BC368 – Biochemistry of the Cell II
Case Study #5: Focal ABCC8-Related Congenital Hyperinsulinism
Background:
Congenital hyperinsulinism is the leading cause of persistent hypoglycemia in infants and children. In newborns, it can present within hours to days after birth and may cause seizures, hypotonia, poor feeding, or apnea. Focal congenital hyperinsulinism accounts for about 30% to 40% of cases and is caused by a heterozygous ABCC8 or KCNJ11 pathogenic variant inherited from the father together with somatic loss of the maternal 11p15 region in pancreatic tissue. Unlike diffuse disease, focal disease is confined to a limited region of the pancreas and can often be cured if that region is accurately localized and surgically removed.
Case Summary:
A male neonate born after a 40-week term and with a birth weight of 3.16 kg (6.97 lb) was hospitalized in the neonatal intensive care unit for transient tachypnea. On the fifth day of hospitalization, he developed a convulsion and was found to have severe persistent hypoglycemia. There was no maternal history of diabetes. He was started on continuous glucose infusion at 8 to 10 mg/kg/min, and diazoxide was added and titrated to 20 mg/kg/day in an attempt to maintain normoglycemia.
Laboratory Discoveries:
During hypoglycemia, the infant’s plasma glucose was 44 mg/dL, beta-hydroxybutyrate was 0.16 mmol/L with a listed normal value of greater than 1.8 mmol/L, and insulin was 3.7 μU/mL with a stated laboratory reference range of 2.6 to 24.9 μU/mL. Even though the insulin value was not dramatically elevated above the reference interval, the combination of hypoglycemia with very low ketone bodies is abnormal and fits hyperinsulinism. During spontaneous hypoglycemia or monitored fasting, expected findings in hyperinsulinism include inappropriately elevated insulin, inappropriately low beta-hydroxybutyrate, and negative urine ketones. Furthermore, it notes that low ketones can serve as a surrogate marker of persistent insulin action when insulin values fluctuate.
Biochemistry:
This case is most consistent with KATP-channel hyperinsulinism involving ABCC8, the gene that encodes the sulfonylurea receptor subunit of the pancreatic beta-cell KATP channel. A study from the University of Washington in Seattle explains that diazoxide works by binding the ABCC8 subunit, increasing the probability that the KATP channel remains open, which hyperpolarizes the beta cell and inhibits insulin release. Because diazoxide acts at the same channel complex that is altered in KATP-related hyperinsulinism, response may be poor or absent, especially in severe cases. In this infant, the biochemical clue is that insulin action is still present when glucose is dangerously low, and the very low beta-hydroxybutyrate supports that interpretation. In focal disease, the abnormal insulin secretion arises from a limited pancreatic region, while the remainder of the pancreas is histologically and functionally normal. Focal lesions also are typically not visible on gross inspection.
Treatment Options:
Initial treatment of severe hyperinsulinemic hypoglycemia is prompt correction of blood glucose with intravenous glucose, often at high infusion rates. The aforementioned study from the University of Washington in Seattle recommends an early trial of enteral diazoxide, and if adequate glucose control is not achieved, escalation to glucagon and then octreotide may be needed. Somatostatin analogs such as octreotide and lanreotide suppress insulin secretion through beta-cell receptor signaling pathways. For focal disease specifically, preoperative localization with 18F-DOPA-PET is recommended because focal lesions may not be visible during surgery. If a focal lesion is identified, localized pancreatic resection is often curative.
In this case, hypoglycemia persisted despite glucose infusion and diazoxide, so the infant was considered diazoxide resistant. Octreotide was then started at 10 μg/kg/day, and blood sugars normalized with octreotide plus feeds every 3 hours. In the second month of follow-up, lanreotide was started for maintenance. Genetic testing showed a heterozygous paternally inherited ABCC8 pathogenic variant, and 18F-DOPA-PET/CT demonstrated a focal lesion in the tail of the pancreas. Surgery was performed on day 90 of life. The lesion could not be identified by direct inspection or palpation, so distal pancreatectomy was guided by the imaging findings. Histopathology confirmed focal endocrine cell hyperplasia, and an 8-hour postoperative fast confirmed surgical cure. Hypoglycemia did not recur during six months of follow-up.
Discussion Questions:
Q1: Why does this infant meet criteria for hyperinsulinemic hypoglycemia even though the insulin concentration is not dramatically elevated above the normal laboratory range?
Q2: Why does a paternally inherited ABCC8 pathogenic variant point toward focal disease, and why was 18F-DOPA-PET/CT necessary before surgery?
Q3: Why was this patient treated first with glucose infusion and diazoxide, then octreotide and lanreotide, and finally surgery?
References:
Gillis, D. (2024). Nonsyndromic genetic hyperinsulinism overview. In M. P. Adam, S. Bick, G. M. Mirzaa, R. A. Pagon, S. E. Wallace, L. J. H. Bean, K. W. Gripp, & A. Amemiya (Eds.), GeneReviews. University of Washington, Seattle.
Misirli Ozdemir, E., Akcay, T., Akdag, A., Karadag, C. A., Demir, M., Tanik, C., Dagdeviren Cakir, A., & Ucar, A. (2025). Successful management of an infant with congenital focal hyperinsulinism with no apparent lesion during surgery. Medical Bulletin of Sisli Etfal Hospital, 59(1), 138–141.
Q1: This infant meets criteria for hyperinsulinemic hypoglycemia because the insulin level is inappropriately present at a time when glucose is only 44 mg/dL. At that glucose concentration, insulin should be strongly suppressed. The very low beta-hydroxybutyrate level of 0.16 mmol/L shows that ketone production is also being suppressed, which is consistent with persistent insulin action. Low beta-hydroxybutyrate during hypoglycemia is an expected finding in hyperinsulinism and can help confirm the diagnosis even when insulin values are not strikingly high.
Q2: A paternally inherited ABCC8 pathogenic variant points toward focal disease because focal congenital hyperinsulinism is produced by a paternal ABCC8 or KCNJ11 mutation together with somatic loss of the maternal 11p15 region in a localized population of pancreatic cells. Genetic testing therefore strongly suggests focal disease, but it does not identify the lesion’s physical location. 18F-DOPA-PET/CT was necessary because focal lesions are often not macroscopically visible, and the surgeon needs accurate preoperative localization to know where to resect. That is exactly what happened here: the lesion was seen on imaging in the pancreatic tail but could not be identified by inspection or palpation during surgery.
Q3: The treatment sequence reflects escalation from emergency stabilization to definitive cure. The treatment was done in steps, starting with the most urgent problem. First, the baby needed glucose infusion to quickly raise blood sugar and prevent brain injury. Next, doctors tried diazoxide, which is the standard first medication for hyperinsulinism. Diazoxide works by helping the KATP channel stay open, which lowers insulin release. But since this child likely had a defect involving the ABCC8 part of that channel, diazoxide did not work well enough. Because of that, doctors switched to octreotide and later lanreotide, which reduce insulin release in a different way. These drugs helped control the hypoglycemia temporarily. Once imaging confirmed that the disease was focal and limited to one small area of the pancreas, surgery became the best long-term treatment. Removing the abnormal part of the pancreas can cure focal disease, which is what happened in this case.