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