The Role of ATP Sensitive Channels in Insulin Secretion and The Implications in Persistent Hyperinsulinemic Hypoglycaemia of Infancy (PHHI)

  • J.H. Shah
  • D.J. Maguire
  • D. Brown
  • A. Cotterill
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 599)


Persistent Hyperinsulinemic Hypoglycaemia of Infancy (PHHI) is a metabolic syndrome of unregulated insulin secretion. It is a heterogenous disease with causes linked to mutations of the ATP sensitive potassium channels of the β cell, as well as to metabolism in the β cell. 5 candidate genes – ABCC8, KCNJ11, GCK, GLUD1 and SCHAD have been implicated in the disease so far, however the aetiology of the disease remains unknown in up to 50% of all patients. We genotyped 43 subjects with PHHI (20 surgically treated and 23 medically treated) for disease associated mutations in the candidate genes. Mutations on ABCC8 were identified in 16 of the 20 (80%) of the surgically treated patients. One putative mutation was identified in the medically treated cohort. The polymorphism E23K on KCNJ11 that is associated with NIDDM was differentially distributed in the 2 cohorts. We discuss the mutations identified, emphasise the importance of the K-ATP channel in physiological processes and discuss the possibility that the disease is caused by mutations in other genes associated with insulin release, glucose metabolism in the β cell or β cell apoptosis and survival. We propose that these processes must be explored in order to further our understanding of PHHI.


