SAT-541 - When Common Is Not as It Seems: A Unique Case of GCK-MODY with Concurrent Check Point Inhibitor Therapy-Induced Autoimmune Diabetes

Background: Glucokinase-Maturity Onset Diabetes of the Young (GCK-MODY) is typically characterized by mild fasting hyperglycemia, does not traditionally require treatment, and is inherited in an autosomal dominant manner . Concurrent occurrence of common type 1 or type 2 diabetes has been described that can modify course and cause departure from the benign course. Here we describe a case of GCK-MODY compounded by occurrence of diabetes related to check-point inhibitor use.
Clinical

Case: A 37-year-old non-Hispanic White woman with Turkish descent with history of triple-negative metastatic carcinoma of the left breast was seen for uncontrolled diabetes. She was status post left mastectomy, neoadjuvant chemotherapy (paclitaxel, carboplatin), and immune checkpoint inhibitor pembrolizumab treatment. Although diabetes was diagnosed formally in the United States at initiation of chemotherapy with hemoglobin A1c levels of 7.6% and 7.5% and a blood glucose level of 197 mg/dL, she was told she had diabetes at least 6 years prior to this date while living abroad. She started insulin due to hyperglycemia in the 200-400 mg/dL range during and after chemotherapy. C-peptide level was 3.0 ng/mL with a corresponding glucose of 182 mg/dL and a GAD 65 autoantibody of 0.0 at initiation of insulin therapy. During month three of immunotherapy, she developed colitis and pancreatitis and experienced refractory hyperglycemia. She was found to have insulin deficiency with a C-peptide < 0.1 ng/mL and concurrent glucose in the 150s two years later (repeat GAD 65, IA-2, and ZnT8 antibody negative). She has been managed with insulin basal+bolus therapy exceeding 200 units daily and not achieving fasting glucose levels at goal (>140 mg/dL) and HbA1c exceeding 7.5%. She noted substantial weight gain (>40 lbs) with ever increasing insulin doses and was often blamed with nonadherence and dietary indiscretion. After she was evaluated in our atypical diabetes program, a decision to obtain genetic testing was made due to three generations of persistent early onset diabetes (before age 30 ) on her maternal side. Genetic testing revealed a pathogenic heterozygous variant in GCK c.469G>A(p. Glu157Lys). Family segregation studies and cascade have not yet been performed since most of her relatives reside in Turkey. Our patient felt validated upon learning of her genetic defect which is compounded with exposure to immune checkpoint therapy and ensuing autoimmune pancreatitis.

Conclusions: Despite known environmental and drug exposures that can lead to pancreatic beta cell failure, paying close attention to historical details and time course of hyperglycemia as well as familial patterns can provide rationale to proceed with genetic testing for monogenic forms of diabetes. In this informative case, setting treatment goals and avoiding over-use of insulin may help ease the difficulty of weight management.

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