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Prolonged episodes of hypoglycaemia in HNF4A-MODY mutation carriers with IGT. Evidence of persistent hyperinsulinism
S Bacon1, M P Kyithar1, E M Condron1
1Department of Diabetes and Endocrinology, UCD School of Medicine, Mater Misericordiae University Hospital, 30, Eccles Street, Dublin 7, Ireland.
Aims:
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.
Insights
HNF4A-MODY patients show prolonged hypoglycemia into adulthood due to a hyperinsulinaemic phase. This study tracked glucose and insulin secretion over six years, revealing key insights into this dual phenotype.
Area of Science:
- Endocrinology
- Genetics
- Metabolic Disorders
Background:
- Hepatocyte nuclear factor 4 alpha (HNF4A) gene mutations cause maturity onset diabetes of the young (MODY).
- HNF4A mutations are also linked to congenital hyperinsulinism, presenting a dual phenotype.
- HNF4A-MODY exhibits hyperinsulinaemic hypoglycemia neonatally, progressing to diabetes in adulthood, but the transition is poorly understood.
Purpose of the Study:
- To investigate the changes in glucose metabolism and insulin secretion over a six-year period in individuals with HNF4A-MODY.
- To characterize glycaemic variability and hypoglycemia in HNF4A-MODY using continuous glucose monitoring systems (CGMS).
Main Methods:
- An oral glucose tolerance test (OGTT) measuring glucose, insulin, and C-peptide was conducted in HNF4A participants with diabetes mellitus (DM), impaired glucose tolerance (IGT), and MODY-negative controls.
- Serial assessments were performed in the HNF4A-IGT cohort.
- Continuous glucose monitoring (CGM) was used for 72 hours in a subset of HNF4A-MODY mutation carriers.
Main Results:
- No decline in glycaemic control was observed in the HNF4A-IGT cohort over the study period.
- The HNF4A-IGT group exhibited significantly lower fasting glucose-to-insulin ratios compared to controls (0.13 vs. 0.24, p=0.03).
- CGMS revealed prolonged hypoglycaemic episodes in the HNF4A-IGT group (432 min) compared to the HNF4A-DM group (138 min, p=0.04).
Conclusions:
- Young adults with HNF4A-IGT maintain preserved glucose, insulin, and C-peptide secretory responses to oral glucose.
- Prolonged hypoglycaemic periods are evident in HNF4A-IGT individuals, even in young adulthood (median age 21 years).
- A persistent hyperinsulinaemic phase extending into adulthood is proposed as the cause of these hypoglycaemic episodes in HNF4A-MODY.
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