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Reviews in Endocrine and Metabolic Disorders
Published in: Reviews in Endocrine and Metabolic Disorders 3/2010

01-09-2010

Congenital Hyperinsulinism due to mutations in HNF4A and HADH

Authors: Ritika R. Kapoor, Amanda Heslegrave, Khalid Hussain

Published in: Reviews in Endocrine and Metabolic Disorders | Issue 3/2010

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Abstract

Mutations in the HADH and HNF4A genes are rare causes of diazoxide responsive congenital hyperinsulinism (CHI). This chapter details the phenotype known to be associated with mutations in these genes. Additionally, the authors give a brief overview of the role of these genes in glucose physiology and the possible mechanisms of CHI in patients with mutations in these genes.
Literature
1.
Kapoor RR, Flanagan SE, James C, Shield J, Ellard S, Hussain K. Hyperinsulinaemic hypoglycaemia. Arch Dis Child. 2009;94(6):450–7.CrossRefPubMed
2.
Noyes BE, Bradshaw RA. L-3-hydroxyacyl coenzyme A dehydrogenase from pig heart muscle. I. Purification and properties. J Biol Chem. 1973;248(9):3052–9.PubMed
3.
He XY, Yang SY, Schulz H. Assay of L-3-hydroxyacyl-coenzyme A dehydrogenase with substrates of different chain lengths. Anal Biochem. 1989;180(1):105–9.CrossRefPubMed
4.
Vredendaal PJ, van den Berg I, Malingre HE, Stroobants AK, Olde Weghuis DE, Berger R. Human short-chain L-3-hydroxyacyl-CoA dehydrogenase: cloning and characterization of the coding sequence. Biochem Biophys Res Commun. 1996;223(3):718–23.CrossRefPubMed
5.
Vredendaal PJ, van den Berg I, Stroobants AK, van der AD, Malingre HE, Berger R. Structural organization of the human short-chain L-3-hydroxyacyl-CoA dehydrogenase gene. Mamm Genome. 1998;9(9):763–8.CrossRefPubMed
6.
Eaton S, Bartlett K, Pourfarzam M. Mammalian mitochondrial beta-oxidation. Biochem J. 1996;320(Pt 2):345–57.PubMed
7.
Rinaldo P, Matern D, Bennett MJ. Fatty acid oxidation disorders. Annu Rev Physiol. 2002;64:477–502.CrossRefPubMed
8.
Agren A, Borg K, Brolin SE, Carlman J, Lundqvist G. Hydroxyacyl CoA dehydrogenase, an enzyme important in fat metabolism in different cell types in the islets of Langerhans. Diabète Métab. 1977;3(3):169–72.PubMed
9.
Martens GA, Vervoort A, Van de CM, Stange G, Hellemans K, Van Thi HV, et al. Specificity in beta cell expression of L-3-hydroxyacyl-CoA dehydrogenase, short chain, and potential role in down-regulating insulin release. J Biol Chem. 2007;282(29):21134–44.CrossRefPubMed
10.
Hardy OT, Hohmeier HE, Becker TC, Manduchi E, Doliba NM, Gupta RK, et al. Functional genomics of the beta-cell: short-chain 3-hydroxyacyl-coenzyme A dehydrogenase regulates insulin secretion independent of K+ currents. Mol Endocrinol. 2007;21(3):765–73.CrossRefPubMed
11.
Lantz KA, Vatamaniuk MZ, Brestelli JE, Friedman JR, Matschinsky FM, Kaestner KH. Foxa2 regulates multiple pathways of insulin secretion. J Clin Invest. 2004;114(4):512–20.PubMed
12.
Sund NJ, Vatamaniuk MZ, Casey M, Ang SL, Magnuson MA, Stoffers DA, et al. Tissue-specific deletion of Foxa2 in pancreatic beta cells results in hyperinsulinemic hypoglycemia. Genes Dev. 2001;15(13):1706–15.CrossRefPubMed
13.
Clayton PT, Eaton S, ynsley-Green A, Edginton M, Hussain K, Krywawych S, et al. Hyperinsulinism in short-chain L-3-hydroxyacyl-CoA dehydrogenase deficiency reveals the importance of beta-oxidation in insulin secretion. J Clin Invest. 2001;108(3):457–65.PubMed
