By: Sofia Arreguin
ABCC8 Gene Mutation
ABCC8 Gene
The ABCC8 gene is known for its role in providing instructions for the creation of SUR1, a protein responsible for encoding ATP-sensitive potassium (KATP) channels situated in beta, or pancreatic, cells (National Library of Medicine, 2026; Butnariu et al., 2024). Normally, these beta cells release the hormone insulin to regulate the amount of glucose, or sugar, present in the bloodstream. Glucose is determined to be a crucial and primary source of energy for the body, especially for cells in the brain and nervous system, but when blood glucose levels rise to heightened levels, hyperglycemia, or high blood sugar, can arise. When such levels occur, the KATP channels are motivated to close, signaling for beta cells to secrete insulin directly into the bloodstream. Once secreted, insulin helps cells to absorb glucose for either immediate or later use, often storing glucose in the form of glycogen, thereby preventing the accumulation of sugar in the body’s bloodstream. As a result of insulin’s ability to combat high blood glucose levels, serious and often life-threatening conditions, such as high blood sugar, can be avoided. However, mutations in the ABCC8 gene can cause deficits within this operation and lead to the opposite of high blood sugar: low blood glucose levels.
ABCC8-Related Epilepsy: Congenital Hyperinsulinism
Mutations in the ABCC8 gene often result in a condition known as congenital hyperinsulinism, characterized by low blood glucose levels and fatigue (National Library of Medicine, 2026). When variants appear in the gene, faulty proteins are produced, which cause an inability of KATP channels to function properly. Through these disruptions in channels, beta cells are signaled to release an immoderate amount of insulin, which results in the removal of glucose from the bloodstream and, therefore, low blood glucose levels. Normally, insulin is secreted as blood glucose levels rise in response to consuming food, maintaining standard blood glucose levels, and allowing glucose to enter the body’s cells to be stored for future use. Once an individual’s consumption of food is complete, blood glucose levels begin to decline, signaling a cessation of insulin secretion and the entrance of glycogen, a form of stored glucose, into the bloodstream to maintain normal blood glucose levels (National Organization for Rare Disorders, 2020). However, individuals with congenital hyperinsulinism experience abnormal secretions of insulin, even when there is no consumption of sugar or food. The body’s beta cells release insulin without regard for the amount of glucose present within the bloodstream, resulting in low blood glucose levels.
The brain relies on fuels to help it carry out its everyday functions, with 3 of its primary fuels consisting of ketones, lactate, and glucose (National Organization for Rare Disorders, 2020). With congenital hyperinsulinism, the brain is prevented from accessing such fuels because insulin levels are maintained at high levels, inhibiting certain processes from occurring. Specifically, the release of glycogen from the liver, the transformation of protein into glucose, and the transformation of fat into ketones are hampered by the release of insulin (National Organization for Rare Disorders, 2020). As a result, the brain is deprived of its fuel, causing its cells to lack sufficient amounts of energy required for proper performance. Without the energy to perform adequately, brain cells simply stop working, which can have damaging effects on the brain and the individual. Insufficient fuel and energy can result in a coma or, if experienced for a lengthy amount of time, the destruction of brain cells.
Further, the release of excess glutamate can occur as a result of insufficient fuels, as depleted energy can hinder the function of sodium-dependent glutamate transporters (EAAT) (Hawkins, R. A., & Viña, J. R., 2016). These transporters work to regulate the amount of glutamate, the excitatory neurotransmitter, present in the extracellular space, characterized as encompassing the surrounding space of a cell, thereby containing neuronal excitability and preventing the occurrence of seizures (Hawkins, R. A., & Viña, J. R., 2016). However, without adequate energy or fuel, the EAATs are unable to prevent neuronal excitability, but rather induce neuronal excitability by releasing excess amounts of glutamate. Without the effectiveness of GABA, the inhibitory neurotransmitter, to counterbalance the presence of glutamate and calm the excitable energy, the brain experiences a seizure. Seizures often occur when too much neuronal excitability is present in the brain, often causing excitotoxicity, in which too much glutamate becomes toxic for neurons, resulting in neuronal death; seizures may also occur from excitotoxicity (Hawkins, R. A., & Viña, J. R., 2016) Cells can become damaged and result in intellectual disability, seizure disorders, and even death (National Organization for Rare Disorders, 2020).
