Skip to main content

Advertisement

SpringerLink
Log in

Hyperinsulinaemic hypoglycaemia—an overview of a complex clinical condition

  • Review
  • Published:
European Journal of Pediatrics Aims and scope Submit manuscript

Abstract

Hyperinsulinaemic hypoglycaemia (HH) is a major cause of hypoglycaemia in the neonatal period, infancy and childhood. It is caused by unsuppressed insulin secretion in the setting of hypoglycaemia and carries a high risk of significant neurological sequelae, such as cognitive impairment. Genetic mutations have been implicated in the pathogenesis of the condition. Other causes include intra-uterine growth retardation, perinatal asphyxia, maternal diabetes mellitus and syndromes, such as Beckwith-Wiedemann. Based on the aetiology, the clinical presentation can range from absence of symptoms to the typical adrenergic symptoms and coma and even death. The diagnosis is based on biochemical findings and the gold-standard imaging technique is 18F-DOPA PET/CT scanning. Treatment options involve medications, such as diazoxide, nifedipine, glucagon and octreotide, as well as surgery. Novel treatment, such as long-acting octreotide, lanreotide and sirolimus, may be used as an alternative to pancreatectomy. Potential future medical treatments include exendin, a GLP-1 receptor antagonist, and glucagon infusion via a pump.

Conclusion: Advances in the fields of genetic testing, imaging techniques and medical treatment are beginning to provide novel insights into earlier detection, less invasive treatment approaches and fewer complications associated with the complex entity of hyperinsulinaemic hypoglycaemia.

What is Known:

• HH is caused by dysregulated insulin release from the β cell due to genetic mutations and carries a risk for complications, such as neurocognitive impairment. 18F-DOPA PET/CT scanning is presented as the gold-standard imaging technique currently in children with hyperinsulinaemic hypoglycaemia.

• Clinical presentation is heterogeneous and treatment options include medical therapy and pancreatectomy.

What is New:

• 18F-DOPA PET/CT is indicated in suspected focal CHI due to paternal transmitted mutations in ABCC8 or KCNJ11.

• Novel treatment options have been introduced, such as long-acting octreotide, lanreotide, sirolimus and selective nonpeptide somatostatin receptor subtype 5 (SSTR5) agonists. Future medical treatments include exendin, a GLP-1 antagonist, and glucagon infusion via a pump. However, all these options are off-label at present.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Abbreviations

ACTH:

Adrenocorticotropic hormone

ADP:

Adenosine diphosphate

ATP:

Adenosine triphosphate

CT:

Computed tomography

EIF2S3:

Eukaryotic translation initiation factor 2 subunit gamma

18F-L-DOPA:

18-Fluoro-L-dihydroxyphenylalanine

FOXA2:

Forkhead box A2

GCK:

Glucokinase

GH:

Growth hormone

GLP-1:

Glucagon-like peptide-1

GLUT2:

Glucose transporter 2

GLUD1:

Glutamate dehydrogenase 1

HA:

Hyperammonia

HADH:

3-hyrdoxyacyl-coenzyme A dehydrogenase

HH:

Hyperinsulinaemic hypoglycaemia

HI:

Hyperinsulinism

HK1:

Hexokinase 1

HNF1A:

Homeobox A

HNF4:

Hepatocyte nuclear factor 4-alpha

IgG:

Immunoglobulin G

KATP channels:

ATP-sensitive potassium channels

Kir6.2:

Inward-rectifier potassium 6.2

mTOR:

Mammalian target of rapamycin

PET:

Positron emission tomography

PGM1:

Phosphoglucomutase 1

SLC16A1:

Solute carrier family 16 member 1

SSTR:

Somatostatin receptor

SUR1:

Sulfonylurea receptor 1

TSH:

Thyroid-stimulating hormone

References

  1. Ajala ON, Huffman DM, Ghobrial II (2016) Glucokinase mutation-a rare cause of recurrent hypoglycemia in adults: a case report and literature review. J Community Hosp Intern Med Perspect 6:32983

