title: Prolonged episodes of hypoglycaemia in HNF4A-MODY mutation carriers with IGT. Evidence of persistent hyperinsulinism into early adulthood.
abstract: OBJECTIVE
  HNF4A is an established cause of maturity onset diabetes of the young (MODY). Congenital hyperinsulinism can also be associated with mutations in the HNF4A gene. A dual phenotype is observed in HNF4A-MODY with hyperinsulinaemic hypoglycaemia in the neonatal period progressing to diabetes in adulthood. The nature and timing of the transition remain poorly defined. We performed an observational study to establish changes in glycaemia and insulin secretion over a 6-year period. We investigated glycaemic variability and hypoglycaemia in HNF4A-MODY using a continuous glucose monitoring system (CGMS).
  
  
  METHODS
  An OGTT with measurement of glucose, insulin and C-peptide was performed in HNF4A participants with diabetes mellitus (DM) (n = 14), HNF4A-IGT (n = 7) and age- and BMI-matched MODY negative family members (n = 10). Serial assessment was performed in the HNF4A-IGT cohort. In a subset of HNF4A-MODY mutation carriers (n = 10), CGMS was applied over a 72-h period.
  
  
  RESULTS
  There was no deterioration in glycaemic control in the HNF4A-IGT cohort. The fasting glucose-to-insulin ratio was significantly lower in the HNF4A-IGT cohort when compared to the normal control group (0.13 vs. 0.24, p = 0.03). CGMS profiling demonstrated prolonged periods of hypoglycaemia in the HNF4A-IGT group when compared to the HNF4A-DM group (432 vs. 138 min p = 0.04).
  
  
  CONCLUSIONS
  In a young adult HNF4A-IGT cohort, we demonstrate preserved glucose, insulin and C-peptide secretory responses to oral glucose. Utilising CGMS, prolonged periods of hypoglycaemia are evident despite a median age of 21 years. We propose a prolonged hyperinsulinaemic phase into adulthood is responsible for the notable hypoglycaemic episodes.
authors.affiliation: Department of Diabetes and Endocrinology, UCD School of Medicine, Mater Misericordiae University Hospital, 30, Eccles Street, Dublin 7, Ireland.
authors.forename: S
authors.initials: S
authors.lastname: Bacon
authors.affiliation: Department of Diabetes and Endocrinology, UCD School of Medicine, Mater Misericordiae University Hospital, 30, Eccles Street, Dublin 7, Ireland.
authors.forename: M P
authors.initials: MP
authors.lastname: Kyithar
authors.affiliation: Department of Diabetes and Endocrinology, UCD School of Medicine, Mater Misericordiae University Hospital, 30, Eccles Street, Dublin 7, Ireland.
authors.forename: E M
authors.initials: EM
authors.lastname: Condron
authors.affiliation: Department of Diabetes and Endocrinology, UCD School of Medicine, Mater Misericordiae University Hospital, 30, Eccles Street, Dublin 7, Ireland.
authors.forename: N
authors.initials: N
authors.lastname: Vizzard
authors.affiliation: Department of Diabetes and Endocrinology, UCD School of Medicine, Mater Misericordiae University Hospital, 30, Eccles Street, Dublin 7, Ireland.
authors.forename: M
authors.initials: M
authors.lastname: Burke
authors.affiliation: Department of Diabetes and Endocrinology, UCD School of Medicine, Mater Misericordiae University Hospital, 30, Eccles Street, Dublin 7, Ireland. mbyrne@mater.ie.
authors.forename: M M
authors.initials: MM
authors.lastname: Byrne
mesh_terms: D000328:Adult; D001786:Blood Glucose / Q000032:analysis; D015190:Blood Glucose Self-Monitoring / Q000379:methods; D002096:C-Peptide / Q000032:analysis; D003924:Diabetes Mellitus, Type 2 / Q000175:diagnosis / Q000235:genetics / Q000503:physiopathology; D018450:Disease Progression; D005260:Female; D005951:Glucose Tolerance Test / Q000379:methods; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics*; D006801:Humans; D006946:Hyperinsulinism / Q000097:blood / Q000175:diagnosis / Q000235:genetics / Q000503:physiopathology; D007003:Hypoglycemia / Q000097:blood / Q000175:diagnosis / Q000209:etiology; D007328:Insulin / Q000097:blood*; D008297:Male; D009154:Mutation
chemical_list: D001786:Blood Glucose; D002096:C-Peptide; C496592:HNF4A protein, human; D051557:Hepatocyte Nuclear Factor 4; D007328:Insulin
keywords: Continuous glucose monitoring system; HNF4A-MODY; Hyperinsulinism