Abstract
Background: Autoimmune diabetes mellitus (CPI-DM) caused by immune checkpoint inhibitors (CPIs) is rare- occurring in approximately one percent of patients exposed to this form of cancer immunotherapy. Typically, this immune related adverse event occurs after treatment with PD-1/PD-L1 inhibitors. It is characterized by abrupt insulinopenia leading to acute hyperglycemia. Beta cell autoantibodies are positive in approximately half the cases. DKA is common at the time of diagnosis. Recovery of beta cell function has been reported in only two case reports. In one case, spontaneous resolution occurred following cessation of CPI therapy and in the other the patient was treated with infliximab for concurrent inflammatory arthritis prior to resolution of CPI-DM.
Clinical Case: A 50-year-old woman was started on adjuvant pembrolizumab for stage IIIC melanoma following surgery. She had no prior history of diabetes mellitus, thyroid disease, or other autoimmune disease. Pre-infusion random blood glucoses (RBG) were 84 - 105 mg/dL. After 36 weeks, she developed hypothyroidism (TSH 17.5 (0.5-4.1 mIU/L), FT4 6 (10-18 ug/dL)) and started levothyroxine. Pembrolizumab was continued. For nine weeks following her diagnosis with CPI- hypothyroidism, her pre-infusion RBG ranged from 102-133. At 45 weeks (15 cycles) after initiating pembrolizumab, her RBG was 260. She was not on glucocorticoids and had no other signs of inflammation or stress. Pembrolizumab was continued. Just prior to her 17th cycle, 48 weeks after initiating adjuvant pembrolizumab, her RBG was 482 with a normal anion gap and HCO3, and her A1c was 8.9%. Her last dose of pembrolizumab was held. She started metformin and liraglutide. In just three weeks, a random c-peptide was inadequate at 1.7 (0.8-3.5 ng/mL) with a recent RBG of 220 and A1c of 10.3%, showing the acuity and extremity of her hyperglycemia. Over the course of the year, she has achieved excellent glucose control (A1c 6.3-7.1) on this regimen with preservation of insulin production (c-peptides 1.4-1.8 with matched RBG 92-129). She never required insulin. Her beta cell autoantibodies are negative.
Clinical Lessons: This is a case of CPI-DM in which the patient did not have complete loss of beta-cell function. The acuity of her hyperglycemia is not consistent with new onset type 2 diabetes. At diagnosis, her c-peptide was inadequate suggesting insufficient insulin production rather than insulin resistance. Therefore, her hyperglycemia is more consistent with CPI-DM than type 2 diabetes. Atypically, she did not progress to fulminant beta cell failure, which could have been due to cessation of pembrolizumab (which is not unique to this case), initiation of liraglutide and metformin, or other unknown immunologic responses that inhibited full beta cell loss. This case raises the possibility of preventing fully insulin dependent CPI-DM if hyperglycemia is caught and treated early.
Decreased TCF7L2 protein levels in type 2 diabetes mellitus correlate with downregulation of GIP- and GLP-1 receptors and impaired beta-cell function