    Article  PubMed  Google Scholar 

  2. Amato LA, Quigley CA, Neville KA, Hameed S, Verge CF, Woodhead HJ, Walker JL (2015) Sirolimus treatment of severe congenital hyperinsulinism. Int J Pediatr Endocrinol 2015:123

    Article  Google Scholar 

  3. Antwi K, Fani M, Heye T, Nicolas G, Rottenburger C, Kaul F, Merkle E, Zech CJ, Boll D, Vogt DR, Gloor B, Christ E, Wild D (2018) Comparison of glucagon-like peptide-1 receptor (GLP-1R) PET/CT, SPECT/CT and 3T MRI for the localization of occult insulinomas: evaluation of diagnostic accuracy in a prospective crossover imaging study. Eur J Nucl Med Mol Imaging 45:2318–2327

    Article  CAS  PubMed  Google Scholar 

  4. Arnoux JB, Verkarre V, Saint-Martin C, Montravers F, Brassier A, Valayannopoulos V, Brunelle F, Fournet JC, Robert JJ, Aigrain Y, Bellanné-Chantelot C, de Lonlay P (2011) Congenital hyperinsulinism: current trends in diagnosis and therapy. Orphanet J Rare Dis 6:63

    Article  PubMed  PubMed Central  Google Scholar 

  5. Ashcroft FM, Harrison DE, Ashcroft SJ (1984) Glucose induces closure of single potassium channels in isolated rat pancreatic β-cells. Nature 312:446–448

    Article  CAS  PubMed  Google Scholar 

  6. Avatapalle HB, Banerjee I, Shah S, Pryce M, Nicholson J, Rigby L, Caine L, Didi M, Skae M, Ehtisham S et al (2013) Abnormal neurodevelopmental outcomes are common in children with transient congenital hyperinsulinism. Front Endocrinol (Lausanne) 4:60

    Article  Google Scholar 

  7. Aynsley-Green A, Hussain K, Hall J, Saudubray JM, Nihoul-Fékété C, De Lonlay-Debeney P, Brunelle F, Otonkoski T, Thornton P, Lindley KJ (2000) Practical management of hyperinsulinism in infancy. Arch Dis Child Fetal Neonatal Ed 82:F98–F107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Banerjee I, Avatapalle B, Padidela R, Stevens A, Cosgrove K, Clayton P, Dunne M (2013) Integrating genetic and imaging investigations into the clinical management of congenital hyperinsulinism. Clin Endocrinol 78:803–813

    Article  CAS  Google Scholar 

  9. Baş F, Darendeliler F, Demirkol D, Bundak R, Saka N, Günöz H (1999) Successful therapy with calcium channel blocker (nifedipine) in persistent neonatal hyperinsulinemic hypoglycemia of infancy. J Pediatr Endocrinol Metab 12:873–878

    Article  PubMed  Google Scholar 

  10. Beltrand J, Caquard M, Arnoux J-B, Laborde K, Velho G, Verkarre V, Rahier J, Brunelle F, Nihoul-Fekete C, Saudubray JM, Robert JJ, de Lonlay P (2012) Glucose metabolism in 105 children and adolescents after pancreatectomy for congenital hyperinsulinism. Diabetes Care 35:198–203

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Blomberg BA, Moghbel MC, Saboury B, Stanley CA, Alavi A (2013) The value of radiologic interventions and 18F-DOPA PET in diagnosing and localizing focal congenital hyperinsulinism: systematic review and meta-analysis. Mol Imaging Biol 15:97–105

    Article  PubMed  Google Scholar 

  12. Bruninig GJ (1990) Recent advances in hyperinsulinism and the pathogenesis of diabetes mellitus. Curr Opin Pediatr 2:758–765

