Endocrine Abstracts

JOINT1985

Introduction: Maturity-onset diabetes of the young (MODY) comprises a heterogeneous group of monogenic diabetes often misclassified as type 1 or type 2 diabetes. We describe a case of ABCC8-Mody with an atypical course and unexpected non-responsiveness to high-dose sulfonylurea therapy.

Case description: A 12-year-old girl initially presented at 8 years of age with polyuria, polydipsia, and weight loss. She had normal weight (10^th percentile), and a BMI of 12 kg/m² with early puberty (Tanner stage II) and no signs of insulin resistance. Laboratory tests revealed severe hyperglycemia (29 mmol/l), normal pH (7. 37), mild-to-moderate ketonuria (+1–2), and HbA1c of 14%. She was diagnosed with new-onset type 1 diabetes (T1DM) and started intensive insulin therapy. During follow-ups, her diagnosis was reconsidered as a detailed family history uncovered early-onset diabetes in three maternal uncles and her grandmother, along with hyperinsulinism in her younger brother—who had a confirmed ABCC8 mutation and underwent near-total pancreatectomy. Her insulin requirements were lower than expected (0. 6 – 0. 7 unit/kg/day at 10 months post-diagnosis) with an HbA1c of 8. 3%. Further evaluation showed mild positive insulin autoantibodies (0. 7 U/ml, cutoff <0. 4) while glutamic acid decarboxylase, zinc transporter 8, and islet cell antibodies were negative. Whole exome sequencing confirmed a pathogenic heterozygous autosomal dominant ABCC8 mutation, consistent with MODY 12. Given the typical sulfonylurea responsiveness in ABCC8-MODY, an inpatient trial of high-dose glibenclamide was initiated and titrated over 8 days to 2 mg/kg/day. However, she continued to require frequent insulin corrections (up to 1 unit/kg/day). After 3 days at the maximum dose, the trial was deemed unsuccessful. Over the subsequent year, her insulin needs increased to 1. 8 IU/kg/day (65% basal) amid factors such as pubertal insulin resistance, menarche, and insulin omission from diabetes burnout and psychosocial challenges. Her glycemic control deteriorated with HbA1c reaching to 10. 5%, compounded by an episode of severe diabetic ketoacidosis due to insulin omission. Emerging evidence supporting GLP-1 receptor agonists in ABCC8-MODY prompted a trial of liraglutide, which improved her time in range by 60% and allowed insulin dose reduction within 6 weeks. Gastrointestinal side effects led to a switch to weekly Semaglutide. Repeat autoantibody testing returned negative.

Discussion: This case underscores the management complexities of ABCC8-MODY in the presence of autoimmune positivity. The failure of sulfonylurea therapy suggests that autoimmunity may alter the therapeutic response, while GLP-1 receptor agonists show promise as an adjunct therapy in such complex cases.