-threatening immune-related adverse event, most commonly associated with programmed cell death protein 1 (PD-1) inhibitors. It is characterized by abrupt and often irreversible β-cell failure, frequently presenting with diabetic ketoacidosis (DKA). Early recognition is challenging because symptoms may be nonspecific and islet autoantibodies may be absent. We report the case of a 62-year-old man with stage IV BRAF V600E-positive metastatic melanoma who developed polyuria, polydipsia, nausea, vomiting, and rapid weight loss approximately 10 days after his third pembrolizumab infusion. He presented with severe DKA, including a glucose level of 658 mg/dL, arterial pH of 7.02, bicarbonate of 6 mmol/L, anion gap of 32 mEq/L, and β-hydroxybutyrate of 7.2 mmol/L. C-peptide was undetectable (<0.1 ng/mL), while GAD65, IA-2, ZnT8, and islet cell antibodies were negative. Pancreatic enzymes and imaging were unremarkable, and no alternative cause of insulin deficiency was identified. He responded promptly to standard DKA management with intravenous fluids, insulin, and electrolyte replacement and was subsequently transitioned to lifelong basal-bolus insulin therapy. C-peptide remained undetectable at 6 months, while HbA1c improved from 8.9% to 6.8% and time in range reached 82%. Pembrolizumab was permanently discontinued following multidisciplinary assessment. ICI-associated diabetes requires early recognition, prompt DKA management, and lifelong insulin therapy. Future research should identify predictive genetic and immunologic biomarkers, optimize glucose and ketone surveillance, clarify mechanisms of β-cell destruction, and establish safe strategies for continuing or rechallenging immunotherapy.