Background: Congenital hyperinsulinism (CHI) is characterized by severe hypoglycemia caused by dysregulated insulin secretion. The long-term outcome is dependent on prevention of hypoglycemic episodes to avoid the high risk of permanent brain damage. Severe cases are usually resistant to diazoxide or nifedipine. In addition, somatostatin analogues are ineffective in a subgroup of patients to achieve stable euglycemia. In these infants the only remaining long-term option has been subtotal pancreatectomy with high risk of diabetes mellitus. Intravenous infusions of glucagon are used as immediate treatment to stabilize euglycemia in affected newborns. The rationale of this treatment comes from the observation of an increased glycogen content of the liver when glycogenolysis is inhibited by insulin. Objective: To review the efficacy and safety of long-term subcutaneous glucagon infusion as a potential therapeutic option for blood glucose stabilization in infants with severe CHI without the need of additional intravenous glucose or immediate surgical intervention. Method: Retrospective review of 9 children with CHI who received continuous subcutaneous infusion of glucagon for weeks or months. Glucagon was added to octreotide to replace octreotide-induced suppression of endogenous glucagon secretion, thereby liberating glucose by stimulation of hepatic glycogenolysis. In 3 cases, a stabilized formulation of glucagon was used to prevent glucagon crystallization that frequently occurs in smaller volumes. Results: Introduction of glucagon allowed the reduction or discontinuation of central glucose infusion in all children studied. In 2 patients, glucagon was introduced due to recurrent hypoglycemia despite subtotal pancreatectomy. Six out of 9 children were discharged home on this treatment, which their parents were able to continue without further symptomatic hypoglycemia, convulsions or unconsciousness. In 3 children, subcutaneous glucagon was continuously administered for 1–4 years leading to stable euglycemia. However, 2 children with diffuse type still required subtotal pancreatectomy. As a possible side effect, 2 children developed erythema necrolyticum, which resolved after discontinuation of the glucagon infusion. This has been described before in glucagonoma. Conclusion: In this retrospective series, combination therapy of low-dose octreotide and subcutaneous glucagon infusion has been effective in preventing hypoglycemic episodes in severe CHI. We propose this may serve as a therapeutic option in place of high rates of glucose infusion through a central venous catheter and as an alternative to subtotal pancreatectomy in diffuse type of CHI.

1.
Cresto JC, Abdenur JP, Bergada I, Martino R: Long-term follow up of persistent hyperinsulinaemic hypoglycaemia of infancy. Arch Dis Child 1998;79:440–444.
2.
Dunne MJ, Cosgrove KE, Shepherd RM, Aynsley-Green A, Lindley KJ: Hyperinsulinism in infancy: from basic science to clinical disease. Physiol Rev 2004;84:239–275.
3.
Izumi T, Takeshige H, Arai T, Sugama M, Mizushima M, Fukuyama Y, Mabuchi G: Prospective study of nesidioblastosis in newborns and infants: hypoglycemic seizures, epileptogenesis and the significance of the C-peptide suppression test in pancreatectomy. Acta Paediatr Jpn 1997;39:10–17.
4.
Koh TH, Eyre JA, Aynsley-Green A: Neonatal hypoglycaemia – the controversy regarding definition. Arch Dis Child 1988;63:1386–1388.
5.
Menni F, de Lonlay P, Sevin C, Touati G, Peigne C, Barbier V, Nihoul-Fekete C, Saudubray JM, Robert JJ: Neurologic outcomes of 90 neonates and infants with persistent hyperinsulinemic hypoglycemia. Pediatrics 2001;107:476–479.
6.
Murakami Y, Yamashita Y, Matsuishi T, Utsunomiya H, Okudera T, Hashimoto T: Cranial MRI of neurologically impaired children suffering from neonatal hypoglycaemia. Pediatr Radiol 1999;29:23–27.
7.
Touati G, Poggi-Travert F, Ogier dB, Rahier J, Brunelle F, Nihoul-Fekete C, Czernichow P, Saudubray JM: Long-term treatment of persistent hyperinsulinaemic hypoglycaemia of infancy with diazoxide: a retrospective review of 77 cases and analysis of efficacy-predicting criteria. Eur J Pediatr 1998;157:628–633.
