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Prolonged episodes of hypoglycaemia in HNF4A-MODY mutation carriers with IGT. Evidence of persistent hyperinsulinism into early adulthood

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Abstract

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.

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Acknowledgments

We would like to acknowledge the laboratory staff in the Mater Misericordiae University Hospital. We would also like to thank Dr. Kevin Colclough and Prof. Sian Ellard of University of Exeter Medical School, Exeter for performing genetic analysis of the cohort.

Funding

This study was supported by the Health Professional Fellowship grant from the Health Research Board of Ireland awarded to Siobhán Bacon. Grant Number; HPF-2013-459. Mentor: Prof Maria M Byrne.

Author information

Authors and Affiliations

  1. Department of Diabetes and Endocrinology, UCD School of Medicine, Mater Misericordiae University Hospital, 30, Eccles Street, Dublin 7, Ireland

    S. Bacon, M. P. Kyithar, E. M. Condron, N. Vizzard, M. Burke & M. M. Byrne

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  1. S. Bacon
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  2. M. P. Kyithar
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  3. E. M. Condron
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  4. N. Vizzard
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  5. M. Burke
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  6. M. M. Byrne
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Correspondence to M. M. Byrne.

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The authors declare that they have no conflict of interest.

Human and animal rights

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008.

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Informed consent was obtained from all patients for being included in the study.

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Bacon, S., Kyithar, M.P., Condron, E.M. et al. Prolonged episodes of hypoglycaemia in HNF4A-MODY mutation carriers with IGT. Evidence of persistent hyperinsulinism into early adulthood. Acta Diabetol 53, 965–972 (2016). https://doi.org/10.1007/s00592-016-0890-9

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