Endocrine Abstracts

Background: Maturity onset diabetes of the young (MODY) is characterized by autosomal dominant inheritance, onset before 25 years of age, absence of β-cell autoimmunity, and sustained pancreatic β-cell function. HNF1A mutations account for 70% of MODY cases. Patients with HNF1A MODY are sensitive to sulfonylureas (SU) and can maintain optimal glycaemic control with SU rather than insulin. We describe 2 siblings from the same family with HNF1A MODY and variable SU responses.

Cases Patient 1: This male patient of Sudanese origin was diagnosed with diabetes at 13 years of age in Sudan and commenced on insulin. A review in the UK (after family migration) revealed a strong family history of young-onset diabetes from the maternal side and no development of ketones or becoming unwell despite days without insulin. The C-Peptide was 1090pmol/l with negative diabetes auto-antibodies and a glycated haemoglobin (HbA1C) of 112 mmol/mol. He showed no clinical features of insulin resistance and BMI was 28 kg/m² (SDS: +2.01) Insulin was commenced and his HbA1C improved to 51 mmol/mol. Subsequent genetic testing confirmed MODY due to a pathogenic missense variant in HNF1A p.(Pro379Arg). Following this, his insulin was stopped and gliclazide commenced. Despite maximal dosing (80 mg BD) and ensuring compliance, the blood glucose (BG) showed no significant response (average BG:10-14 mmol/l) with deterioration of HbA1C (94 mmol/mol). Subsequently, his insulin has been restarted.

Patient 2: The 14 year old female sibling of patient 1, developed osmotic symptoms (polydipsia) and random BG testing both at home and with her GP was consistently high (13 mmol/l). She had an increased BMI of 47 kg/m² (SDS: +4) without clinical features of insulin resistance. The HbA1C was 85 mmol/mol, diabetic auto-antibodies were negative and the c-peptide was 2080pmol/l. Genetic testing confirmed the same mutation HNF1A p.(Pro379Arg). Gliclazide was commenced at 20 mg OD, increased to 40 mg OD and insulin was stopped. The BG remains between 8-9 mmol/l with an improvement of HbA1C to 63 mmol/mol.

Discussion: The above cases describe unusual variable responses to SU in siblings from the same family with the same mutation. The precise reason for this is currently unclear but may be secondary to a potential decline in β-cell function.