    Article  Google Scholar 

  13. Calabria AC, Li C, Gallagher PR, Stanley CA, De León DD (2012) 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 61:2585–2591

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Cartier EA, Conti LR, Vandenberg CA, Shyng SL (2001) Defective trafficking and function of KATP channels caused by a sulfonylurea receptor 1 mutation associated with persistent hyperinsulinemic hypoglycemia of infancy. PNAS 98:2882–2887

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Christesen HB, Tribble ND, Molven A, Siddiqui J, Sandal T, Brusgaard K, Ellard S, Njolstad PR, Alm J, Brock Jacobsen B et al (2008) Activating glucokinase (GCK) mutations as a cause of medically responsive congenital hyperinsulinism: prevalence in children and characterisation of a novel GCK mutation. Eur J Endocrinol 159:27–34

    Article  CAS  PubMed  Google Scholar 

  16. de Lonlay P, Cornier-Daire V, Amiel J, Touati G, Goldenberg A, Fournet JC, Brunelle F, Nihoul-Fekete C, Rahier J, Junien C, Robert JJ, Saudubreay JM (2002) Facial appearance in persistent hyperinsulinemic hypoglycaemia. Am J Med Genet 111:130–133

    Article  PubMed  Google Scholar 

  17. Dehdashtian M (2014) Reversible pulmonary hypertension in an infant treated with diazoxide. APJMT 3:84–86

    Google Scholar 

  18. Demirbilek H, Hussain K (2017) Congenital hyperinsulinism: diagnosis and treatment update. J Clin Res Pediatr Endocrinol 9:69–87

    PubMed  PubMed Central  Google Scholar 

  19. Dunne MJ, Kane C, Shepherd RM, Sanchez JA, James RF, Johnson PR, Aynsley- Green A, Lu S, Clement JP IV, Lindley KJ et al (1997) Familial persistent hyperinsulinemic hypoglycemia of infancy and mutations in the sulfonylurea receptor. N Engl J Med 336:703–706

    Article  CAS  PubMed  Google Scholar 

  20. Durmaz E, Flanagan SE, Parlak M, Ellard S, Akcurin S, Bircan I (2014) A combination of nifedipine and octreotide treatment in an hyperinsulinemic hypoglycemic infant. J Clin Res Pediatr Endocrinol 6:119–121

    Article  PubMed  PubMed Central  Google Scholar 

  21. Eichmann D, Hufnagel M, Quick P, Santer R (1999) Treatment of hyperinsulinaemic hypoglycaemia with nifedipine. Eur J Pediatr 158:204–206

    Article  CAS  PubMed  Google Scholar 

  22. Flanagan SE, Kapoor RR, Hussain K (2011) Genetics of congenital hyperinsulinemic hypoglycemia. Semin Pediatr Surg 20:13–17

    Article  PubMed  Google Scholar 

  23. Fournet JC, Junien C (2003) The genetics of neonatal hyperinsulinism. Horm Res 59:30–34

    CAS  PubMed  Google Scholar 

  24. Glaser B, Hirsch HJ, Landau H (1993) Persistent hyper-insulinemic hypoglycemia of infancy: long-term octreotide treatment without pancreatectomy. J Pediatr 123:644–650

    Article  CAS  PubMed  Google Scholar 

  25. Glaser B, Thornton PS, Otonkoski T, Junien C (2000) The genetics of neonatal hyperinsulinism. Arch Dis Child 82:79–86

    Article  Google Scholar 

  26. Gregory LC, Ferreira CB, Young-Baird SK, Williams HJ, Harakalova M, van Haaften G, Rahman SA, Gaston-Massuet C, Kelberman D, GOSgene, Qasim W, Camper SA, Dever TE, Shah P, Iain C.A.F., Robinson ICAF, Dattani MT (2019) Impaired EIF2S3 function associated with a novel phenotype of X-linked hypopituitarism with glucose dysregulation. EBioMedicine 42:470–480

