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Hyperinsulinism (HI) is a disorder of dysregulated insulin secretion resulting in hypoglycemia. Congenital HI refers to a permanent inborn condition, other forms can be transient.
Most common cause of persistent or recurrent hypoglycemia in children
- Annual incidence estimated at ∼1:40,000–50,000 live births in United States.
- May be as high as 1:2,500 in select populations (Saudi Arabians, Ashkenazi Jews)
- KATPHI: inactivating mutations in KATP channel genes ABCC8 and KCNJ11 (on 11p15)
- Mutations inherited in an autosomal recessive manner result in diffuse involvement throughout the pancreas (diffuse HI).
- Autosomal dominantly inherited mutations can also rarely cause diffuse HI.
- Non-Mendelian inheritance: A paternally inherited recessive mutation of KATP channel gene and a loss of maternal alleles on the imprinted chromosome region 11p15, leads to paternal uniparental disomy; results in focal adenomatous lesion (focal HI)
- Glucokinase-HI: autosomal dominant–activating mutations of glucokinase (GCK)
- GDH-HI: autosomal dominant–activating mutations of glutamate dehydrogenase (GDH), encoded by GLUD1; known as hyperinsulinism/hyperammonemia (HI/HA) syndrome
- SCHAD-HI: autosomal recessive mutations of mitochondrial enzyme short-chain-3-hydroxyacyl-CoA dehydrogenase (SCHAD), encoded by HADH
- UCP2-HI: autosomal dominant mutations of mitochondrial carrier uncoupling protein 2 (UCP2), encoded by UCP2
- HNF4A and HNF1A-HI: autosomal dominant mutations in transcription factors, HNF4A and HNF1A. Mutations in HNF4A and HNF1A also are known to cause familial monogenic diabetes.
- MCT1-HI: autosomal dominant mutations in the regulatory region of SLC16A1–encoding monocarboxylate transporter 1 (MCT1)
- Causes exercise-induced HI
- These mutations result in uncoupling of insulin secretion from the glucose-sensing machinery of the pancreatic β cell.
- Leads to inappropriate insulin secretion even in the face of low plasma glucose concentrations
- In the absence of functional KATP channels, plasma membrane is depolarized leading to opening of voltage-dependent calcium channels and constant insulin secretion.
- In the focal form of the disease (∼60% of cases), a cluster of pancreatic β cells are affected, whereas in diffuse HI, all β cells are abnormal.
- In HI/HA syndrome, activating mutations of GDH (an enzyme that regulates amino acid–stimulated insulin secretion) cause dysregulated insulin secretion (particularly after ingestion of protein) and persistently elevated ammonia levels.
- Glucokinase acts as “glucose sensor” of the β cell. Activating mutations result in lower glucose threshold for insulin secretion.
- SCHAD is an inhibitory regulator of GDH. Inactivating mutations of HADH result in insulin dysregulation due to loss of GDH inhibition.
- UCP2 is a negative regulator of insulin secretion. Loss-of-function mutations lead to HI.
- In exercise-induced HI, ectopic expression of MCT1 allows transport of pyruvate, elevated during anaerobic exercise, into the β cell; leads to an increased ATP-to-ADP ratio, thus stimulating insulin secretion
- Mutations in 9 genes have been associated with congenital HI: Genes coding for the two subunits of the β cell KATP channel [SUR1, sulfonylurea receptor (ABCC8); Kir6.2, inwardly rectifying potassium channel (KCNJ11)]; glucokinase (GCK), glutamate dehydrogenase (GLUD1), SCHAD (HADH), UCP2 (UCP2), HNF4A, HNF1A and monocarboxylate transporter-1 (SLC16A1).
- A transient form of HI has been associated with perinatal stress (small for gestational age [SGA] birth weight, maternal hypertension, precipitous delivery, or hypoxia), but the mechanism has not been elucidated.
Commonly Associated Conditions
HI can be associated with Beckwith-Wiedemann syndrome and congenital disorders of glycosylation (CDG). The underlying mechanism of HI in these disorders is not clear.