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Medical Management of Hyperinsulinism

  • Khalid Hussain
  • Thomas Meissner
  • Jean-Baptiste ArnouxEmail author
Chapter
Part of the Contemporary Endocrinology book series (COE)

Abstract

Congenital hyperinsulinism (HI) comprises conditions of various initial severities, which might improve with time. Short-term management, to normalize glycemia and avoid brain damage, frequently includes the use of glucagon and intravenous and/or enteral dextrose. A long-term medical management plan is considered when the condition does not resolve over a few days or is not curable by a selective and partial pancreatectomy. The long-term management plan must be tailored for each patient, weighting the limitations, side effects, and contraindications of each drug. When the patient is not responsive to diazoxide, the first-line oral treatment, treatment with a somatostatin analogue is usually considered. If the efficacy of somatostatin analogues is not sufficient to prevent hypoglycemia, alternative measures may include carbohydrate-enriched diets, sometimes through an enteral tube (nasogastric or gastric) and/or continuous enteral dextrose.

Keywords

Diazoxide Glucagon Octreotide Lanreotide mTOR inhibitor Calcium blockers Enteral feeding 

References

  1. 1.
    Lord K, Dzata E, Snider KE, Gallagher PR, De Leon DD. Clinical presentation and management of children with diffuse and focal hyperinsulinism: a review of 223 cases. J Clin Endocrinol Metab. 2013;98:E1786–9.  https://doi.org/10.1210/jc.2013-2094.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Lord K, et al. High risk of diabetes and neurobehavioral deficits in individuals with surgically treated hyperinsulinism. J Clin Endocrinol Metab. 2015;100:4133–9.  https://doi.org/10.1210/jc.2015-2539.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Beltrand J, et al. Glucose metabolism in 105 children and adolescents after pancreatectomy for congenital hyperinsulinism. Diabetes Care. 2012;35:198–203.  https://doi.org/10.2337/dc11-1296.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Welters A, et al. Long-term medical treatment in congenital hyperinsulinism: a descriptive analysis in a large cohort of patients from different clinical centers. Orphanet J Rare Dis. 2015;10:150.  https://doi.org/10.1186/s13023-015-0367-x.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Gataullina S, et al. Comorbidity and metabolic context are crucial factors determining neurological sequelae of hypoglycaemia. Dev Med Child Neurol. 2012;54:1012–7.  https://doi.org/10.1111/j.1469-8749.2012.04400.x.CrossRefPubMedGoogle Scholar
  6. 6.
    Hussain K, Hindmarsh P, Aynsley-Green A. Neonates with symptomatic hyperinsulinemic hypoglycemia generate inappropriately low serum cortisol counterregulatory hormonal responses. J Clin Endocrinol Metab. 2003;88:4342–7.  https://doi.org/10.1210/jc.2003-030135.CrossRefPubMedGoogle Scholar
  7. 7.
    Hussain K, Bryan J, Christesen HT, Brusgaard K, Aguilar-Bryan L. Serum glucagon counterregulatory hormonal response to hypoglycemia is blunted in congenital hyperinsulinism. Diabetes. 2005;54:2946–51.CrossRefGoogle Scholar
  8. 8.
    Hussain K, Blankenstein O, De Lonlay P, Christesen HT. Hyperinsulinaemic hypoglycaemia: biochemical basis and the importance of maintaining normoglycaemia during management. Arch Dis Child. 2007;92:568–70.  https://doi.org/10.1136/adc.2006.115543.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Thornton PS, et al. Recommendations from the pediatric endocrine society for evaluation and management of persistent hypoglycemia in neonates, infants, and children. J Pediatr. 2015;167:238–45.  https://doi.org/10.1016/j.jpeds.2015.03.057.CrossRefPubMedGoogle Scholar
  10. 10.
    Arnoux JB, et al. Congenital hyperinsulinism: current trends in diagnosis and therapy. Orphanet J Rare Dis. 2011;6:63.  https://doi.org/10.1186/1750-1172-6-63.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Rubin AA, Roth FE, Taylor RM, Rosenkilde H. Pharmacology of diazoxide, an antihypertensive, nondiuretic benzothiadiazine. J Pharmacol Exp Ther. 1962;136:344–52.PubMedGoogle Scholar
  12. 12.
    Black J. Diazoxide and the treatment of hypoglycemia: an historical review. Ann N Y Acad Sci. 1968;150:194–203.CrossRefGoogle Scholar
  13. 13.
