Biomarkers of Insulin for the Diagnosis of Hyperinsulinemic Hypoglycemia in Infants and Children

Objective To evaluate thresholds of various biomarkers for defining excess insulin activity to recognize congenital hyperinsulinism. Study design This was a retrospective chart review of diagnostic fasting tests in children with ketotic hypoglycemia (n = 30) and genetically/pathology confirmed congenital hyperinsulinism (n = 28). Sensitivity and specificity for congenital hyperinsulinism were determined for plasma insulin, beta-hydroxybutyrate, free fatty acids (FFA), C-peptide, insulin-like growth factor binding protein-1 (IGFBP-1), and the glycemic response to glucagon (through the glucagon stimulation test [GST]) at the time of hypoglycemia. Results Only 23 of the 28 subjects with congenital hyperinsulinism had detectable insulin (median, 6.7 mu IU/mL), and insulin was undetectable in all subjects with ketotic hypoglycemia. Compared with ketotic hypoglycemia, subjects with congenital hyperinsulinism had higher GST values (57 vs 13 mg/dL; Delta GST >= 30 mg/dL in 24 of 27 subjects with congenital hyperinsulinism vs 0 of 30 subjects with ketotic hypoglycemia) and C-peptide levels (1.55 vs 0.11 ng/mL), with lower levels of FFA (0.82 vs 2.51 mM) and IGFBP-1 (59.5 vs 634 ng/mL). At the time of hypoglycemia, the upper limits of beta-hydroxybutyrate and FFA in subjects with congenital hyperinsulinism were higher than reported previously (beta-hydroxybutyrate <1.8 mM and FFA <1.7 mM), providing the best sensitivity for congenital hyperinsulinism vs ketotic hypoglycemia. A C-peptide level >= 0.5 ng/mL was 89% sensitive and 100% specific, and an IGFBP-1 level <= 110 ng/mL was 85% sensitive and 96.6% specific. Conclusion Because low or undetectable insulin level during hypoglycemia does not exclude the diagnosis of hyperinsulinism, C-peptide and IGFBP-1 may inform the diagnosis of congenital hyperinsulinism. In this group of children with well-defined congenital hyperinsulinism, thresholds for suppressed beta-hydroxybutyrate and FFA are higher than previously reported levels.