KATP Channels in the Pancreas: Hyperinsulinism and Diabetes. Hyperinsulinism and Diabetes.

ATP-sensitive potassium (K_ATP) channels are present in the surface membranes of many organs and cell types. Over the last two decades, significant advances have been made in understanding the molecular basis of K_ATP channel activity, as well as their role in physiology and pathophysiology. K_ATP channels are heterooctameric complexes of coassembly of four pore-forming Kir6.2 subunits and four regulatory SUR1 subunits (encoded by KCNJ11 and ABCC8 genes, respectively). K_ATP channels are regulated by adenosine nucleotides, are inhibited by intracellular ATP, and activated by ADP. In the pancreatic ?-cell, K_ATP channels play a critical role in coupling glucose metabolism to insulin secretion. Normally, glucose oxidation leads to a rise in [ATP]:[ADP] ratio, which reduces K_ATP channel activity and causes membrane depolarization. This leads to subsequent opening of voltage-dependent Ca²⁺ channels, and increase in intracellular [Ca²⁺], which in turn promotes insulin vesicles to fuse to the plasma membrane and release insulin. Sulfonylureas (SUs), oral hypoglycemic agents widely used in the treatment of diabetes, act by binding to the SUR1 subunit thus inhibiting K_ATP current and inducing insulin secretion, independently of the metabolic state of the cell. Conversely, K_ATP-specific channel openers (ie, diazoxide) suppress insulin release by activating K_ATP and preventing depolarization-dependent rise in intracellular [Ca²⁺]. Loss-of-function mutations in the KCNJ11 and ABCC8 genes of the K_ATP channel underlie hyperinsulinism that can in some cases be treated by potassium channel openers. Conversely, gain-of-function mutations are the main cause of human neonatal diabetes mellitus which can now be treated by SUs, and a common K_ATP variant (E23K) is highly associated as a risk factor for development of type-2 diabetes. This chapter will focus on advances in K_ATP channel biochemistry and physiology, as well as on the mechanistic basis by which K_ATP mutations underlie these insulin secretory disorders.