Endocrine Abstracts

JOINT1295

Introduction: Maturity-Onset Diabetes of the Young (MODY), is a rare monogenic form of diabetes mellitus, comprising 1-2% of cases. Disguised by its atypical clinical features, it is commonly misdiagnosed, with an estimated 80% of MODY patients presumed to have type 1 (T1DM) or type 2 diabetes (T2DM). We hereby present a unique case of MODY, diagnosed in adulthood due to an inactivating mutation of the ABCC8 gene, with no history of neonatal hypoglycaemia, and a lack of clinical response to sulfonylureas.

Case Report: A 22-year-old female was incidentally diagnosed with diabetes in 2017 after presenting with lower abdominal pain and symptoms of urinary tract infection. Urinalysis showed significant glucosuria. She lacked osmotic symptoms, and never experienced diabetic ketoacidosis. She was presumed to have T2DM. Initially treated with gliclazide and metformin, gliclazide was discontinued due to lack of clinical response, and replaced with metformin/empagliflozin combination therapy. She was referred to our pre-pregnancy clinic in 2024. Her BMI was 25 kg/m², and HbA1c was 69 mmol/mol. Her atypical presentation, lack of insulin resistant features, and strong family history, prompted MODY probability testing, predicting 75%. T1DM serology, including GAD, IA2, and ZnT8 autoantibodies, was negative. C-peptide was 357pmol/l. Subsequent genetic testing identified a heterozygous inactivating ABCC8 mutation, p.Arg1353His (c.4058G>A), previously associated with Congenital Hyperinsulinism (CHI). The patient has no medical history of neonatal hypoglycaemia.

Discussion: The genes commonly associated with MODY include HNF1A, HNF4A, and GCK. While GCK-MODY and HNF1A-MODY account for 90% of cases, ABCC8-MODY makes up only 1%. The ABCC8 gene encodes Sulfonylurea receptor 1, a subunit of K-ATP channels in β-cells, modulating insulin release. Activating ABCC8 mutations are associated with Neonatal Diabetes and MODY. Inactivating ABCC8 mutations typically cause CHI. Only a handful of cases have reported inactivating ABCC8 mutations causing MODY, with even fewer being unresponsive to sulfonylureas. Gliclazide therapy proved unsuccessful, with her HbA1c reaching 97 mmol/mol, and the development of symptoms suggesting peripheral neuropathy. A trial of metformin/empagliflozin significantly reduced HbA1c, suggesting alternative therapeutic pathways may be necessary for cases involving inactivating ABCC8 mutations. To our knowledge, this is the first reported case linking this specific mutation to diabetes demonstrating a poor response to sulfonylureas. This case highlights the phenotypic heterogeneity of ABCC8-MODY, underscoring the importance of genetic testing in young patients with atypical diabetes presentations. It should inform future research into the precise pathophysiological mechanisms linking inactivating ABCC8 mutations to diabetes and their variable treatment responses.