    Hennessy A, et al. A randomised comparison of hydralazine and mini-bolus diazoxide for hypertensive emergencies in pregnancy: the PIVOT trial. Aust N Z J Obstet Gynaecol. 2007;47:279–85.  https://doi.org/10.1111/j.1479-828X.2007.00738.x.CrossRefPubMedGoogle Scholar
  14. 14.
    Quast U, Cook NS. Moving together: K+ channel openers and ATP-sensitive K+ channels. Trends Pharmacol Sci. 1989;10:431–5.  https://doi.org/10.1016/S0165-6147(89)80003-3.CrossRefPubMedGoogle Scholar
  15. 15.
    Standen NB, et al. Hyperpolarizing vasodilators activate ATP-sensitive K+ channels in arterial smooth muscle. Science. 1989;245:177–80.CrossRefGoogle Scholar
  16. 16.
    Drash A, Wolff F. Drug therapy in leucine-sensitive hypoglycemia. Metabolism. 1964;13:487–92.CrossRefGoogle Scholar
  17. 17.
    Garrino MG, Plant TD, Henquin JC. Effects of putative activators of K+ channels in mouse pancreatic beta-cells. Br J Pharmacol. 1989;98:957–65.CrossRefGoogle Scholar
  18. 18.
    Trube G, Rorsman P, Ohno-Shosaku T. Opposite effects of tolbutamide and diazoxide on the ATP-dependent K+ channel in mouse pancreatic beta-cells. Pflugers Arch. 1986;407:493–9.CrossRefGoogle Scholar
  19. 19.
    Garlid KD, Paucek P, Yarov-Yarovoy V, Sun X, Schindler PA. The mitochondrial KATP channel as a receptor for potassium channel openers. J Biol Chem. 1996;271:8796–9.CrossRefGoogle Scholar
  20. 20.
    Drose S, Brandt U, Hanley PJ. K+-independent actions of diazoxide question the role of inner membrane KATP channels in mitochondrial cytoprotective signaling. J Biol Chem. 2006;281:23733–9.  https://doi.org/10.1074/jbc.M602570200.CrossRefPubMedGoogle Scholar
  21. 21.
    Drose S, Hanley PJ, Brandt U. Ambivalent effects of diazoxide on mitochondrial ROS production at respiratory chain complexes I and III. Biochim Biophys Acta. 2009;1790:558–65.  https://doi.org/10.1016/j.bbagen.2009.01.011.CrossRefPubMedGoogle Scholar
  22. 22.
    Martin GM, et al. Pharmacological correction of trafficking defects in ATP-sensitive potassium channels caused by sulfonylurea receptor 1 mutations. J Biol Chem. 2016;291:21971–83.  https://doi.org/10.1074/jbc.M116.749366.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Cooper PE, Sala-Rabanal M, Lee SJ, Nichols CG. Differential mechanisms of Cantu syndrome-associated gain of function mutations in the ABCC9 (SUR2) subunit of the KATP channel. J Gen Physiol. 2015;146:527–40.  https://doi.org/10.1085/jgp.201511495.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Yoshida K, et al. High prevalence of severe circulatory complications with diazoxide in premature infants. Neonatology. 2014;105:166–71.  https://doi.org/10.1159/000356772.CrossRefPubMedGoogle Scholar
  25. 25.
    Timlin MR, Black AB, Delaney HM, Matos RI, Percival CS. Development of pulmonary hypertension during treatment with Diazoxide: a case series and literature review. Pediatr Cardiol. 2017;38:1247–50.  https://doi.org/10.1007/s00246-017-1652-3.CrossRefPubMedGoogle Scholar
  26. 26.
    Communication, F. D. S. Pulmonary hypertension in infants and newborns. Available at: http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm455125.htm (July 2015).
  27. 27.
    Abu-Osba YK, Manasra KB, Mathew PM. Complications of diazoxide treatment in persistent neonatal hyperinsulinism. Arch Dis Child. 1989;64:1496–500.CrossRefGoogle Scholar
  28. 28.
    Ponmani C, Gannon H, Hussain K, Senniappan S. Paradoxical hypoglycaemia associated with diazoxide therapy for hyperinsulinaemic hypoglycaemia. Horm Res Paediatr. 2013;80:129–33.  https://doi.org/10.1159/000353773.CrossRefPubMedGoogle Scholar
  29. 29.
    Milner RD, Chouksey SK. Effects of fetal exposure to diazoxide in man. Arch Dis Child. 1972;47:537–43.CrossRefGoogle Scholar
  30. 30.
