Abstract
Background: Congenital hyperinsulinism (CHI), a rare disease of excessive and dysregulated insulin secretion, can lead to prolonged and severe hypoglycemia. Dextrose infusions are a mainstay of therapy to restore normal glycemia, but can be associated with volume overload, especially in infants. By releasing intrahepatic glucose stores, glucagon infusions can reduce dependency on dextrose infusions. Recent studies have reported positive outcomes with glucagon infusions in patients with CHI; however, to date, there are no reports describing the clinical utility of titrated doses of infused glucagon to achieve glycemic stability.Objective: To assess the potential clinical utility of dose-titrated glucagon infusions in stabilizing glycemic status in pediatric patients with CHI, who were managed by medical and/or surgical approaches.Methods: Patients with CHI (N = 33), with or without mutations in the ATP-sensitive K+ channel genes, ABCC8, and KCNJ11 requiring glucagon by dose titration in addition to intravenous dextrose and medical therapy with diazoxide/octreotide to achieve glycemic stability were recruited. Following glucagon titration and a 24-h glucose stable period, glucose infusion rate (GIR) was reduced over a 24-h period. Achievement of glycemic stability and decrease in GIR were considered end points of the study.Results: All patients achieved glycemic stability with glucagon infusion, demonstrating clinical benefit. GIR reduced from 15.6 (4.5) to 13.4 (4.6) mg/kg/min mean (SD) (p = 0.00019 for difference; n = 32; paired t-test) over 24 h. By univariate analysis, no individual baseline characteristic was associated with changes in the GIR. However, by baseline-adjusted modeling, mutational status of the patient (p = 0.011) was inversely associated with a reduction in GIR. Adverse events were infrequent with diarrhea possibly attributed to glucagon treatment in 1 patient. With long-term treatment following GIR reduction, necrolytic migratory erythema was observed in another patient.Conclusion: These data suggest that dose-titrated glucagon infusion therapy aids hypoglycemia prevention and reduction in GIR in the clinical management of patients with CHI.
Highlights
Congenital hyperinsulinism (CHI), a rare disease of excessive and dysregulated insulin secretion, can lead to prolonged and severe hypoglycemia
Recent studies have reported positive outcomes with glucagon infusions in patients with CHI; to date, there are no reports describing the clinical utility of titrated doses of infused glucagon to achieve glycemic stability
Adverse events were infrequent with diarrhea possibly attributed to glucagon treatment in 1 patient
Summary
Congenital hyperinsulinism (CHI), a rare disease of excessive and dysregulated insulin secretion, can lead to prolonged and severe hypoglycemia. CHI is caused by dysregulated and excess secretion of insulin from pancreatic β-cells in patients with or without genetic mutations in ATP-sensitive K+ channels [3]. This uncontrolled release of insulin in CHI can lead to frequent and severe bouts of hypoglycemia, which in turn can have severe and lasting consequences on central nervous system (CNS) function and neurodevelopment in young children [4]. These consequences include elevated risks for seizures, delayed developmental milestones, and ongoing CNS injury [4,5,6]. In light of the gravity and lifelong impact of the adverse effects on early CNS development resulting from severe hypoglycemia in infants, prevention, and risk mitigation are critically important for the preservation of CNS function in affected children [2, 6]
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