Update of variants identified in the pancreatic β-cell KATP channel genes KCNJ11 and ABCC8 in individuals with congenital hyperinsulinism and diabetes

Abstract

The most common genetic cause of neonatal diabetes and hyperinsulinism is pathogenic variants in ABCC8 and KCNJ11. These genes encode the subunits of the β-cell ATP-sensitive potassium channel, a key component of the glucose-stimulated insulin secretion pathway. Mutations in the two genes cause dysregulated insulin secretion; inactivating mutations cause an oversecretion of insulin, leading to congenital hyperinsulinism, whereas activating mutations cause the opposing phenotype, diabetes. This review focuses on variants identified in ABCC8 and KCNJ11, the phenotypic spectrum and the treatment implications for individuals with pathogenic variants.

Keywords: ABCC8; K-ATP channel; KCNJ11; congenital hyperinsulinism; neonatal diabetes.

Figure 1

Schematic representation of insulin secretion in the pancreatic β‐cell. (a) In a normal cell in a high plasma glucose environment. (b) In a cell with an activating K_ATP channel mutation. (c) In a cell with an inactivating mutation resulting in the absence/reduction in protein at the membrane surface d) In a cell with an inactivating mutation that impairs the stimulatory effect of MgADP (a) Glucose is metabolized after entry into the β‐cell via a GLUT transporter. This results in change in the ATP:ADP ratio, leading to channel closure and membrane depolarization and activation of voltage‐dependent calcium channels. Calcium enters the cell, which triggers insulin release. (b) An activating mutation in a K_ATP channel gene results in the membrane being maintained in a hyperpolarized state. Calcium channels remain closed and insulin is not secreted. (c) Loss‐of‐function mutations can result in an absence/reduction in protein at the membrane surface. This keeps the membrane in a depolarized state, regardless of the metabolic state ultimately leading to unregulated insulin secretion. (d) Loss‐of‐function missense mutations can produce channels that traffic to the membrane but have impaired mgADP activation