Beta Cell KATP Channel Putative Mutation Hyperinsulinemic Hypoglycaemia Sulfonylurea Receptor 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Dabrowski M, Tarasov A, Ashcroft FM. Mapping the architecture of the ATP binding site of the K-ATP channel subunit KIR6.2. The Journal of Physiology, 2004. 557(2): p. 347-354.PubMedCrossRefGoogle Scholar
  2. 2.
    Ashcroft FM. Adenosine 5’-triphosphate-sensitive potassium channels. Annu Rev Neurosci, 1988. 11: p. 97–118.PubMedCrossRefGoogle Scholar
  3. 3.
    Seino S. and T Miki. Physiological and pathophysiological roles of ATP sensitive potassium channels. Progress in biophysics and molecular biology,2003. 76: p. 133-176.CrossRefGoogle Scholar
  4. 4.
    Noma A. ATP-regulated K + channels in cardiac muscle. Nature, 1983. 305 (5930): p. 147-8.PubMedCrossRefGoogle Scholar
  5. 5.
    Cook DL, and Hales CN. Intracellular ATP directly blocks K + channels in pancreatic B-cells. Nature, 1984. 311(5983): p. 271-3.PubMedCrossRefGoogle Scholar
  6. 6.
    Dunne MJ, Cosgrove KE, Shepherd RM, Aynsley-Green A, Lindley KJ.Hyperinsulinism in Infancy: from Basic Science to Clinical Disease. Physiol Rev, 2004. 84(1): p. 239-275.PubMedCrossRefGoogle Scholar
  7. 7.
    Aguilar-Bryan L, Clement JP 4th, Gonzalez G, Kunjilwar K, Babenko A, Bryan J. Toward understanding the assembly and structure of KATP channels. Physiol Rev, 1998. 78(1): p. 227–245.PubMedGoogle Scholar
  8. 8.
    Inagaki N, Gonoi T, Clement JP 4th, Namba N, Inazawa J, Gonzalez G, Aguilar-Bryan L, Seino S, Bryan J. Reconstitution of IKATP an inward rectifier subunit plus the sulfonylurea receptor. Science, 1995. 270(5239): p. 1166.PubMedCrossRefGoogle Scholar
  9. 9.
    Shyng SL and Nichols CG. Octameric stoichiometry of the KATP channel complex. Journal of General Physiology, 1997. 110(6): p. 655–664.PubMedCrossRefGoogle Scholar
  10. 10.
    Zerangue N, Schwappach B, Jan YN, Jan LY. A new ER trafficking signal regulates the subunit stoichiometry of plasma membrane KATP channels. Neuron, 1999.22(3): p. 537–548.PubMedCrossRefGoogle Scholar
  11. 11.
    Aynsley-Green A, Hussain K, Hall J, Saudubray JM, Nihoul-Fekete C, De Lonlay-Debeney P, Brunelle F, Otonkoski T, Thornton P, Lindley KJ. Practical management of hyperinsulinism in infancy.Arch Dis Child Fetal Neonatal Ed. Arch Dis Child, 2000. 82(2): p. F98–F107.CrossRefGoogle Scholar
  12. 12.
    Jack MM, Greer RM, Thomsett MJ, Walker RM, Bell JR, Choong C, Cowley DM, Herington AC, Cotterill AM. The outcome in Australian children with hyperinsulinism of infancy: early extensive surgery in severe cases lowers risk of diabetes. Clin Endocrinol (Oxf), 2003. 58(3): p. 355-64.CrossRefGoogle Scholar
  13. 13.
    Davis EA, Cuesta-Munoz A, Raoul M, Buettger C, Sweet I, Moates M, Magnuson MA, Matschinsky FM. Mutants of glucokinase cause hypoglycaemia- and hyperglycaemia syndromes and their analysis illuminates fundamental quantitative concepts of glucose homeostasis. Diabetologia, 1999. 42(10): p. 1175-1186.PubMedCrossRefGoogle Scholar
  14. 14.
    Stanley CA, Lieu YK, Hsu BY, Burlina AB, Greenberg CR, Hopwood NJ, Perlman K, Rich BH, Zammarchi E, Poncz M. Hyperinsulinism and Hyperammonemia in Infants with Regulatory Mutations of the Glutamate Dehydrogenase Gene. N Engl J Med, 1998. 338(19): p. 1352-1357.PubMedCrossRefGoogle Scholar
  15. 15.
    Molven A, Matre GE, Duran M, Wanders RJ, Rishaug U, Njolstad PR, Jellum E, Sovik O. Familial Hyperinsulinemic Hypoglycemia caused by a defect in the SCHAD enzyme of mitochondrial fatty acid oxidation.Diabetes, 2004. 53(1): p. 221-227.PubMedCrossRefGoogle Scholar
  16. 16.
    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): p. 40-46.PubMedCrossRefGoogle Scholar
  17. 17.
    Ghosh A, Ronner P, Cheong E, Khalid P, Matschinsky FM. The role of ATP and free ADP in metabolic coupling during fuel-stimulated insulin release from islet β-cells in the isolated perfused rat pancreas. J Biol Chem, 1991. 266(34): p. 22887–22892.PubMedGoogle Scholar
  18. 18.
    Hansen L, Hansen T, Urhammer SA, Clausen JO, Pedersen O. Amino acid polymorphisms in the ATP-regulatable inward rectifier Kir6.2 and their relationships to glucose- and tolbutamide-induced insulin secretion, the insulin sensitivity index, and NIDDM. Diabetes 1997. 46: p. 508-512,PubMedCrossRefGoogle Scholar
  19. 19.
    MutDB, Indiana School of Medicine. (15th Aug 2005); Scholar
  20. 20.
    Uhde I, Toman A, Gross I, Schwanstecher C, Schwanstecher M. Identification of the potassium channel opener site on Sulfonylurea ReceptorsJ Biol Chem, 1999. 274(40): p. 28079-28082.PubMedCrossRefGoogle Scholar
  21. 21.
    Hani EH, Boutin P, Durand E, Inoue H, Permutt MA, Velho G, Froguel P. Missense mutations in the pancreatic islet beta cell inwardly rectifying K+ channel gene (KIR6.2/BIR): a meta-analysis suggests a role in the polygenic basis of Type II diabetes mellitus in Caucasians. Diabetologia, 1998. 41(12): p. 1511-1515.PubMedCrossRefGoogle Scholar
  22. 22.
    Elbein SC, Sun J, Scroggin E, Teng K, Hasstedt SJ. Role of Common Sequence Variants in Insulin Secretion in Familial Type 2 Diabetic Kindreds: The sulfonylurea receptor, glucokinase, and hepatocyte nuclear factor 1α genes. Diabetes Care, 2001. 24(3): p. 472-478.PubMedCrossRefGoogle Scholar
  23. 23.
    Kukuvitis A, Deal C, Arbour L, Polychronakos C. An autosomal dominant form of familial persistent hyperinsulinemic hypoglycemia of infancy, not linked to the sulfonylurea receptor locus. J Clin Endocrinol Metab, 1997. 82(4): p. 1192-1194.PubMedCrossRefGoogle Scholar
  24. 24.
    Gloyn AL, H.Y., Ashcroft SJ, Ashfield R, Gloyn AL, Hashim Y, Ashcroft SJ, Ashfield R,, Association studies of variants in promoter and coding regions of beta-cell ATP-sensitive K-channel genes SUR1 and Kir6.2 with Type 2 diabetes mellitus (UKPDS 53). Diabet Med, 2001. 18(3): p. 206-212.PubMedCrossRefGoogle Scholar
  25. 25.
    Kassem SA, Ariel I, Thornton PS, Scheimberg I, Glaser B. Beta cell proliferation and apoptosis in the developing normal pancreas and in Hyperinsulinism of Infancy. Diabetes, 2000. 49(8): p. 1325-1333.PubMedCrossRefGoogle Scholar
  26. 26.
    Voet, D. and J. Voet, Biochemistry. Second ed. 1995: John Wiley & Sons Inc.Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • J.H. Shah
    • 1
    • 2
  • D.J. Maguire
    • 1
  • D. Brown
    • 2
  • A. Cotterill
    • 2
  1. 1.School of Biomolecular and Biomedical SciencesGriffith UniversityNathanAustralia
  2. 2.Dept of Paediatric EndocrinologyMater Children’s HospitalBristaneAustralia

Personalised recommendations