  27. Güemes M, Shah P, Silvera S, Morgan K, Gilbert C, Hinchey L, Hussain K (2017) Assessment of nifedipine therapy in hyperinsulinemic hypoglycemia due to mutations in the ABCC8 gene. J Clin Endocrinol Metab 102:822–830

    PubMed  Google Scholar 

  28. Gutgold A, Gutgold DJ, Glaser B, Szalat A (2017) Diagnosis of ABCC8 congenital hyperinsulinism of infancy in a 20-year-old man evaluated for factitious hypoglycemia. J Clin Endocrinol Metab 102:345–349

    PubMed  Google Scholar 

  29. Herrera A, Vajravelu ME, Givler S, Mitteer L, Avitabile CM, Lord K, De Leon DD (2018) Prevalence of adverse events in children with congenital hyperinsulinism treated with diazoxide. JCEM 103:4365–4372

    PubMed  PubMed Central  Google Scholar 

  30. Hussain K, Aynsley-Green A (2003) Hyperinsulinism in infancy: understanding the pathophysiology. Int J Biochem Cell Biol 35:1312–1317

    Article  CAS  PubMed  Google Scholar 

  31. Hussain K, Thornton PS, Otonkoski T, Aynsley-Green A (2004) Severe transient neonatal hyperinsulinism associated with hyperlactataemia in non-asphyxiated infants. J Pediatr Endocrinol Metab 17:203–209

    CAS  PubMed  Google Scholar 

  32. Hussain K, Aynsley-Green A, Stanley CA (2004) Medications used in the treatment of hypoglycemia due to congenital hyperinsulinism of infancy (HI). Pediatr Endocrinol Rev 2:163–167

    PubMed  Google Scholar 

  33. Hussain K, Clayton PT, Krywawych S, Chatziandreou I, Mills P, Ginbey DW, Geboers AJ, Berger R, van den Berg IE, Eaton S (2005) Hyperinsulinism of infancy associated with a novel splice site mutation in the SCHAD gene. J Pediatr 146:706–708

    Article  CAS  PubMed  Google Scholar 

  34. Inagaki N, Gonoi T, Clement JP 4th, Namba N, Inazawa J, Gonzalez G, Aguilar- Bryan L, Seino S, Bryan J (1995) Reconstitution of KATP: an inward rectifier subunit plus the sulphonylurea receptor. Science 270:1166–1170

    Article  CAS  PubMed  Google Scholar 

  35. Kane C, Shepherd RM, Squires PE, Johnson PR, James RF, Milla PJ, Aynsley-Green A, Lindley KJ, Dune MJ (1996) Loss of functional KATP channels in pancreatic β-cells causes persistent hyperinsulinemic hypoglycemia of infancy. Nat Med 2:1344–1347

    Article  CAS  PubMed  Google Scholar 

  36. Kapoor RR, Locke J, Colclough K, Wales J, Conn JJ, Hattersley AT, Ellard S, Hussain K (2008) Persistent hyperinsulinemic hypoglycemia and maturity-onset diabetes of the young due to heterozygous HNF4A mutations. Diabetes 57:1659–1663

    Article  CAS  PubMed  Google Scholar 

  37. Kapoor RR, James C, Flanagan SE, Ellard S, Eaton S, Hussain K (2009) 3-Hydroxyacyl-coenzyme A dehydrogenase deficiency and hyper-insulinemic hypoglycemia: characterization of a novel mutation and severe dietary protein sensitivity. JCEM 94:2221–2225

    CAS  PubMed  Google Scholar 

  38. Kapoor RR, Flanagan SE, James C, Shield J, Ellard S, Hussain K (2009) Hyperinsulinaemic hypoglycaemia. Arch Dis Child 94:450–457

    Article  CAS  PubMed  Google Scholar 

  39. Khawash P, Hussain K, Flanagan SE, Chatterjee S, Basak D (2015) Nifedipine in congenital Hyperinsulinism - a case report. J Clin Res Pediatr Endocrinol 7:151–154

