(CSEMP024) FROM OVERDRIVE TO BURNOUT: DEVELOPMENT OF DIABETES MELLITUS OVER 40 YEARS AFTER DIAGNOSIS OF CONGENITAL HYPERINSULINISM CAUSED BY A HOMOZYGOUS ABCC8 MUTATION

Abstract:

Background:
Congenital hyperinsulinism (CHI) is a rare disorder characterized by insulin oversecretion and hypoglycemia. Loss-of-function mutations in the ABCC8 gene, which encodes the SUR1 subunit of the ATP-sensitive potassium channel, are the most common genetic cause of CHI. Treatment involves either conservative management, including feeding and diazoxide, or pancreatectomy. Due to its rarity, the long-term metabolic outcomes for patients with CHI, especially those managed conservatively, are not well understood.

Case Presentation
A 44-year-old woman presented with a new diagnosis of diabetes mellitus. Her medical history was significant for CHI diagnosed in the neonatal period. Genetic testing later confirmed a homozygous loss-of-function mutation in the ABCC8 gene (c.3992-9G>A). Her CHI was initially managed conservatively and did not require pancreatectomy. She continued to have occasional hypoglycemia into adulthood, including severe hypoglycemic episodes, prompting a dietary pattern of frequent carbohydrate intake to avoid hypoglycemia. She later developed gestational diabetes briefly requiring insulin at the age of 37. At presentation to us, initial investigations revealed an A1C of 8.7%, fasting glucose of 11.6 mmol/L, and 2-hour 75g-OGTT glucose of 19.8 mmol/L. C-peptide was 835 pmol/L with a corresponding plasma glucose of 7.2 mmol/L. Her weight was 100 kg and BMI was 34.6 kg/m2. She was started on low-dose metformin and counselled on lifestyle modification. At follow up 6 months later, she had lost 15 kg of weight and had improved glycemic control with a reduction in A1C to 5.9%.

Discussion
Although CHI causes recurrent hypoglycemia early in life, there is increasing recognition that it may progress to hyperglycemia and diabetes mellitus over time, as illustrated in our case. Prior studies have suggested that this could be due to prolonged β-cell overactivation and stress leading to perturbations in metabolic pathways and gene expression, as well as cumulative apoptosis and diminished β-cell mass. The impact of genetic predisposition and its complex interplay with acquired factors, such as obesity, in the development of diabetes is also highlighted in this case. Clinicians should be aware of the natural history of genetic CHI and recognize it as a possible risk factor for diabetes in order to effectively screen, monitor, and treat these patients.