8.
Daneman D, Ehrlich RM: The enigma of persistent hyperinsulinemic hypoglycemia of infancy. J Pediatr 1993;123:573–575.
9.
Kane C, Lindley KJ, Johnson PR, James RF, Milla PJ, Aynsley-Green A, Dunne MJ: Therapy for persistent hyperinsulinemic hypoglycemia of infancy. Understanding the responsiveness of β cells to diazoxide and somatostatin. J Clin Invest 1997;100:1888–1893.
10.
Lonlay-Debeney P, Poggi-Travert F, Fournet JC, Sempoux C, Vici CD, Brunelle F, Touati G, Rahier J, Junien C, Nihoul-Fekete C, Robert JJ, Saudubray JM: Clinical features of 52 neonates with hyperinsulinism. N Engl J Med 1999;340:1169–1175.
11.
Mohnike K, Blankenstein O, Christesen HT, De Lonlay J, Hussain K, Koopmans KP, Minn H, Mohnike W, Mutair A, Otonkoski T, Rahier J, Ribeiro M, Schoenle E, Fekete CN: Proposal for a standardized protocol for 18F-DOPA-PET (PET/CT) in congenital hyperinsulinism. Horm Res 2006;66:40–42.
12.
Aynsley-Green A, Hussain K, Hall J, Saudubray JM, Nihoul-Fekete C, Lonlay-Debeney P, Brunelle F, Otonkoski T, Thornton P, Lindley KJ: Practical management of hyperinsulinism in infancy. Arch Dis Child Fetal Neonatal Ed 2000;82:F98–F107.
13.
Bougneres PF, Landier F, Garnier P, Job JC, Chaussain JL: Treatment of insulin excess by continuous subcutaneous infusion of somatostatin and glucagon in an infant. J Pediatr 1985;106:792–794.
14.
Glaser B, Hirsch HJ, Landau H: Persistent hyperinsulinemic hypoglycemia of infancy: long-term octreotide treatment without pancreatectomy. J Pediatr 1993;123:644–650.
15.
Lindley K, Knafelz D, St Louis D, Dunne M, Aynsley-Green A, Milla PJ: Surface electrogastrographic evidence of foregut dysmotility in persistent hyperinsulinaemic hypoglycaemia of infancy (abstract). J Physiol 1997;499:108.
16.
Glaser B, Landau H, Permutt MA: Neonatal hyperinsulinism. Trends Endocrinol Metab 1999;10:55–61.
17.
Stanley CA, Baker L: Hyperinsulinism in infants and children: diagnosis and therapy. Adv Pediatr 1976;23:315–355.
18.
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;123:637–643.
19.
De Lonlay P, Fournet JC, Rahier J, Gross-Morand MS, Poggi-Travert F, Foussier V, Bonnefont JP, Brusset MC, Brunelle F, Robert JJ, Nihoul-Fekete C, Saudubray JM, Junien C: Somatic deletion of the imprinted 11p15 region in sporadic persistent hyperinsulinemic hypoglycemia of infancy is specific of focal adenomatous hyperplasia and endorses partial pancreatectomy. J Clin Invest 1997;100:802–807.
20.
Eichmann D, Hufnagel M, Quick P, Santer R: Treatment of hyperinsulinaemic hypoglycaemia with nifedipine. Eur J Pediatr 1999;158:204–206.
21.
Cederblad F, Ewald U, Gustafsson J: Effect of glucagon on glucose production, lipolysis, and gluconeogenesis in familial hyperinsulinism. Horm Res 1998;50:94–98.
22.
Finegold DN, Stanley CA, Baker L: Glycemic response to glucagon during fasting hypoglycemia: an aid in the diagnosis of hyperinsulinism. J Pediatr 1980;96:257–259.
23.
Rose SR, Chrousos G, Cornblath M, Sidbury J: Management of postoperative nesidioblastosis with zinc protamine glucagon and oral starch. J Pediatr 1986;108:97–100.
24.
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;54:2946–2951.
25.
