MON-423 - Type 1 Diabetes Mellitus Unmasked by Teprotumumab in Autoimmune Polyglandular Syndrome Type 4

Background: Teprotumumab, an insulin-like growth factor-1 receptor inhibitor indicated for treatment of thyroid eye disease (TED), improves proptosis and inflammatory manifestations but can cause hyperglycemia as adverse event in 5–12% of patients. New-onset diabetes mellitus appears to be uncommon, and cases of type 1 diabetes mellitus (T1DM) have not been reported. We describe a case of T1DM unmasked following teprotumumab therapy.

Case: A 66-year-old woman with rheumatoid arthritis, Graves’ disease (post-radioactive iodine and thyroidectomy), and a three-year history of diabetes developed progressive thyroid eye disease from 2022 to 2025. Teprotumumab was initiated in August 2025, leading to early improvement in proptosis but marked hyperglycemia (glucose 250–300 mg/dL, time-in-range 5% from 70% prior to treatment), requiring increased basal and prandial insulin. HbA1c rose from 7.3% to 10.4% after six infusions. Evaluation revealed low C-peptide (0.48 ng/mL; RR 0.8–3.5) with positive GAD, ZnT8, and islet cell antibodies, consistent with T1DM. Additional testing showed pernicious anemia and hypoparathyroidism, suggesting autoimmune polyglandular syndrome (APS) type 4.

Discussion: Teprotumumab primarily worsens hyperglycemia in patients with prediabetes or type 2 diabetes, occasionally causing severe presentations such as hyperglycemic hyperosmolar state or diabetic ketoacidosis. New-onset diabetes is uncommon; in trials, about one-third of patients with hyperglycemia had no prior glucose intolerance. There is no evidence linking teprotumumab to autoimmune β-cell destruction or T1DM, as it mainly induces insulin resistance via IGF-1 receptor blockade, enhancing growth hormone signaling and hepatic glucose production.

In contrast, patients with Graves’ disease have a 3–4-fold increased risk of developing T1DM, either as an isolated autoimmune condition or as part of autoimmune polyglandular syndrome (APS). APS type 4 involves multiple autoimmune endocrine disorders, as seen in our patient with pernicious anemia, hypoparathyroidism, Graves’ disease, and T1DM. Although 36.4% of patients with treatment-related hyperglycemia return to baseline after discontinuation, those with T1DM require ongoing insulin therapy, often at lower doses.

Conclusion: Although teprotumumab does not directly induce T1DM, its insulin-resistance effects may unmask insulin deficiency in susceptible individuals. Clinicians should suspect T1DM in patients with severe or rapidly progressive hyperglycemia during therapy, especially those with autoimmune disease. Baseline and serial glucose monitoring, with targeted autoantibody and C-peptide testing, may allow timely diagnosis and management.

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