O-18 SUCCESSFUL ANTIHYPERGLYCEMIC AND WEIGHT LOSS EFFECTS OF TIRZEPATIDE IN A WOMAN WITH OBESITY AND GENETICALLY CONFIRMED TBC1D4 MUTATION

Abstract Introduction TBC1D4 encodes a protein that regulates GLUT4 translocation. Mutations in TBC1D4 are among the genetic variants associated with type 2 diabetes. In the presence of a TBC1D4 mutation, insulin-mediated glucose uptake into muscle is impaired, leading to prominent postprandial hyperglycemia. We present a female patient with obesity and type 2 diabetes carrying a TBC1D4 mutation. Clinical Case A 39-year-old woman presented with complaints of hyperglycemia and obesity. At the age of 23, during her first pregnancy in 2019, she was diagnosed with gestational diabetes and received insulin therapy. In her second and third pregnancies in 2013 and 2017, respectively, she also required insulin. Since the last pregnancy, she continued intensive insulin regimen together with vildagliptin, metformin, and dapagliflozin. In November 2024, her treatment was arranged as glargine/lixisenatide combination (30 units/10 mcg), glulisine (3×4unit),dapagliflozin 10 mg, pioglitazone 15 mg, and metformin 1000 mg. Physical examination revealed a height of 171 cm, body weight103.1 kg, and body mass index (BMI) of 35.3 kg/m²; apart from abdominal obesity, systemic examination findings were unremarkable. Laboratory evaluation showed HbA1c 10.7%, fasting blood glucose 308 mg/dL, negative anti-GAD and islet cell antibodies, and a C-peptide level of 2.14 ng/mL.Glargine/lixisenatide was adjusted as 40 units. Due to a family history of type 2 diabetes (mother and sibling) and her history of gestational diabetes, genetic testing for MODY was performed. Mutation analysis of 25 genes, including 14 known MODY-related genes, revealed no pathogenic variants in MODY genes; however, a likely pathogenic heterozygous mutation was detected in TBC1D4. Since fasting and postprandial hyperglycemia persisted, her regimen was adjusted to U300 glargine 40 units and insulin glulisine 3 × 4 units, with continuation of oral antidiabetic therapy. Despite this, she experienced persistent hyperglycemia and weight gain (body weight 107.8 kg, BMI 36.9 kg/m²). Her treatment was subsequently modified to subcutaneous U300 glargine 26 units, metformin 1000 mg twice daily, and subcutaneous tirzepatide 2.5 mg once weekly. After one month, the tirzepatide dose was increased to 5 mg weekly. She achieved a weight loss of 4.9 kg (BMI 35.2 kg/m²), with HbA1c reduced to 7.4% and fasting blood glucose to 168 mg/dL. Conclusion To the best of our knowledge, this is the first reported case in the literature of a patient with type 2 diabetes carrying a TBC1D4 mutation who achieved glycemic control with tirzepatide. Although tirzepatide does not correct the underlying pathophysiological mechanism caused by the TBC1D4 mutation, it contributed to glycemic control through mechanisms such as increased insulin secretion, delayed gastric emptying leading to reduced postprandial hyperglycemia, glucagon suppression, and weight loss with improvement in insulin sensitivity in the liver and adipose tissue.