Treatment
The inheritance of variations in the ABCC8 gene depends on the type of condition of congenital hyperinsulinism: either a diffuse or a focal form. The diffuse form is characterized by the release of excess insulin by beta cells of the pancreas, and has an autosomal recessive pattern of inheritance (National Library of Medicine, 2014). Through this, each parent holds one copy of a mutated gene, often showing no symptoms as a result of holding both a normal and mutated copy of the gene; however, their offspring inherit both mutated copies of the gene, resulting in the development of a disorder and its symptoms (National Library of Medicine, 2014). With the focal form, only some beta cells of the pancreas release excess insulin, and this condition is characterized by an autosomal dominant inheritance pattern (National Library of Medicine, 2014). Through this, the offspring inherits only the mutated gene from the father, yet these variants are only found in some beta cells, resulting in the secretion of excess insulin by those select few.
The aim of treatments for individuals with ABCC8 genetic variants is to maintain normal blood glucose levels in the bloodstream and, therefore, defend the brain from damage. Some forms of treatment include medications, surgery, or management of one’s diet. In children with symptoms related to ABCC8 genetic mutations, glucose is administered intravenously, directly into the vein, to increase the depleted levels of blood glucose (JScreen, n.d.). Similarly, when managing symptoms in infants, routine feedings, often through a tube, are utilized by incorporating a substantial amount of carbohydrates into their diet. Specifically, complex carbohydrates are used to maintain blood glucose levels, reducing the risk of low blood glucose levels (Demirbilek, H., & Hussain, K., 2017). Certain medications are also prescribed to manage glucose levels, such as Diazoxide and Octreotide. Diazoxide works to inhibit the release of insulin from beta cells in the pancreas, resulting in less insulin within the bloodstream and a lower risk of low blood glucose levels, or hyperinsulinism (Children’s Hospital of Philadelphia, n.d.). Octreotide is often recommended and administered when a patient does not respond well to Diazoxide, working as a second-line treatment (https://pmc.ncbi.nlm.nih.gov/articles/PMC8749021/).
Surgery can be carried out depending on the condition of the congenital hyperinsulinism. For a focal form, surgery would likely focus on the removal of only a certain region or area of the pancreas, and is associated with full recovery of the patient. However, with diffuse forms, surgery would focus on removing nearly the whole pancreas, and it is not guaranteed to produce a full recovery (Faletra, F. et al., 2012).
Treatment for ABCC8-related variants depends on the form of congenital hyperinsulinism a patient has, and consultations with medical professionals can best help individuals find an effective treatment plan. Knowing how to manage its symptoms can help improve a patient’s lifestyle and condition.
References
Butnariu, L. I., et al. (2024). Congenital Hyperinsulinism Caused by Mutations in ABCC8 Gene Associated with Early-Onset Neonatal Hypoglycemia: Genetic Heterogeneity Correlated with Phenotypic Variability. International Journal of Molecular Sciences, 25(10), 5533. https://doi.org/10.3390/ijms25105533
Children’s Hospital of Philadelphia. (n.d.). Diazoxide (Proglycem). https://www.chop.edu/treatments/diazoxide
Demirbilek, H., & Hussain, K. (2017). Congenital Hyperinsulinism: Diagnosis and Treatment Update. Journal of Clinical Research in Pediatric Endocrinology, 9(Suppl 2), 69–87. https://doi.org/10.4274/jcrpe.2017.S007
Faletra, F., et al. (2012). Co-inheritance of two ABCC8 mutations causing an unresponsive congenital hyperinsulinism: Clinical and functional characterization of two novel ABCC8 mutations. Gene, 516(1), 122-125. https://doi.org/10.1016/j.gene.2012.12.055
Hawkins, R. A., & Viña, J. R. (2016). How Glutamate Is Managed by the Blood-Brain Barrier. Biology, 5(4), 37. https://doi.org/10.3390/biology5040037
JScreen. (n.d.). ABCC8-related Hyperinsulinism. https://www.jscreen.org/hereditary-diseases/familial-hyperinsulinism
National Library of Medicine. (2026, January 13). ABCC8 gene. MedlinePlus. https://medlineplus.gov/genetics/gene/abcc8/
National Library of Medicine. (2014, January 1). Congenital hyperinsulinism. MedlinePlus. https://medlineplus.gov/genetics/condition/congenital-hyperinsulinism/National Organization for Rare Disorders. (2020, March 24). Congenital Hyperinsulinism. https://rarediseases.org/rare-diseases/congenital-hyperinsulinism/
