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.

Deprivation impedes success of insulin intensification in children and adolescents with Type 1 diabetes; longitudinal linear mixed modelling of a retrospective observational cohort.

AIMS: To examine the relationship between social deprivation, intensification of insulin therapy (≥ three injections per day) and diabetes control in children and adolescents. METHODS: We performed a longitudinal observational study of 283 children and adolescents with Type 1 diabetes from three UK paediatric centres from 2005 to 2007. We used linear mixed modelling to identify the contribution of the Index of Multiple Deprivation 2004, insulin regimen and demographic factors in explaining longitudinal differences in HbA(1c) levels. RESULTS: Overall mean HbA(1c) levels were 8.9% [sd 1.4, 74 mmol/mol (8 mmol/mol)]. Prescribing of intensive therapy increased from 49.2 to 70.1% (χ(2) = 32.9, P < 0.001), but there was no corresponding improvement in HbA(1c) levels. Those from more educationally deprived backgrounds were less likely to be started on intensive therapy (P = 0.04). In linear mixed modelling, factors independently associated with poor metabolic control were greater social deprivation (P = 0.01), particularly lower educational levels (P = 0.006), and non-White ethnicity (P = 0.04). Nested terms analysis showed that increased deprivation interacted with non-White ethnicity (P = 0.009) and with intensive insulin therapy (P = 0.03) to result in poorer metabolic control. In a subgroup intensified from conventional regimens during follow-up (n = 75), greater social deprivation was associated with least success of intensive therapy (P = 0.02). CONCLUSIONS: Social deprivation was associated with low uptake and poor success of insulin intensification and this appeared to be largely mediated via lower educational levels.