    Article  PubMed  PubMed Central  Google Scholar 

  40. Laje P, States LJ, Zhuang H, Becker SA, Palladino AA, Stanley CA, Adzick NC (2013) Accuracy of PET/CT scan in the diagnosis of the focal form of congenital hyperinsulinism. J Pediatr Surg 48:388–393

    Article  PubMed  PubMed Central  Google Scholar 

  41. Le Quan Sang KH, Arnoux JB, mamoune A, Saint-Martin C, Bellanne-Chantelot C, Valayannopoulos V, Brassier A, Kayirangwa H, Barbier V, Broissand C, Fabreguettes JR, Charron B, Thalabard JC, de Lonlay P (2012) Successful treatment of congenital hyperinsulinism with long-acting release octreotide. Eur J Endocrinol 166:333–339

    Article  CAS  PubMed  Google Scholar 

  42. Li C, Chen P, Palladino A, Narayan S, Russell LK, Sayed S, Xiong G, Chen J, Stokes D, Butt YM, Jones PM, Collins HW, Cohen NA, Cohen AS, Nissim I, Smith TJ, Strauss AW, Matschinsky FM, Bennett MJ, Stanley CA (2010) Mechanism of hyperinsulinism in short-chain 3-hydroxyacyl-CoA dehydrogenase deficiency involves activation of glutamate dehydrogenase. J Biol Chem 285:31806–31818

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Lord K, De León DD (2013) Monogenic hyperinsulinemic hypoglycemia: current insights into the pathogenesis and management. Int J Pediatr Endocrinol 2013:3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Ludwig A, Enke S, Heindorf J, Empting S, Meissner T, Mohnike K (2018) Formal neurocognitive testing in 60 patients with congenital hyperinsulinism. Horm Res Paediatr 89:1–6

    Article  CAS  PubMed  Google Scholar 

  45. Matsuo M, Trapp S, Tanizawa Y, Kioka N, Amachi T, Oka Y, Ashcroft FM, Ueda K (2000) Functional analysis of a mutant sulfonylurea receptor, SUR1-R1420C, that is responsible for persistent hyperinsulinemic hypoglycemia of infancy. J Biol Chem 275:41184–41191

    Article  CAS  PubMed  Google Scholar 

  46. Mazor-Aronovitch K, Gillis D, Lobel D, Hirsch HJ, Pinhas-Hamiel O, Modan-Moses D, Glaser B, Landau H (2007) Long-term neurodevelopmental outcome in conservatively treated congenital hyperinsulinism. Eur J Endocrinol 157:491–497

    Article  CAS  PubMed  Google Scholar 

  47. Mohnike K, Blankenstein O, Pfuetzner A, Potzsch S, Schober E, Steiner S, Hardy OT, Grimberg A, van Waarde WM (2008) Long-term non-surgical therapy of severe persistent congenital hyperinsulinism with glucagon. Horm Res 70:59–64

    Article  CAS  PubMed  Google Scholar 

  48. Nestorowicz A, Inagaki N, Gonoi T, Schoor KP, Wilson BA, Glaser B, Landau H, Stanley CA, Thornton PS, Seino S, Permutt MA (1997) A nonsense mutation in the inward rectifier potassium channel gene, Kir6.2, is associated with familial hyperinsulinism. Diabetes 46:1743–1748

    Article  CAS  PubMed  Google Scholar 

  49. Neylon OM, Moran MM, Pellicano A, Nightingale M, O’Connell MA (2013) Successful subcutaneous glucagon use for persistent hypoglycaemia in congenital hyperinsulinism. J Pediatr Endocrinol Metab 26:1157–1161

