When hyperglycemia is not type 2 diabetes: A case report of diagnostic challenges in immune checkpoint inhibitor-associated diabetes

Introduction: Immune checkpoint inhibitors (ICIs) have improved outcomes across multiple malignancies but are associated with immune-related adverse events affecting diverse organ systems. Immune checkpoint inhibitor-induced diabetes mellitus is a rare endocrine toxicity characterized by abrupt pancreatic β-cell destruction and rapid onset insulin deficiency. Because the presentation may mimic new-onset type 2 diabetes, delayed recognition may occur, particularly outside oncology settings. Case Report: A 48-year-old female with T2N0M0 triple-negative breast cancer has undergone chemoimmunotherapy with Pembrolizumab every three weeks and Paclitaxel/Carboplatin weekly for 12 weeks. Two weeks later, she presented for her second phase of chemoimmunotherapy with Pembrolizumab, Doxorubicin, and Cyclophosphamide to be administered every three weeks. Pre-infusion laboratory testing revealed severe hyperglycemia with serum glucose of 489 mg/dL. Urinalysis demonstrated marked glucosuria and ketonuria. The patient was referred to the emergency department for evaluation and treatment. She received intravenous (IV) fluids and insulin, resulting in a significant reduction in blood glucose to 203. The patient was discharged with metformin therapy and outpatient follow-up. Subsequent evaluation revealed hemoglobin A1C of 10%, increased from 5.9% two months earlier, and a markedly suppressed C-peptide level of 0.1 ng/mL, indicating severe insulin deficiency. The patient was referred to endocrinology for lifelong insulin management. Follow-up HbA1C three months later improved from 10 to 7.6. The patient was maintained on long-acting insulin Glargine, short-acting insulin for meals, and Metformin. The rapid transition from normoglycemia to severe hyperglycemia, presence of ketosis, and profound insulin deficiency were consistent with immune checkpoint inhibitor-associated diabetes. Initial management focused on treatment of hyperglycemia rather than recognition of immune-mediated β-cell destruction. This case illustrates the diagnostic challenges that may arise when patients receiving immunotherapy present in non-oncology clinical environments. Conclusion: Immune checkpoint inhibitor-associated diabetes is an uncommon but potentially life-threatening complication of programmed cell death protein-1 (PD-1) blockade therapy. Increased awareness and structured evaluation of hyperglycemia in patients receiving immunotherapy may facilitate earlier diagnosis and appropriate management.