Background 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-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 Findings 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 β-cell deletion of Hnf4a had hyperinsulinaemia in utero and hyperinsulinaemic hypoglycaemia at birth. Conclusions 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.
References
[1]
American College of Obstetricians and Gynecologists (ACOG) (2000) Fetal macrosomia. ACOG Practice Bulletin no. 22. Washington (DC): American College of Obstetricians and Gynecologists (ACOG). 11 November 2000.
[2]
Chauhan SP, Grobman WA, Gherman RA, Chauhan VB, Chang G, et al. (2005) Suspicion and treatment of the macrosomic fetus: A review. Am J Obstet Gynecol 193: 332–346.
[3]
Thomas PM, Cote GJ, Wohllk N, Haddad B, Mathew PM, et al. (1995) Mutations in the sulfonylurea receptor gene in familial persistent hyperinsulinemic hypoglycemia of infancy. Science 268: 426–429.
[4]
Thomas P, Ye Y, Lightner E (1996) Mutation of the pancreatic islet inward rectifier Kir6.2 also leads to familial persistent hyperinsulinemic hypoglycemia of infancy. Hum Mol Genet 5: 1809–1812.
[5]
Dunne MJ, Kane C, Shepherd RM, Sanchez JA, James RF, et al. (1997) Familial persistent hyperinsulinemic hypoglycemia of infancy and mutations in the sulfonylurea receptor. N Engl J Med 336: 703–706.
[6]
Glaser B, Kesavan P, Heyman M, Davis E, Cuesta A, et al. (1998) Familial hyperinsulinism caused by an activating glucokinase mutation. N Engl J Med 338: 226–230.
[7]
Stanley CA, Lieu YK, Hsu BY, Burlina AB, Greenberg CR, et al. (1998) Hyperinsulinism and hyperammonemia in infants with regulatory mutations of the glutamate dehydrogenase gene. N Engl J Med 338: 1352–1357.
[8]
Huopio H, Reimann F, Ashfield R, Komulainen J, Lenko HL, et al. (2000) Dominantly inherited hyperinsulinism caused by a mutation in the sulfonylurea receptor type 1. J Clin Invest 106: 897–906.
[9]
Clayton PT, Eaton S, Aynsley-Green A, Edginton M, Hussain K, et al. (2001) Hyperinsulinism in short-chain L-3-hydroxyacyl-CoA dehydrogenase deficiency reveals the importance of beta-oxidation in insulin secretion. J Clin Invest 108: 457–465.
[10]
Molven A, Matre GE, Duran M, Wanders RJ, Rishaug U, et al. (2004) Familial hyperinsulinemic hypoglycemia caused by a defect in the SCHAD enzyme of mitochondrial fatty acid oxidation. Diabetes 53: 221–227.
[11]
Gloyn AL, Cummings EA, Edghill EL, Harries LW, Scott R, et al. (2004) Permanent neonatal diabetes due to paternal germline mosaicism for an activating mutation of the KCNJ11 gene encoding the Kir6.2 subunit of the beta-cell potassium adenosine triphosphate channel. J Clin Endocrinol Metab 89: 3932–3935.
[12]
Proks P, Arnold AL, Bruining J, Girard C, Flanagan SE, et al. (2006) A heterozygous activating mutation in the sulphonylurea receptor SUR1 (ABCC8) causes neonatal diabetes. Hum Mol Genet 15: 1793–1800.
[13]
Hattersley AT, Beards F, Ballantyne E, Appleton M, Harvey R, et al. (1998) Mutations in the glucokinase gene of the fetus result in reduced birth weight. Nat Genet 19: 268–270.
[14]
Edghill EL, Bingham C, Slingerland AS, Minton JA, Noordam C, et al. (2006) Hepatocyte nuclear factor-1 beta mutations cause neonatal diabetes and intrauterine growth retardation: Support for a critical role of HNF-1beta in human pancreatic development. Diabet Med 23: 1301–1306.
[15]
Byrne MM, Sturis J, Fajans SS, Ortiz FJ, Stoltz A, et al. (1995) Altered insulin secretory responses to glucose in subjects with a mutation in the MODY1 gene on chromosome 20. Diabetes 44: 699–704.
[16]
Byrne MM, Sturis J, Menzel S, Yamagata K, Fajans SS, et al. (1996) Altered insulin secretory responses to glucose in diabetic and nondiabetic subjects with mutations in the diabetes susceptibility gene MODY3 on Chromosome 12. Diabetes 45: 1503–1510.
[17]
Odom DT, Zizlsperger N, Gordon DB, Bell GW, Rinaldi NJ, et al. (2004) Control of pancreas and liver gene expression by HNF transcription factors. Science 303: 1378–1381.
[18]
Ferrer J (2002) A genetic switch in pancreatic beta-cells: Implications for differentiation and haploinsufficiency. Diabetes 51: 2355–2362.
[19]
Silander K, Mohlke KL, Scott LJ, Peck EC, Hollstein P, et al. (2004) Genetic variation near the hepatocyte nuclear factor-4 alpha gene predicts susceptibility to type 2 diabetes. Diabetes 53: 1141–1149.
