A Case of Acute Severe Insulin Resistance and Fulminant Type 1 Diabetes after Immune Checkpoint Blockade Cancer Therapy

Presentation Number: MON 609
Date of Presentation: April 3rd, 2017

Janet Yi Man Lee*1, Jeremy T Warshauer1, Lisa Katherine Gilliam2, Jennifer Park-Sigal1, Elizabeth J Murphy1 and Mark Stuart Anderson3
1University of California, San Francisco, San Francisco, CA, 2Kaiser Permanente, South San Francisco Medical Center, South San Francisco, CA, 3University of California at San Francisco, San Francisco, CA


Background: Immune checkpoint inhibitors are promising therapies for unresectable metastatic melanoma and other cancers (1). Anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed death 1 (PD-1) checkpoint inhibitors are being approved for a growing number of malignancies, and with this rise in use, resultant autoimmune endocrinopathies such as thyroid dysfunction, hypophysitis, adrenalitis, and type 1 diabetes have also emerged (2,3). We describe a case of severely insulin resistant autoimmune diabetes following recent treatment of metastatic melanoma with the PD-1 checkpoint inhibitor pembrolizumab.

Clinical Case: An 84 yr old man with impaired glucose tolerance on metformin (HbA1c 5.7% 4 days prior to admission) and stage 4 melanoma on pembrolizumab (2 mg/kg given 1 month and 4 days prior to admission) was admitted with altered mental status. His initial labs of blood glucose (BG) 1076 mg/dl, pH 6.8, β-hydroxybutyrate 4.92 mM (nl <0.28), Cr 2.12 mg/dL (nl 0.7-1.30) revealed DKA and acute kidney injury. He was resuscitated aggressively with intravenous (IV) fluids and insulin infusion per DKA protocol.

However, he remained extremely hyperglycemic (BG 800-900 mg/dL) requiring upward titration of the insulin to 800 units/h. Given concerns that he had type B insulin resistance due to pembrolizumab, he was given IV methylprednisolone 1g 12h after admission and on hospital day (HD) 2, followed by dexamethasone 40mg on HD 3. After the first dose of methylprednisolone, his BG levels dropped precipitously and continued to fall after discontinuation of his insulin infusion (total 5,500 units in first 24h), necessitating 20% dextrose infusion for > 24h to maintain euglycemia.

He had positive GAD65 antibodies at 115 IU/mL (nl 0-5.0) and negative ZnT8 and IA-2 antibodies. C-peptide levels were low at 0.1 ng/mL with BGs >200 mg/dL.

He was gradually tapered off steroids and transitioned to a subcutaneous insulin regimen. When he was discharged on HD 11, he required only 20 units of insulin/day with BGs 100-200 mg/dL. C-peptide level was <0.5 ng/mL with BG 113 mg/dL 6 weeks after presentation. The patient was ultimately diagnosed with fulminant type 1 diabetes, as well as type B (autoimmune) insulin resistance, attributed to suspected antibodies to the insulin receptor (to be measured), with no further pembrolizumab treatment planned.

Conclusions: This is the first case of type B (autoimmune) insulin resistance in combination with fulminant autoimmune beta-cell destruction associated with pembrolizumab, an immune checkpoint inhibitor. The patient responded to high dose glucocorticoids, although plasmapheresis, cyclophosphamide, and rituximab were also considered (4). Immunologic studies will need to be undertaken to understand how immunotherapy induces autoimmune endocrinopathies in certain individuals and to better elucidate risk factors for this potentially fatal complication.


Nothing to Disclose: JYML, JTW, LKG, JP, EJM, MSA