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.


METHODS
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, β-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 μIU/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; ΔGST ≥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 β-hydroxybutyrate and FFA in subjects with congenital hyperinsulinism were higher than reported previously (β-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.


CONCLUSIONS
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" β-hydroxybutyrate and FFA are higher than previously reported levels.
Division of Endocrinology and Diabetes, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA.
Christine
C
Ferrara
Division of Pediatric Endocrinology, Department of Pediatrics, New York Medical College, Valhalla, NY.
Payal
P
Patel
Division of Endocrinology and Diabetes, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA.
Susan
S
Becker
Division of Endocrinology and Diabetes, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA.
Charles A
CA
Stanley
Division of Endocrinology and Diabetes, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA. Electronic address: kellya@email.chop.edu.
Andrea
A
Kelly
D000293:Adolescent; D015415:Biomarkers / Q000097:blood; D002096:C-Peptide / Q000097:blood; D002648:Child; D002675:Child, Preschool; D044903:Congenital Hyperinsulinism / Q000097:blood* / Q000175:diagnosis*; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007328:Insulin / Q000097:blood*; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000097:blood; D008297:Male; D012189:Retrospective Studies
D015415:Biomarkers; D002096:C-Peptide; D007328:Insulin; D018970:Insulin-Like Growth Factor Binding Protein 1