[20]
Love-Gregory LD, Wasson J, Ma J, Jin CH, Glaser B, et al. (2004) A common polymorphism in the upstream promoter region of the hepatocyte nuclear factor-4 alpha gene on chromosome 20q is associated with type 2 diabetes and appears to contribute to the evidence for linkage in an Ashkenazi Jewish population. Diabetes 53: 1134–1140.
[21]
Gupta RK, Vatamaniuk MZ, Lee CS, Flaschen RC, Fulmer JT, et al. (2005) The MODY1 gene HNF-4alpha regulates selected genes involved in insulin secretion. J Clin Invest 115: 1006–1015.
[22]
Pearson ER, Pruhova S, Tack CJ, Johansen A, Castleden HA, et al. (2005) Molecular genetics and phenotypic characteristics of MODY caused by hepatocyte nuclear factor 4alpha mutations in a large European collection. Diabetologia 48: 878–885.
[23]
Freeman JV, Cole TJ, Chinn S, Jones PR, White EM, et al. (1995) Cross sectional stature and weight reference curves for the UK, 1990. Arch Dis Child 73: 17–24.
[24]
Hayhurst GP, Lee YH, Lambert G, Ward JM, Gonzalez FJ (2001) Hepatocyte nuclear factor 4alpha (nuclear receptor 2A1) is essential for maintenance of hepatic gene expression and lipid homeostasis. Mol Cell Biol 21: 1393–1403.
[25]
Herrera PL (2000) Adult insulin- and glucagon-producing cells differentiate from two independent cell lineages. Development 127: 2317–2322.
[26]
Luco RF, Maestro MA, Del Pozo N, Philbrick WM, de la Ossa PP, et al. (2006) A conditional model reveals that induction of hepatocyte nuclear factor-1alpha in hnf1alpha-null mutant beta-cells can activate silenced genes postnatally, whereas overexpression is deleterious. Diabetes 55: 2202–2211.
[27]
Boulet SL, Alexander GR, Salihu HM, Pass M (2003) Macrosomic births in the United States: Determinants, outcomes, and proposed grades of risk. Am J Obstet Gynecol 188: 1372–1378.
[28]
Accili D, Drago J, Lee EJ, Johnson MD, Cool MH, et al. (1996) Early neonatal death in mice homozygous for a null allele of the insulin receptor gene. Nat Genet 12: 106–109.
[29]
Stoffel M, Duncan SA (1997) The maturity-onset diabetes of the young (MODY1) transcription factor HNF4alpha regulates expression of genes required for glucose transport and metabolism. Proc Natl Acad Sci U S A 94: 13209–13214.
[30]
Wang H, Maechler P, Antinozzi PA, Hagenfeldt KA, Wollheim CB (2000) Hepatocyte nuclear factor 4alpha regulates the expression of pancreatic beta-cell genes implicated in glucose metabolism and nutrient-induced insulin secretion. J Biol Chem 275: 35953–35959.
[31]
Stoffers DA, Zinkin NT, Stanojevic V, Clarke WL, Habener JF (1997) Pancreatic agenesis attributable to a single nucleotide deletion in the human IPF1 gene coding sequence. Nat Genet 15: 106–110.
[32]
Gloyn AL, Pearson ER, Antcliff JF, Proks P, Bruining GJ, et al. (2004) Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes. N Engl J Med 350: 1838–1849.
[33]
Slingerland AS, Hattersley AT (2006) Activating mutations in the gene encoding Kir6.2 alter fetal and postnatal growth as well as causing neonatal diabetes. J Clin Endocrinol Metab 91: 2782–2788.
[34]
Babenko AP, Polak M, Cave H, Busiah K, Czernichow P, et al. (2006) Activating mutations in the ABCC8 gene in neonatal diabetes mellitus. N Engl J Med 355: 456–466.
[35]
Leibowitz G, Glaser B, Higazi AA, Salameh M, Cerasi E, et al. (1995) Hyperinsulinemic hypoglycemia of infancy (nesidioblastosis) in clinical remission: High incidence of diabetes mellitus and persistent beta-cell dysfunction at long-term follow-up. J Clin Endocrinol Metab 80: 386–392.
[36]
Huopio H, Otonkoski T, Vauhkonen I, Reimann F, Ashcroft FM, et al. (2003) A new subtype of autosomal dominant diabetes attributable to a mutation in the gene for sulfonylurea receptor 1. Lancet 361: 301–307.
[37]
Kassem SA, Ariel I, Thornton PS, Scheimberg I, Glaser B (2000) Beta-cell proliferation and apoptosis in the developing normal human pancreas and in hyperinsulinism of infancy. Diabetes 49: 1325–1333.
[38]
Miura A, Yamagata K, Kakei M, Hatakeyama H, Takahashi N, et al. (2006) Hepatocyte nuclear factor-4alpha is essential for glucose-stimulated insulin secretion by pancreatic beta-cells. J Biol Chem 281: 5246–5257.
[39]
Thomas H, Jaschkowitz K, Bulman M, Frayling TM, Mitchell SM, et al. (2001) A distant upstream promoter of the HNF-4alpha gene connects the transcription factors involved in maturity-onset diabetes of the young. Hum Mol Genet 10: 2089–2097.
[40]
Boj SF, Parrizas M, Maestro MA, Ferrer J (2001) A transcription factor regulatory circuit in differentiated pancreatic cells. Proc Natl Acad Sci U S A 98: 14481–14486.
