SAT-214 - GCK-MODY with Significant Postprandial Hyperglycemia in A Transgender Male

Objective: GCK mutations are one of the most common causes of MODY. Most individuals are asymptomatic and present with incidental fasting hyperglycemia. They do not develop microvascular complications despite years of mild fasting hyperglycemia. Hence treatment is not recommended outside of pregnancy. GCK MODY typically does not lead to post prandial hyperglycemia. We present a case of transgender male with a novel GCK mutation that has not been previously reported and is associated with post prandial hyperglycemia.

Case: This is a 19 year old AFAB followed in endocrinology clinic for gender dysphoria. Initially presented as gender fluid around 13 years and had persistent male identity since age 15 years. Diagnosis of gender dysphoria was confirmed by mental health professional, and he was started on weekly SQ testosterone regimen at 16.5 years of age. Therapy monitoring labs obtained 6 months after initiation of testosterone showed HbA1c 5.5% and fasting glucose of 133 mg/dL. He did not have any symptoms of hyperglycemia. Patient's father and sibling had diagnosis of diabetes in their mid 20's. They were on treatment with oral agents but had opted not to follow up and discontinued therapy.

Our patient had a sensor placed which showed both fasting and post prandial hyperglycemia to greater than 200 mg/dL. Follow up HbA1c was 5.8%. Autoimmune markers for type 1 diabetes were negative. Testosterone dose was decreased due to risk of metabolic syndrome and type 2 DM. Blood sugars had continued to stay higher despite decrease in dose. Subsequently, he started to develop symptoms of headaches and dizziness with sensor readings >250 post meals. Patient was started on Glipizide which along with dietary changes led to improvement in blood sugars.
MODY gene panel obtained due to high suspicion based on the family history showed positive GCK mutation c.527C>A. This mutation has not been reported previously and hence got classified as VUS. Based on the clinical presentation and family history, this is believed to be pathogenic mutation. Testing for dad and sibling has been recommended to help with reclassifying this mutation.

Conclusion: GCK-MODY is asymptomatic and has been underdiagnosed for the same reason. The post prandial hyperglycemia would not be explained by GCK mutations but has been reported. In our patient, Glipizide was discontinued following these results. We suspect that the testosterone therapy in the setting of GCK mutation has also contributed to insulin resistance leading to significant postprandial hyperglycemia. It is unclear at this time on whether the phenotype of the novel mutation may lead to postprandial hyperglycemia in other individuals who are not at risk for insulin resistance. Treatment for MODY 2 perhaps with metformin (due to insulin resistance) will be indicated for our patient if he continues to have increase in blood sugars and HbA1c to prevent micro and macrovascular complications.

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