Abstract
Persistent hyperinsulinemic hypoglycemia of infancy (PHHI) is a disorder of childhood associated with inappropriate hypersecretion of insulin by the pancreas. The pathogenesis of the condition has hitherto remained controversial. We show here that insulinsecreting cells from a homogeneous group of five infants with PHHI lack ATP–sensitive K+ channel (KATP) activity. As a consequence, PHHI β–cells are spontaneously electrically active with high basal cytosolic Ca2+ concentrations due to Ca2+ influx. Our findings define the pathogenesis of this disease as a novel K+ channel disorder.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Morris, A.A.M. et al. Evaluation of fasts for investigating hypoglycaemia or suspected metabolic disease. Arch. Dis. Child. 75, 115–119 (1996).
Aynsley-Green, A. Nesidioblastosis of the pancreas in infancy. Dev. Med. Child. Neurol. 23, 372–9 (1981).
Aynsley-Green, A. et al. Nesidioblastosis of the pancreas: Definition of the syndrome and the management of the severe neonatal hyperinsulinaemic hypoglycaemia. Arch. Dis. Child. 56, 496–508 (1981).
Woolf, D.A., Leonard, J.V., Trembath, R.C., Pembury, M. & Grant, D.B., Evidence for an autosomal recessive variant. Arch. Dis. Child. 66, 529–530 (1991).
Thornton, P.S. et al. Familial hyperinsulinism (HI) inherited in an autosomal dominant (AD) form differs clinically and genetically from the more common autosomal recessive (AR) form. Pediatr. Res. 37, 100A (1995).
Spitz, L., Bhargav, R.K., Grant, D.B. & Leonard, J.V., Surgical treatment of hyperinsulinaemic hypoglycaemia in infancy and childhood. Arch. Dis. Child. 67, 201–205 (1992).
Kaiser, N. et al. Regulation of insulin release in persistent hyperinsulinaemic hypoglycaemia of infancy studied in long-term culture of pancreatic tissue. Diabetologia 33, 482–488 (1990).
Glaser, B. et al. Familial hyperinsulinism maps to chromosome 11pl4–15.1, 30 cM centromeric to the insulin gene. Nature Genet. 7, 185–188 (1994).
Thomas, P.M. et al. Mutations in the sulfonylurea receptor gene in familial hyperinsulinemic hypoglycemia of infancy. Science 268, 426–429 (1995).
Aguilar-Bryan, L. et al. Cloning of the beta Cell high-affinity sulfonylurea receptor: A regulator of insulin secretion. Science 268, 423–426 (1995).
Inagaki, N. et al. Reconstitution of IKATP: An inward rectifier subunit plus the sulfonylurea receptor. Science 270, 1166–1170 (1995).
Ashcroft, F.M., Harrison, D.E. & Ashcroft, S.J.H., Glucose induces closure of single potassium channels in isolated rat pancreatic beta-Cells. Nature 312, 446–448 (1984).
Dunne, M.J. & Petersen, O.H., Potassium selective ion channels in insulin-secreting Cells: Physiology, pharmacology and their role in stimulus secretion coupling. Biochim. Biophys. Acta (Rev. Biomembr.) 1071, 67–82 (1991).
Mathew, P.M. et al. Persistent neonatal hyperinsulinism. Clin. Pediatr (USA) 27, 148–151 (1988).
Sempoux, C. et al. Nesidioblastosis and persistent neonatal hyperinsulinism. Diabete Metab. 21, 402–407 (1995).
Sakura, H., Ämmälä, C., Smith, P.A., Gribble, F.M. & Ashcroft, F.M. Cloning and functional expression of the cDNA encoding a novel ATP-sensitive potassium channel expressed in pancreatic B-cells, brain, heart and skeletal muscle. FEBS Lett. 377, 338–344 (1995).
Nichols, C.G. et al. Adenosine diphosphate as an intraCellular regulator of insulin secretion. Science 272, 1785–1787 (1996).
Welsh, M.J. & Smith, H.E., (1993) Molecular mechanisms of CFTR chloride channel dysfunction in cystic fibrosis. Cell 73, 1251–1254.
Kristidis, P. et al. Genetic determination of exocrine pancreatic function in cystic fibrosis. Am. J. Hum. Genet. 50, 1178–1184 (1992).
Sheppard, D.N. et al. Mutations in CFTR associated with mild-disease-forms of cr channels with altered pore properties. Nature 362, 160–164 (1993).
Higgins, C.F. The ABC of channel regulation. Cell 82, 693–618 (1995).
Lindley, K.J. et al. Ionic control of β-Cell function in nesidioblastosis: A possible therapeutic role for calcium channel blockade. Arch. Dis. Child. 74, 373–378 (1996).
Brandhorst, H., Klitcsher, D., Hering, B.J., Ferderlin, R. & Bretzel, R.G., Influence of organ procurement on human islet isolation. Harm. Metab. Res. 25, 51–52 (1993).
Hamill, O.P., Marty, A., Neher, E., Sakmann, B. & Sigworth, F.J., Improved patch-clamp techniques for high-resolution current recording from Cells and Cell-free membrane patches. Pfluegers Arch., 391, 85–100 (1981).
Lebrun, P. et al. Activation of ATP-dependent K+ channels and inhibition of insulin release; effect of BPDZ-62. J. Pharmacol. Exp. Ther. 277, 156–162 (1996).
Squires, P.E., James, R.F.L., London, N.J.M. & Dunne, M.J. ATP-induced intracellular Ca2+ signals in isolated human insulin-secreting Cells. Pfluegers Arch. 427, 181–183 (1994).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Kane, C., Shepherd, R., Squires, P. et al. Loss of functional KATP channels in pancreatic β–cells causes persistent hyperinsulinemic hypoglycemia of infancy. Nat Med 2, 1344–1347 (1996). https://doi.org/10.1038/nm1296-1344
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/nm1296-1344
This article is cited by
-
Genetic variants of ABCC8 and clinical manifestations in eight Chinese children with hyperinsulinemic hypoglycemia
BMC Endocrine Disorders (2024)
-
Role of cytosolic and endoplasmic reticulum Ca2+ in pancreatic beta-cells: pros and cons
Pflügers Archiv - European Journal of Physiology (2024)
-
Hyperinsulinaemic hypoglycaemia—an overview of a complex clinical condition
European Journal of Pediatrics (2019)
-
Calcium Oscillation Frequency-Sensitive Gene Regulation and Homeostatic Compensation in Pancreatic \(\upbeta \)-Cells
Bulletin of Mathematical Biology (2017)
-
Genotype and phenotype correlations in Iranian patients with hyperinsulinaemic hypoglycaemia
BMC Research Notes (2015)