HNF4A mutation: switch from hyperinsulinaemic hypoglycaemia to maturity-onset diabetes of the young, and incretin response.

BACKGROUND: Hepatocyte nuclear factor 4α (HNF4A) is a member of the nuclear receptor family of ligand-activated transcription factors. HNF4A mutations cause hyperinsulinaemic hypoglycaemia in early life and maturity-onset diabetes of the young. Regular screening of HNF4A mutation carriers using the oral glucose tolerance test has been recommended to diagnose diabetes mellitus at an early stage. Glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide are incretin hormones, responsible for up to 70% of the secreted insulin after a meal in healthy individuals. We describe, for the first time, gradual alteration of glucose homeostasis in a patient with HNF4A mutation after resolution of hyperinsulinaemic hypoglycaemia, on serial oral glucose tolerance testing. We also measured the incretin response to a mixed meal in our patient. CASE REPORT: Our patient was born with macrosomia and developed hyperinsulinaemic hypoglycaemia in the neonatal period. Molecular genetic analysis confirmed HNF4A mutation (p.M116I, c.317G>A) as an underlying cause of hyperinsulinaemic hypoglycaemia. Serial oral glucose tolerance testing, after the resolution of hyperinsulinaemic hypoglycaemia, confirmed the diagnosis of maturity-onset diabetes of the young at the age of 10 years. Interestingly, the intravenous glucose tolerance test revealed normal glucose disappearance rate and first-phase insulin secretion. Incretin hormones showed a suboptimal rise in response to the mixed meal, potentially explaining the discrepancy between the oral glucose tolerance test and the intravenous glucose tolerance test. CONCLUSIONS: Maturity-onset diabetes of the young can develop as early as the first decade of life in persons with an HNF4A mutation. Impaired incretin response might be contributory in the early stages of HNF4A maturity-onset diabetes of the young.

Hyperinsulinaemic hypoglycaemia.

Insulin secretion from pancreatic ß-cells is tightly regulated to maintain fasting blood glucose level between 3.5-5.5 mmol/l. In hyperinsulinaemic hypoglycaemia (HH) insulin secretion becomes unregulated so that insulin secretion persists despite low blood glucose levels. HH can be due to a large number of causes and recent advances in genetics have begun to provide novel insights into the molecular mechanisms of HH. Defects in key genes involved in regulating insulin secretion have been linked to HH. The most severe forms of HH are clinically observed in the newborn period whereas in adults an insulinoma is the commonest cause of HH. This review provides an overview on the molecular mechanisms leading to HH in children and adults, it describes the clinical presentation and diagnosis, and finally the treatment options for the different forms of HH are discussed.