14.
Molven A, Matre GE, Duran M, Wanders RJ, Rishaug U, Njolstad PR, et al. Familial hyperinsulinemic hypoglycemia caused by a defect in the SCHAD enzyme of mitochondrial fatty acid oxidation. Diabetes. 2004;53(1):221–7.CrossRefPubMed
15.
Hussain K, Clayton PT, Krywawych S, Chatziandreou I, Mills P, Ginbey DW, et al. Hyperinsulinism of infancy associated with a novel splice site mutation in the SCHAD gene. J Pediatr. 2005;146(5):706–8.CrossRefPubMed
16.
Di CS, Gessi A, Pepe G, Sogno VP, Mangano E, Chiumello G, et al. Identification of a diffuse form of hyperinsulinemic hypoglycemia by 18-fluoro-L-3, 4 dihydroxyphenylalanine positron emission tomography/CT in a patient carrying a novel mutation of the HADH gene. Eur J Endocrinol. 2009;160(6):1019–23.CrossRef
17.
Kapoor RR, James C, Flanagan SE, Ellard S, Eaton S, Hussain K. 3-Hydroxyacyl-coenzyme A dehydrogenase deficiency and hyperinsulinemic hypoglycemia: characterization of a novel mutation and severe dietary protein sensitivity. J Clin Endocrinol Metab. 2009;94(7):2221–5.CrossRefPubMed
18.
Molven A, Rishaug U, Matre GE, Njolstad PR, Sovik O. Hunting for a hypoglycemia gene: severe neonatal hypoglycemia in a consanguineous family. Am J Med Genet. 2002;113(1):40–6.CrossRefPubMed
19.
Eaton S, Chatziandreou I, Krywawych S, Pen S, Clayton PT, Hussain K. Short-chain 3-hydroxyacyl-CoA dehydrogenase deficiency associated with hyperinsulinism: a novel glucose-fatty acid cycle? Biochem Soc Trans. 2003;31(Pt 6):1137–9.CrossRefPubMed
20.
Cochrane WA, Payne WW, Simpkiss MJ, Woolf LI. Familial hypoglycemia precipitated by amino acids. J Clin Invest. 1956;35(4):411–22.CrossRefPubMed
21.
Fahien LA, MacDonald MJ, Kmiotek EH, Mertz RJ, Fahien CM. Regulation of insulin release by factors that also modify glutamate dehydrogenase. J Biol Chem. 1988;263(27):13610–4.PubMed
22.
Fourtner SH, Stanley CA, Kelly A. Protein-sensitive hypoglycemia without leucine sensitivity in hyperinsulinism caused by K(ATP) channel mutations. J Pediatr. 2006;149(1):47–52.CrossRefPubMed
23.
Li C, Chen P, Palladino A, Narayan S, Russell LK, Sayed S, et al. Mechanism of hyperinsulinism in short-chain 3-hydroxyacyl-CoA dehydrogenase deficiency involves activation of glutamate dehydrogenase. J Biol Chem. 2010;29.
24.
Filling C, Keller B, Hirschberg D, Marschall HU, Jornvall H, Bennett MJ, et al. Role of short-chain hydroxyacyl CoA dehydrogenases in SCHAD deficiency. Biochem Biophys Res Commun. 2008;368(1):6–11.CrossRefPubMed
25.
Sladek FM, Zhong WM, Lai E, Darnell Jr JE. Liver-enriched transcription factor HNF-4 is a novel member of the steroid hormone receptor superfamily. Genes Dev. 1990;4(12B):2353–65.CrossRefPubMed
26.
Boj SF, Parrizas M, Maestro MA, Ferrer J. A transcription factor regulatory circuit in differentiated pancreatic cells. Proc Natl Acad Sci USA. 2001;98(25):14481–6.CrossRefPubMed
27.
Odom DT, Zizlsperger N, Gordon DB, Bell GW, Rinaldi NJ, Murray HL, et al. Control of pancreas and liver gene expression by HNF transcription factors. Science. 2004;303(5662):1378–81.CrossRefPubMed
28.
Boj SF, Petrov D, Ferrer J. Epistasis of transcriptomes reveals synergism between transcriptional activators Hnf1alpha and Hnf4alpha. PLoS Genet. 2010;6(5):e1000970.CrossRefPubMed