    Article  CAS  PubMed  Google Scholar 

  50. Otonkoski T, Kaminen N, Ustinov J, Lapatto R, Meissner T, Mayatepek E, Kere J, Sipila I (2003) Physical exercise-induced hyperinsulinemic hypoglycemia is an autosomal-dominant trait characterized by abnormal pyruvate-induced insulin release. Diabetes 52:199–204

    Article  CAS  PubMed  Google Scholar 

  51. Otonkoski T, Näntö-Salonen K, Seppänen M, Veijola R, Huopio H, Hussain K, Tapanainen P, Eskola O, Parkkola R, Ekstrom K et al (2006) Noninvasive diagnosis of focal hyperinsulinism of infancy with [18F]-DOPA positron emission tomography. Diabetes 55:13–18

    Article  CAS  PubMed  Google Scholar 

  52. Otonkoski T, Jiao H, Kaminen-Ahola N, Tapia-Paez I, Ullah MS, Parton LE, Schuit F, Quintens R, Sipila I, Mayatepek E et al (2007) Physical exercise-induced hypoglycemia caused by failed silencing of monocarboxylate transporter 1 in pancreatic β cells. Am J Hum Genet 81:467–474

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Palladino AA, Bennett MJ, Stanley CA (2008) Hyperinsulinism in infancy and childhood: when an insulin level is not always enough. Clin Chem 54:256–263

    Article  CAS  PubMed  Google Scholar 

  54. Pallet N, Legendre C (2013) Adverse events associated with mTOR inhibitors. Expert Opin Drug Saf 12:177–186

    Article  CAS  PubMed  Google Scholar 

  55. Pierro A, Nah SA (2011) Surgical management of congenital hyperinsulinism of infancy. Semin Pediatr Surg 20:50–53

    Article  PubMed  Google Scholar 

  56. Pinney SE, MacMullen C, Becker S, Lin YW, Hanna C, Thornton P, Ganguly A, Shyng SL, Stanley CA (2008) Clinical characteristics and biochemical mechanisms of congenital hyperinsulinism associated with dominant KATP channel mutations. J Clin Invest 118:2877–2886

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Rahier J, Guiot Y, Sempoux C (2000) Persistent hyperinsulinaemic hypoglycaemia of infancy: a heterogeneous syndrome unrelated to nesidioblastosis. Arch Dis Child Fetal Neonatal Ed 82:F108–F112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Rahman SA, Nessa A, Hussain K (2015) Molecular mechanisms of congenital hyperinsulinism. J Mol Endocrinol 54:119–129

    Article  CAS  Google Scholar 

  59. Rico-Bautista E, Kusnetzow AK, Fowler ΜΑ, Athanacio J, Kredel TA, Zhao J, Wang S, Markinson S, Fei Zhu Y, Struthers RS, Betz SF, Crinetics Pharmaceuticals, San Diego, CA (2019) Selective nonpeptide somatostatin receptor subtype 5 (sst5) agonists suppress induced insulin secretion in pancreatic islets from both rats and healthy human donors. Presented in Endo 2019

  60. Rozenkova K, Malikova J, Nessa A, Dusatkova L, Bjørkhaug L, Obermannova B, Dusatkova P, Kytnarova J, Aukrust I, Najmi LA, Rypackova B, Sumnik Z, Lebl J, Njølstad PR, Hussain K, Pruhova S (2015) High incidence of heterozygous ABCC8 and HNF1A mutations in Czech patients with congenital hyperinsulinism. J Clin Endocrinol Metab 100:E1540–E1549

    Article  PubMed  Google Scholar 

  61. Sakakibara A, Hashimoto Y, Kawakita R, Hosokawa Y, Nagahara K, Hasegawa Y, Hoshino S, Nagasaka H, Yorifuji T (2018) Diagnosis of congenital hyperinsulinism: biochemical profiles during hypoglycaemia. Pediatr Diabetes 19:259–264

