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PMID: 17407387 Published · ppublish English Comparative Study Journal Article Research Support, Non-U.S. Gov't

Macrosomia and hyperinsulinaemic hypoglycaemia in patients with heterozygous mutations in the HNF4A gene.

PLoS medicine ·Vol. 4 ·No. 4 ·2007-04-00 ·Pages e118

Pearson ER, Boj SF, Steele AM, Barrett T, Stals K, Shield JP, Ellard S, Ferrer J, Hattersley AT

Abstract

Macrosomia is associated with considerable neonatal and maternal morbidity. Factors that predict macrosomia are poorly understood. The increased rate of macrosomia in the offspring of pregnant women with diabetes and in congenital hyperinsulinaemia is mediated by increased foetal insulin secretion. We assessed the in utero and neonatal role of two key regulators of pancreatic insulin secretion by studying birthweight and the incidence of neonatal hypoglycaemia in patients with heterozygous mutations in the maturity-onset diabetes of the young (MODY) genes HNF4A (encoding HNF-4alpha) and HNF1A/TCF1 (encoding HNF-1alpha), and the effect of pancreatic deletion of Hnf4a on foetal and neonatal insulin secretion in mice. We examined birthweight and hypoglycaemia in 108 patients from families with diabetes due to HNF4A mutations, and 134 patients from families with HNF1A mutations. Birthweight was increased by a median of 790 g in HNF4A-mutation carriers compared to non-mutation family members (p < 0.001); 56% (30/54) of HNF4A-mutation carriers were macrosomic compared with 13% (7/54) of non-mutation family members (p < 0.001). Transient hypoglycaemia was reported in 8/54 infants with heterozygous HNF4A mutations, but was reported in none of 54 non-mutation carriers (p = 0.003). There was documented hyperinsulinaemia in three cases. Birthweight and prevalence of neonatal hypoglycaemia were not increased in HNF1A-mutation carriers. Mice with pancreatic beta-cell deletion of Hnf4a had hyperinsulinaemia in utero and hyperinsulinaemic hypoglycaemia at birth. HNF4A mutations are associated with a considerable increase in birthweight and macrosomia, and are a novel cause of neonatal hypoglycaemia. This study establishes a key role for HNF4A in determining foetal birthweight, and uncovers an unanticipated feature of the natural history of HNF4A-deficient diabetes, with hyperinsulinaemia at birth evolving to decreased insulin secretion and diabetes later in life.

MeSH Terms
Adolescent Adult Age of Onset Aged Aged, 80 and over Animals Birth Weight Blood Glucose/analysis Child Child, Preschool Congenital Hyperinsulinism/embryology,genetics,physiopathology Diabetes Mellitus, Type 2/genetics,physiopathology Female Fetal Blood/chemistry Fetal Macrosomia/genetics,physiopathology Hepatocyte Nuclear Factor 1-alpha/genetics Hepatocyte Nuclear Factor 4/deficiency,genetics,physiology Heterozygote Humans Hyperinsulinism/congenital,genetics Hypoglycemia/congenital,genetics Infant Infant, Newborn Insulin/metabolism Insulin Secretion Islets of Langerhans/metabolism Male Mice Mice, Knockout Mice, Transgenic Middle Aged Pregnancy Prevalence Retrospective Studies
Chemicals
Blood Glucose HNF1A protein, human HNF4A protein, human Hepatocyte Nuclear Factor 1-alpha Hepatocyte Nuclear Factor 4 Insulin
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Pearson Ewan R
Peninsula Medical School, Exeter, United Kingdom.
Boj Sylvia F
Steele Anna M
Barrett Timothy
Stals Karen
Shield Julian P
Ellard Sian
Ferrer Jorge
Hattersley Andrew T
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Article Info
Journal
PLoS medicine
Abbr.
PLoS Med
ISSN
1549-1676
DOI
10.1371/journal.pmed.0040118
Published
2007-04-00
Pages
e118
Language
English
Region
United States
NLM ID
101231360
PMCID
PMC1845156
Subset
IM
Grants
Wellcome Trust · United Kingdom
Corrections
CommentIn
PMID: 17407388
CommentIn
PMID: 17891372
External Links
PubMed source DOI: 10.1371/journal.pmed.0040118 PMC Full Text View journal details
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