    Baker Norton Pharmaceuticals, I. 670–671 (Medical Economics Data, Montvale, 1993).Google Scholar
  31. 31.
    Smoak IW. Embryopathic effects of diazoxide and the reduction of sulfonylurea-induced dysmorphogenesis in vitro. Toxicol In Vitro. 1994;8:1121–7.CrossRefGoogle Scholar
  32. 32.
    Lamberts SW, van der Lely AJ, de Herder WW, Hofland L. J Octreotide N Engl J Med. 1996;334:246–54.  https://doi.org/10.1056/NEJM199601253340408.CrossRefGoogle Scholar
  33. 33.
    Plockinger U, Holst JJ, Messerschmidt D, Hopfenmuller W, Quabbe HJ. Octreotide suppresses the incretin glucagon-like peptide (7–36) amide in patients with acromegaly or clinically nonfunctioning pituitary tumors and in healthy subjects. Eur J Endocrinol. 1999;140:538–44.CrossRefGoogle Scholar
  34. 34.
    Grosman I, Simon D. Potential gastrointestinal uses of somatostatin and its synthetic analogue octreotide. Am J Gastroenterol. 1990;85:1061–72.PubMedGoogle Scholar
  35. 35.
    Hirsch HJ, et al. Hypoglycemia of infancy and nesidioblastosis. Studies with somatostatin. N Engl J Med. 1977;296:1323–6.  https://doi.org/10.1056/NEJM197706092962305.CrossRefPubMedGoogle Scholar
  36. 36.
    Aynsley-Green A, et al. Effect of somatostatin infusion on intermediary metabolism and entero-insular hormone release in infants with hyperinsulinaemic hypoglycaemia. Acta Paediatr Scand. 1981;70:889–95.CrossRefGoogle Scholar
  37. 37.
    U.S. Food and Drug Administration Web site. Sandostatin (octreotide acetate) injection. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2003/19667scm044_Sandostatin_lbl.pdf.
  38. 38.
    Glaser B, Landau H, Smilovici A, Nesher R. Persistent hyperinsulinaemic hypoglycaemia of infancy: long-term treatment with the somatostatin analogue Sandostatin. Clin Endocrinol. 1989;31:71–80.CrossRefGoogle Scholar
  39. 39.
    Glaser B, Landaw H. Long-term treatment with the somatostatin analogue SMS 201–995: alternative to pancreatectomy in persistent hyperinsulinaemic hypoglycaemia of infancy. Digestion. 1990;45(Suppl 1):27–35.  https://doi.org/10.1159/000200258.CrossRefPubMedGoogle Scholar
  40. 40.
    Glaser B, Hirsch HJ, Landau H. Persistent hyperinsulinemic hypoglycemia of infancy: long-term octreotide treatment without pancreatectomy. J Pediatr. 1993;123:644–50.CrossRefGoogle Scholar
  41. 41.
    Thornton PS, Alter CA, Katz LE, Baker L, Stanley CA. Short- and long-term use of octreotide in the treatment of congenital hyperinsulinism. J Pediatr. 1993;123:637–43.CrossRefGoogle Scholar
  42. 42.
    Yorifuji T, et al. Efficacy and safety of long-term, continuous subcutaneous octreotide infusion for patients with different subtypes of KATP-channel hyperinsulinism. Clin Endocrinol. 2013;78:891–7.  https://doi.org/10.1111/cen.12075.CrossRefGoogle Scholar
  43. 43.
    Palladino AA, Stanley CA. A specialized team approach to diagnosis and medical versus surgical treatment of infants with congenital hyperinsulinism. Semin Pediatr Surg. 2011;20:32–7.  https://doi.org/10.1053/j.sempedsurg.2010.10.008.CrossRefPubMedGoogle Scholar
  44. 44.
    Demirbilek H, et al. Long-term follow-up of children with congenital hyperinsulinism on octreotide therapy. J Clin Endocrinol Metab. 2014;99:3660–7.  https://doi.org/10.1210/jc.2014-1866.CrossRefPubMedGoogle Scholar
  45. 45.
    Laje P, Halaby L, Adzick NS, Stanley CA. Necrotizing enterocolitis in neonates receiving octreotide for the management of congenital hyperinsulinism. Pediatr Diabetes. 2010;11:142–7.  https://doi.org/10.1111/j.1399-5448.2009.00547.x.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    McMahon AW, Wharton GT, Thornton P, De Leon DD. Octreotide use and safety in infants with hyperinsulinism. Pharmacoepidemiol Drug Saf. 2017;26:26–31.  https://doi.org/10.1002/pds.4144.CrossRefPubMedGoogle Scholar
  47. 47.