Wald M, Lawrenz K, Luckner D, Seimann R, Mohnike K, Schober E: Glucagon therapy as a possible cause of erythema necrolyticum migrans in two neonates with persistent hyperinsulinaemic hypoglycaemia. Eur J Pediatr 2002;161:600–603.
26.
Grimberg A, Ferry RJ Jr, Kelly A, Koo-McCoy S, Polonsky K, Glaser B, Permutt MA, Aguilar-Bryan L, Stafford D, Thornton PS, Baker L, Stanley CA: Dysregulation of insulin secretion in children with congenital hyperinsulinism due to sulfonylurea receptor mutations. Diabetes 2001;50:322–328.
27.
Haymond MW: Hypoglycemia in infants and children. Endocrinol Metab Clin North Am 1989;18:211–252.
28.
Macfarlane WM, Chapman JC, Shepherd RM, Hashmi MN, Kamimura N, Cosgrove KE, O’Brien RE, Barnes PD, Hart AW, Docherty HM, Lindley KJ, Aynsley-Green A, James RF, Docherty K, Dunne MJ: Engineering a glucose-responsive human insulin-secreting cell line from islets of Langerhans isolated from a patient with persistent hyperinsulinemic hypoglycemia of infancy. J Biol Chem 1999;274:34059–34066.
29.
Glaser B, Thornton P, Otonkoski T, Junien C: Genetics of neonatal hyperinsulinism. Arch Dis Child Fetal Neonatal Ed 2000;82:F79–F86.
30.
Magge SN, Shyng SL, MacMullen C, Steinkrauss L, Ganguly A, Katz LE, Stanley CA: Familial leucine-sensitive hypoglycemia of infancy due to a dominant mutation of the β-cell sulfonylurea receptor. J Clin Endocrinol Metab 2004;89:4450–4456.
31.
De Leon DD, Stanley CA: Mechanisms of disease: advances in diagnosis and treatment of hyperinsulinism in neonates. Nat Clin Pract Endocrinol Metab 2007;3:57–68.
32.
Katz LE, Ferry RJ Jr, Stanley CA, Collett-Solberg PF, Baker L, Cohen P: Suppression of insulin oversecretion by subcutaneous recombinant human insulin-like growth factor I in children with congenital hyperinsulinism due to defective β-cell sulfonylurea receptor. J Clin Endocrinol Metab 1999;84:3117–3124.
33.
Shepherd RM, Cosgrove KE, O’Brien RE, Barnes PD, Ammala C, Dunne MJ: Hyperinsulinism of infancy: towards an understanding of unregulated insulin release. European Network for Research into Hyperinsulinism in Infancy. Arch Dis Child Fetal Neonatal Ed 2000;82:F87–F97.
34.
Tauber MT, Harris AG, Rochiccioli P: Clinical use of the long acting somatostatin analogue octreotide in pediatrics. Eur J Pediatr 1994;153:304–310.
35.
Alexopoulou O, Abrams P, Verhelst J, Poppe K, Velkeniers B, Abs R, Maiter D: Efficacy and tolerability of lanreotide Autogel therapy in acromegalic patients previously treated with octreotide LAR. Eur J Endocrinol 2004;151:317–324.
36.
Aynsley-Green A: Nesidioblastosis of the pancreas in infancy. Dev Med Child Neurol 1981;23:372–379.
37.
Kuhl C, Hvorslev V, Tygstrup I, Lindkaer JS: Elevated serum proinsulin in β-cell nesidioblastosis. Report of a case in a newborn. Scand J Gastroenterol Suppl 1979;53:49–52.
38.
Pfutzner A, Mann AE, Steiner SS: Technosphere/insulin – a new approach for effective delivery of human insulin via the pulmonary route. Diabetes Technol Ther 2002;4:589–594.
39.
Pfutzner A, Flacke F, Pohl R, Linkie D, Engelbach M, Woods R, Forst T, Beyer J, Steiner SS: Pilot study with Technosphere/PTH – a new approach for effective pulmonary delivery of parathyroid hormone (1–34). Horm Metab Res 2003;35:319–323.
40.
Pfutzner A, Forst T: Pulmonary insulin delivery by means of the Technosphere drug carrier mechanism. Expert Opin Drug Deliv 2005;2:1097–1106.
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