    Article  CAS  PubMed  Google Scholar 

  62. Salomon-Estebanez M, Flanagan SE, Ellard S, Rigby L, Bowden L, Mohamed Z, Nicholson J, Skae M, Hall C, Craigie R, Padidela R, Murphy N, Randell T, Cosgrove KE, Dunne MJ, Banerjee I (2016) Conservatively treated Congenital Hyperinsulinism (CHI) due to K-ATP channel gene mutations: reducing severity over time. Orphanet J Rare Dis 11:163

    Article  PubMed  PubMed Central  Google Scholar 

  63. Sayed S, Langdon DR, Odili S, Chen P, Buettger C, Schiffman AB, Suchi M, Taub R, Grimsby J, Matschinsky FM, Stanley CA (2009) Extremes of clinical and enzymatic phenotypes in children with hyperinsulinism caused by glucokinase activating mutations. Diabetes 58:1419–1427

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Senniappan S, Alexandrescu S, Tatevian N, Shah P, Arya V, Flanagan S, Ellard S, Rampling D, Ashworth M, Brown R et al (2014) Sirolimus therapy in infants with severe hyperinsulinemic hypoglycemia. N Engl J Med 370:1131–1137

    Article  CAS  PubMed  Google Scholar 

  65. Shah P, Rahman SA, McElroy S, Gilbert C, Morgan K, Hinchey L, Senniappan S, Levy H, Amin R, Hussain K (2015) Use of long-acting Somatostatin analogue (Lanreotide) in an adolescent with Diazoxide-responsive congenital Hyperinsulinism and its psychological impact. Horm Res Paediatr 84:355–360

    Article  CAS  PubMed  Google Scholar 

  66. Shah P, Rahman SA, Demirbilek H, Güemes M, Hussain K (2016) Hyperinsulinaemic hypoglycaemia in children and adults. Lancet Diabetes Endocrinol 5:729–742

    Article  PubMed  Google Scholar 

  67. Shanbag P, Pathak A, Vaidya M, Shahid SK (2002) Persistent hyperinsulinemic hypoglycemia of infancy-successful therapy with nifedipine. Indian J Pediatr 69:271–272

    Article  PubMed  Google Scholar 

  68. Skae M, Avatapalle HB, Banerjee I, Rigby L, Vail A, Foster P, Charalambous C, Bowden L, Padidela R, Patel L, Ehthsham S, Cosgrove KE, Dunne MJ, Clayton P (2014) Reduced glycemic variability in diazoxide-responsive children with congenital hyperinsulinism using supplemental omega-3-polyunsaturated fatty acids; a pilot trial with MaxEPAR. Front Endocrinol 5:31

    Article  Google Scholar 

  69. Stanley CA (2004) Hyperinsulinism/hyperammonemia syndrome: insights into the regulatory role of glutamate dehydrogenase in ammonia metabolism. Mol Genet Metab 81:S45–S51

    Article  CAS  PubMed  Google Scholar 

  70. Stanley CA (2016) Perspective on the genetics and diagnosis of congenital hyperinsulinism disorders. JCEM 101:815–826

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Suprasongsin C, Suthutvoravut U, Mahachoklertwattana P, Preeyasombat C (1999) Combined raw cornstarch and nifedipine as an additional treatment in persistent hyperinsulinemic hypoglycemia of infancy. J Med Assoc Thail 82:S39–S42

    Google Scholar 

  72. Szymanowski M, Estebanez MS, Padidela R, Han B, Mosinska K, Stevens A, Damaj L, Pihan-Le Bars F, Lascouts E, Reynaud R et al (2016) mTOR inhibitors for the treatment of severe congenital hyperinsulinism: perspectives on limited therapeutic success. J Clin Endocrinol Metab 101:4719–4729

    Article  CAS  PubMed  Google Scholar 

  73. Thomas PM, Cote GJ, Wohllk N, Haddad B, Mathew PM, Rabl W, Aguilar-Bryan L, Gagel RF, Bryan J (1995) Mutations in the sulfonylurea receptor gene in familial persistent hyperinsulinemic hypoglycemia of infancy. Science 268:426–429