29.
Wang H, Maechler P, Antinozzi PA, Hagenfeldt KA, Wollheim CB. Hepatocyte nuclear factor 4alpha regulates the expression of pancreatic beta -cell genes implicated in glucose metabolism and nutrient-induced insulin secretion. J Biol Chem. 2000;275(46):35953–9.CrossRefPubMed
30.
Thomas H, Jaschkowitz K, Bulman M, Frayling TM, Mitchell SM, Roosen S, et al. A distant upstream promoter of the HNF-4alpha gene connects the transcription factors involved in maturity-onset diabetes of the young. Hum Mol Genet. 2001;10(19):2089–97.CrossRefPubMed
31.
Yamagata K, Furuta H, Oda N, Kaisaki PJ, Menzel S, Cox NJ, et al. Mutations in the hepatocyte nuclear factor-4alpha gene in maturity-onset diabetes of the young (MODY1). Nature. 1996;384(6608):458–60.CrossRefPubMed
32.
Pearson ER, Boj SF, Steele AM, Barrett T, Stals K, Shield JP, et al. Macrosomia and hyperinsulinaemic hypoglycaemia in patients with heterozygous mutations in the HNF4A gene. PLoS Med. 2007;4(4):e118.CrossRefPubMed
33.
Fajans SS, Bell GI. Macrosomia and neonatal hypoglycaemia in RW pedigree subjects with a mutation (Q268X) in the gene encoding hepatocyte nuclear factor 4alpha (HNF4A). Diabetologia. 2007;50(12):2600–1.CrossRefPubMed
34.
Kapoor RR, Locke J, Colclough K, Wales J, Conn JJ, Hattersley AT, et al. Persistent hyperinsulinemic hypoglycemia and maturity-onset diabetes of the young due to heterozygous HNF4A mutations. Diabetes. 2008;57(6):1659–63.CrossRefPubMed
35.
Flanagan SE, Kapoor RR, Mali G, Cody D, Murphy N, Schwahn B, et al. Diazoxide-responsive hyperinsulinemic hypoglycemia caused by HNF4A gene mutations. Eur J Endocrinol. 2010;162(5):987–92.CrossRefPubMed
36.
Gupta RK, Vatamaniuk MZ, Lee CS, Flaschen RC, Fulmer JT, Matschinsky FM, et al. The MODY1 gene HNF-4alpha regulates selected genes involved in insulin secretion. J Clin Invest. 2005;115(4):1006–15.PubMed
37.
Miura A, Yamagata K, Kakei M, Hatakeyama H, Takahashi N, Fukui K, et al. Hepatocyte nuclear factor-4alpha is essential for glucose-stimulated insulin secretion by pancreatic beta-cells. J Biol Chem. 2006;281(8):5246–57.CrossRefPubMed
38.
Prentki M, Joly E, El-Assaad W, Roduit R. Malonyl-CoA signaling, lipid partitioning, and glucolipotoxicity: role in beta-cell adaptation and failure in the etiology of diabetes. Diabetes. 2002;51 Suppl 3:S405–13.CrossRefPubMed
39.
Gremlich S, Nolan C, Roduit R, Burcelin R, Peyot ML, ghingaro-Augusto V, et al. Pancreatic islet adaptation to fasting is dependent on peroxisome proliferator-activated receptor alpha transcriptional up-regulation of fatty acid oxidation. Endocrinology. 2005;146(1):375–82.CrossRefPubMed
40.
Kaestner KH. Transcriptional regulation in islet expansion during pregnancy. Paper presented at ENDO 2010, 19–22 June, San Diego USA.
Metadata
Title
Congenital Hyperinsulinism due to mutations in HNF4A and HADH
Authors
Ritika R. Kapoor
Amanda Heslegrave
Khalid Hussain
Publication date
01-09-2010
Publisher
Springer US
Published in
Reviews in Endocrine and Metabolic Disorders / Issue 3/2010
Print ISSN: 1389-9155
Electronic ISSN: 1573-2606
DOI
https://doi.org/10.1007/s11154-010-9148-y

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WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

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