    Hawkes CP, Adzick NS, Palladino AA, De Leon DD. Late presentation of fulminant necrotizing enterocolitis in a child with hyperinsulinism on octreotide therapy. Horm Res Paediatr. 2016;86:131–6.  https://doi.org/10.1159/000443959.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Ronchi CL, et al. Efficacy of a slow-release formulation of lanreotide (Autogel) 120 mg in patients with acromegaly previously treated with octreotide long acting release (LAR): an open, multicentre longitudinal study. Clin Endocrinol. 2007;67:512–9.  https://doi.org/10.1111/j.1365-2265.2007.02917.x.CrossRefGoogle Scholar
  49. 49.
    Bakker B, Oostdijk W. Diagnosis and management of congenital hyperinsulinism: a case report. Eur J Endocrinol. 2006;155:S153–5.CrossRefGoogle Scholar
  50. 50.
    Modan-Moses D, Koren I, Mazor-Aronovitch K, Pinhas-Hamiel O, Landau H. Treatment of congenital hyperinsulinism with Lanreotide acetate (Somatuline Autogel). J Clin Endocrinol Metab. 2011;96:2312–7.  https://doi.org/10.1210/jc.2011-0605.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Le Quan Sang K-H, et al. Successful treatment of congenital hyperinsulinism with long-acting release octreotide. Eur J Endocrinol. 2012;166:333–9.  https://doi.org/10.1530/eje-11-0874.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Kuhnen P, et al. Long-term lanreotide treatment in six patients with congenital hyperinsulinism. Horm Res Paediatr. 2012;78:106–12.  https://doi.org/10.1159/000341525.CrossRefPubMedGoogle Scholar
  53. 53.
    Corda H, et al. Treatment with long-acting lanreotide autogel in early infancy in patients with severe neonatal hyperinsulinism. Orphanet J Rare Dis. 2017;12:108.  https://doi.org/10.1186/s13023-017-0653-x.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    de Lonlay P, et al. Heterogeneity of persistent hyperinsulinaemic hypoglycaemia. A series of 175 cases. Eur J Pediatr. 2002;161:37–48.CrossRefGoogle Scholar
  55. 55.
    Hosokawa Y, et al. Efficacy and safety of octreotide for the treatment of congenital hyperinsulinism: a prospective, open-label clinical trial and an observational study in Japan using a nationwide registry. Endocr J. 2017;64:867–80.  https://doi.org/10.1507/endocrj.EJ17-0024.CrossRefPubMedGoogle Scholar
  56. 56.
    Szollosi A, Nenquin M, Henquin JC. Pharmacological stimulation and inhibition of insulin secretion in mouse islets lacking ATP-sensitive K+ channels. Br J Pharmacol. 2010;159:669–77.  https://doi.org/10.1111/j.1476-5381.2009.00588.x.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Yamaguchi I, Akimoto Y, Nakajima H, Kiyomoto A. Effect of diltiazem on insulin secretion. I. Experiments in vitro. Jpn J Pharmacol. 1977;27:679–87.CrossRefGoogle Scholar
  58. 58.
    Braun M, et al. Voltage-gated ion channels in human pancreatic beta-cells: electrophysiological characterization and role in insulin secretion. Diabetes. 2008;57:1618–28.  https://doi.org/10.2337/db07-0991.CrossRefPubMedGoogle Scholar
  59. 59.
    Lindley KJ, et al. Ionic control of beta cell function in nesidioblastosis. A possible therapeutic role for calcium channel blockade. Arch Dis Child. 1996;74:373–8.CrossRefGoogle Scholar
  60. 60.
    De Marinis L, Barbarino A. Calcium antagonists and hormone release. I. Effects of verapamil on insulin release in normal subjects and patients with islet-cell tumor. Metabolism. 1980;29:599–604.CrossRefGoogle Scholar
  61. 61.
    Guemes M, et al. Assessment of nifedipine therapy in hyperinsulinemic hypoglycemia due to mutations in the ABCC8 gene. J Clin Endocrinol Metab. 2017;102:822–30.  https://doi.org/10.1210/jc.2016-2916.CrossRefPubMedGoogle Scholar
  62. 62.
    Huang K, Fingar DC. Growing knowledge of the mTOR signaling network. Semin Cell Dev Biol. 2014;36:79–90.  https://doi.org/10.1016/j.semcdb.2014.09.011.CrossRefPubMedGoogle Scholar
  63. 63.
