Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1997 Oct 1;100(7):1888–1893. doi: 10.1172/JCI119718

Therapy for persistent hyperinsulinemic hypoglycemia of infancy. Understanding the responsiveness of beta cells to diazoxide and somatostatin.

C Kane 1, K J Lindley 1, P R Johnson 1, R F James 1, P J Milla 1, A Aynsley-Green 1, M J Dunne 1
PMCID: PMC508376  PMID: 9312191

Abstract

The neonatal disorder persistent hyperinsulinemic hypoglycemia of infancy (PHHI) arises as the result of mutations in the subunits that form the ATP-sensitive potassium (KATP) channel in pancreatic beta cells, leading to insulin hypersecretion. Diazoxide (a specific KATP channel agonist in normal beta cells) and somatostatin (octreotide) are the mainstay of medical treatment for the condition. To investigate the mechanism of action of these agents in PHHI beta cells that lack KATP currents, we applied patch clamp techniques to insulin-secreting cells isolated from seven patients with PHHI. Five patients showed favorable responses to medical therapy, and two were refractory. Our data reveal, in drug-responsive patients, that a novel ion channel is modulated by diazoxide and somatostatin, leading to termination of the spontaneous electrical events that underlie insulin hypersecretion. The drug-resistant patients, both of whom carried a mutation in one of the genes that encode KATP channel subunits, also lacked this novel K+ channel. There were no effects of diazoxide and somatostatin on beta cell function in vitro. These findings elucidate for the first time the mechanisms of action of diazoxide and somatostatin in infants with PHHI in whom KATP channels are absent, and provide a rationale for development of new therapeutic opportunities by K+ channel manipulation in PHHI treatment.

