Date Published: April 3, 2007
Publisher: Public Library of Science
Author(s): Ewan R Pearson, Sylvia F Boj, Anna M Steele, Timothy Barrett, Karen Stals, Julian P Shield, Sian Ellard, Jorge Ferrer, Andrew T Hattersley, Leif C Groop
Abstract: BackgroundMacrosomia 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-4α) and HNF1A/TCF1 (encoding HNF-1α), and the effect of pancreatic deletion of Hnf4a on foetal and neonatal insulin secretion in mice.Methods and FindingsWe 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 β-cell deletion of Hnf4a had hyperinsulinaemia in utero and hyperinsulinaemic hypoglycaemia at birth.ConclusionsHNF4A 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.
Partial Text: Macrosomia is associated with considerable foetal and maternal morbidity . Factors that predict macrosomia are still poorly understood . In humans, foetal insulin secretion is one of the key determinants of foetal growth, acting mainly in the third trimester when the weight of the foetus increases greatly. This is seen in pregnant women with diabetes when foetal sensing of maternal hyperglycemia drives insulin secretion, insulin-mediated growth, and subsequent macrosomia. In addition to such environmental factors, mutations in the genes involved in insulin secretion are also known to affect birthweight. Mutations that cause hyperinsulinaemic hypoglycaemia of infancy [3–10] are associated with increased birthweight. Conversely, genes in which mutations cause neonatal diabetes [11,12] and some forms of maturity-onset diabetes of the young (MODY) [13,14] are associated with decreased birthweight.
We have shown that increased birthweight and macrosomia are common features of patients with HNF4A mutations and, in addition, that some individuals with HNF4A have neonatal hypoglycaemia. Although in young adults the same genetic defect results in diabetes due to reduced insulin secretion [15,22], we have shown that the mechanism for the phenotype in newborns is likely to be increased insulin secretion in utero and in the neonatal period. This is supported by hyperinsulinaemia in some affected infants with HNF4A mutations, and studies in mice with β-cell deletion of Hnf4a clearly show hyperinsulinaemia in utero and hyperinsulinaemic hypoglycaemia in the early neonatal period.