    Article  CAS  PubMed  Google Scholar 

  74. Thomas P, Ye Y, Lightner E (1996) Mutation of the pancreatic islet inward rectifier Kir6.2 also leads to familial persistent hyperinsulinemic hypoglycemia of infancy. Hum Mol Genet 5:1809–1812

    Article  CAS  PubMed  Google Scholar 

  75. Thornton PS, Alter CA, Katz LE, Baker L, Stanley CA (1993) Short- and long-term use of octreotide in the treatment of congenital hyperinsulinism. J Pediatr 123:637–643

    Article  CAS  PubMed  Google Scholar 

  76. Timlin MR, Black AB, Delaney HM, Matos RI, Percival CS (2017) Development of pulmonary hypertension during treatment with diazoxide: a case series and literature review. Pediatr Cardiol 38:1247–1250

    Article  PubMed  Google Scholar 

  77. Tornehave D, Kristensen P, Rorner J, Knudsen LB, Heller RS (2008) Expression of the GLP-1 receptor in mouse, rat, and human pancreas. J Histochem Cytochem 56:841–851

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Verkarre V, Fournet JC, de Lonlay P, Gross-Morand MS, Devillers M, Rahier J, Brunelle F, Robert JJ, Nihoul-Fekete C, Saudubray JM et al (1998) Paternal mutation of the sulfonylurea receptor (SUR1) gene and maternal loss of 11p15 imprinted genes lead to persistent hyperinsulinism in focal adenomatous hyperplasia. J Clin Invest 102:1286–1291

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Welters A, Lerch C, Kummer S, Marquard J, Salgin B, Mayatepek E, Meissner T (2015) Long-term medical treatment in congenital hyperinsulinism: a descriptive analysis in a large cohort of patients from different clinical centers. Orphanet J Rare Dis 10:150

    Article  PubMed  PubMed Central  Google Scholar 

  80. Welters A, Meissner T, Grulich-Henn J, Frohlich-Reiterer E, Warncke K, Mohnike K, Blankenstein O, Menzel U, Datz N, Bollow E, Holl RW (2017) Characterization of diabetes following pancreatic surgery in patients with congenital hyperinsulinism. Orphanet J Rare Dis 13:230

    Article  Google Scholar 

  81. Wullschleger S, Loewith R, Oppliger W, Hall MN (2005) Molecular organization of target of rapamycin complex 2. J Biol Chem 280:30697–30704

    Article  CAS  PubMed  Google Scholar 

  82. Yang SB, Lee HY, Rapamycin DM, Tien AC, Rowson-Baldwin A, Shu YY, Jan YN, Jan LY (2012) Rapamycin induces glucose intolerance in mice by reducing islet mass, insulin content, and insulin sensitivity. J Mol Med (Berl) 90:575–585

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Research Laboratory of the Division of Paediatric Endocrinology and Diabetes, Department of Paediatrics, School of Medicine, University of Patras, 26500, Patras, Greece

    Eirini Kostopoulou

  2. Endocrinology Department, Great Ormond Street Hospital for Children, NHS Foundation Trust, London, UK

    Pratik Shah

  3. Genetics and Genomic Medicine Programme, UCL Great Ormond Street Institute of Child Health, 30 Guilford Street, London, WC1N 1EH, UK

    Pratik Shah

Authors
  1. Eirini Kostopoulou
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Pratik Shah
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Eirini Kostopoulou.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Communicated by Peter de Winter

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kostopoulou, E., Shah, P. Hyperinsulinaemic hypoglycaemia—an overview of a complex clinical condition. Eur J Pediatr 178, 1151–1160 (2019). https://doi.org/10.1007/s00431-019-03414-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00431-019-03414-8

Keywords

Search

Navigation