    Alexandrescu S, Tatevian N, Olutoye O, Brown RE. Persistent hyperinsulinemic hypoglycemia of infancy: constitutive activation of the mTOR pathway with associated exocrine-islet transdifferentiation and therapeutic implications. Int J Clin Exp Pathol. 2010;3:691–705.PubMedPubMedCentralGoogle Scholar
  64. 64.
    Wullschleger S, Loewith R, Hall MN. TOR signaling in growth and metabolism. Cell. 2006;124:471–84.  https://doi.org/10.1016/j.cell.2006.01.016.CrossRefPubMedGoogle Scholar
  65. 65.
    Leibiger IB, Leibiger B, Moede T, Berggren PO. Exocytosis of insulin promotes insulin gene transcription via the insulin receptor/PI-3 kinase/p70 s6 kinase and CaM kinase pathways. Mol Cell. 1998;1:933–8.CrossRefGoogle Scholar
  66. 66.
    Senniappan S, et al. Sirolimus therapy in infants with severe hyperinsulinemic hypoglycemia. N Engl J Med. 2014;370:1131–7.  https://doi.org/10.1056/NEJMoa1310967.CrossRefPubMedGoogle Scholar
  67. 67.
    Abraham MB, et al. Efficacy and safety of sirolimus in a neonate with persistent hypoglycaemia following near-total pancreatectomy for hyperinsulinaemic hypoglycaemia. JPEM. 2015;28:1391–8.  https://doi.org/10.1515/jpem-2015-0094.CrossRefPubMedGoogle Scholar
  68. 68.
    Minute M, et al. Sirolimus therapy in congenital hyperinsulinism: a successful experience beyond infancy. Pediatrics. 2015;136:e1373–6.  https://doi.org/10.1542/peds.2015-1132.CrossRefPubMedGoogle Scholar
  69. 69.
    Unal S, et al. A novel homozygous mutation in the KCNJ11 gene of a neonate with congenital hyperinsulinism and successful management with Sirolimus. J Clin Res Pediatr Endocrinol. 2016;8:478–81.  https://doi.org/10.4274/jcrpe.2773.CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Shah P, et al. Sirolimus therapy in a patient with severe hyperinsulinaemic hypoglycaemia due to a compound heterozygous ABCC8 gene mutation. JPEM. 2015;28:695–9.  https://doi.org/10.1515/jpem-2014-0371.CrossRefPubMedGoogle Scholar
  71. 71.
    Szymanowski M, et al. mTOR inhibitors for the treatment of severe congenital hyperinsulinism: perspectives on limited therapeutic success. J Clin Endocrinol Metab. 2016;101:4719–29.  https://doi.org/10.1210/jc.2016-2711.CrossRefPubMedGoogle Scholar
  72. 72.
    Banerjee I, De Leon D, Dunne MJ. Extreme caution on the use of sirolimus for the congenital hyperinsulinism in infancy patient. Orphanet J Rare Dis. 2017;12:70.  https://doi.org/10.1186/s13023-017-0621-5.CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Calabria AC, Li C, Gallagher PR, Stanley CA, De Leon DD. GLP-1 receptor antagonist exendin-(9-39) elevates fasting blood glucose levels in congenital hyperinsulinism owing to inactivating mutations in the ATP-sensitive K+ channel. Diabetes. 2012;61:2585–91.  https://doi.org/10.2337/db12-0166.CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Patel P, et al. A unique allosteric insulin receptor monoclonal antibody that prevents hypoglycemia in the SUR-1(-/-) mouse model of KATP hyperinsulinism. MAbs. 2018;10:796–802.  https://doi.org/10.1080/19420862.2018.1457599.CrossRefPubMedGoogle Scholar
  75. 75.
    Johnson KW, et al. Attenuation of insulin action by an allosteric insulin receptor antibody in healthy volunteers. J Clin Endocrinol Metab. 2017;102:3021–8.  https://doi.org/10.1210/jc.2017-00822.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Khalid Hussain
    • 1
  • Thomas Meissner
    • 2
  • Jean-Baptiste Arnoux
    • 3
  1. 1.Department of Pediatric Medicine, Division of EndocrinologySidra MedicineDohaQatar
  2. 2.Department of Pediatric EndocrinologyUniversity Children’s HospitalDüsseldorfGermany
  3. 3.Reference Centre for Inherited Metabolic Diseases, Necker-Enfants Malades HospitalParis Descartes University, APHPParisFrance

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