Full Text

The Full Text of this article is available as a PDF (200.8 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Aguilar-Bryan L., Nichols C. G., Wechsler S. W., Clement J. P., 4th, Boyd A. E., 3rd, González G., Herrera-Sosa H., Nguy K., Bryan J., Nelson D. A. Cloning of the beta cell high-affinity sulfonylurea receptor: a regulator of insulin secretion. Science. 1995 Apr 21;268(5209):423–426. doi: 10.1126/science.7716547. [DOI] [PubMed] [Google Scholar]
  2. Aynsley-Green A. Nesidioblastosis of the pancreas in infancy. Dev Med Child Neurol. 1981 Jun;23(3):372–379. [PubMed] [Google Scholar]
  3. Aynsley-Green A., Polak J. M., Bloom S. R., Gough M. H., Keeling J., Ashcroft S. J., Turner R. C., Baum J. D. Nesidioblastosis of the pancreas: definition of the syndrome and the management of the severe neonatal hyperinsulinaemic hypoglycaemia. Arch Dis Child. 1981 Jul;56(7):496–508. doi: 10.1136/adc.56.7.496. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Dunne M. J., Kane C., Shepherd R. M., Sanchez J. A., James R. F., Johnson P. R., Aynsley-Green A., Lu S., Clement J. P., 4th, Lindley K. J. Familial persistent hyperinsulinemic hypoglycemia of infancy and mutations in the sulfonylurea receptor. N Engl J Med. 1997 Mar 6;336(10):703–706. doi: 10.1056/NEJM199703063361005. [DOI] [PubMed] [Google Scholar]
  5. 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. 1991 Mar 7;1071(1):67–82. doi: 10.1016/0304-4157(91)90012-l. [DOI] [PubMed] [Google Scholar]
  6. Glaser B., Chiu K. C., Anker R., Nestorowicz A., Landau H., Ben-Bassat H., Shlomai Z., Kaiser N., Thornton P. S., Stanley C. A. Familial hyperinsulinism maps to chromosome 11p14-15.1, 30 cM centromeric to the insulin gene. Nat Genet. 1994 Jun;7(2):185–188. doi: 10.1038/ng0694-185. [DOI] [PubMed] [Google Scholar]
  7. Glaser B., Hirsch H. J., Landau H. Persistent hyperinsulinemic hypoglycemia of infancy: long-term octreotide treatment without pancreatectomy. J Pediatr. 1993 Oct;123(4):644–650. doi: 10.1016/s0022-3476(05)80970-9. [DOI] [PubMed] [Google Scholar]
  8. Grant D. B., Dunger D. B., Burns E. C. Long-term treatment with diazoxide in childhood hyperinsulinism. Acta Endocrinol Suppl (Copenh) 1986;279:340–345. doi: 10.1530/acta.0.112s340. [DOI] [PubMed] [Google Scholar]
  9. Hirsch H. J., Loo S., Evans N., Crigler J. F., Filler R. M., Gabbay K. H. Hypoglycemia of infancy and nesidioblastosis. Studies with somatostatin. N Engl J Med. 1977 Jun 9;296(23):1323–1326. doi: 10.1056/NEJM197706092962305. [DOI] [PubMed] [Google Scholar]
  10. Inagaki N., Gonoi T., Clement J. P., 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 Nov 17;270(5239):1166–1170. doi: 10.1126/science.270.5239.1166. [DOI] [PubMed] [Google Scholar]
  11. Kane C., Shepherd R. M., Squires P. E., Johnson P. R., James R. F., Milla P. J., Aynsley-Green A., Lindley K. J., Dunne M. J. Loss of functional KATP channels in pancreatic beta-cells causes persistent hyperinsulinemic hypoglycemia of infancy. Nat Med. 1996 Dec;2(12):1344–1347. doi: 10.1038/nm1296-1344. [DOI] [PubMed] [Google Scholar]
  12. Lindley K. J., Dunne M. J., Kane C., Shepherd R. M., Squires P. E., James R. F., Johnson P. R., Eckhardt S., Wakeling E., Dattani M. Ionic control of beta cell function in nesidioblastosis. A possible therapeutic role for calcium channel blockade. Arch Dis Child. 1996 May;74(5):373–378. doi: 10.1136/adc.74.5.373. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Nestorowicz A., Wilson B. A., Schoor K. P., Inoue H., Glaser B., Landau H., Stanley C. A., Thornton P. S., Clement J. P., 4th, Bryan J. Mutations in the sulonylurea receptor gene are associated with familial hyperinsulinism in Ashkenazi Jews. Hum Mol Genet. 1996 Nov;5(11):1813–1822. doi: 10.1093/hmg/5.11.1813. [DOI] [PubMed] [Google Scholar]
  14. Nichols C. G., Shyng S. L., Nestorowicz A., Glaser B., Clement J. P., 4th, Gonzalez G., Aguilar-Bryan L., Permutt M. A., Bryan J. Adenosine diphosphate as an intracellular regulator of insulin secretion. Science. 1996 Jun 21;272(5269):1785–1787. doi: 10.1126/science.272.5269.1785. [DOI] [PubMed] [Google Scholar]
  15. Pirotte B., de Tullio P., Lebrun P., Antoine M. H., Fontaine J., Masereel B., Schynts M., Dupont L., Herchuelz A., Delarge J. 3-(Alkylamino)-4H-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxides as powerful inhibitors of insulin release from rat pancreatic B-cells: a new class of potassium channel openers? J Med Chem. 1993 Oct 15;36(21):3211–3213. doi: 10.1021/jm00073a025. [DOI] [PubMed] [Google Scholar]
  16. Sempoux C., Poggi F., Brunelle F., Saudubray J. M., Fekete C., Rahier J. Nesidioblastosis and persistent neonatal hyperinsulinism. Diabete Metab. 1995 Dec;21(6):402–407. [PubMed] [Google Scholar]
  17. Spitz L., Bhargava R. K., Grant D. B., Leonard J. V. Surgical treatment of hyperinsulinaemic hypoglycaemia in infancy and childhood. Arch Dis Child. 1992 Feb;67(2):201–205. doi: 10.1136/adc.67.2.201. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Thomas P. M., Cote G. J., Wohllk N., Haddad B., Mathew P. M., Rabl W., Aguilar-Bryan L., Gagel R. F., Bryan J. Mutations in the sulfonylurea receptor gene in familial persistent hyperinsulinemic hypoglycemia of infancy. Science. 1995 Apr 21;268(5209):426–429. doi: 10.1126/science.7716548. [DOI] [PubMed] [Google Scholar]
  19. Thomas P. M., Wohllk N., Huang E., Kuhnle U., Rabl W., Gagel R. F., Cote G. J. Inactivation of the first nucleotide-binding fold of the sulfonylurea receptor, and familial persistent hyperinsulinemic hypoglycemia of infancy. Am J Hum Genet. 1996 Sep;59(3):510–518. [PMC free article] [PubMed] [Google Scholar]
  20. Thomas P., Ye Y., Lightner E. Mutation of the pancreatic islet inward rectifier Kir6.2 also leads to familial persistent hyperinsulinemic hypoglycemia of infancy. Hum Mol Genet. 1996 Nov;5(11):1809–1812. doi: 10.1093/hmg/5.11.1809. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES