ATP-Sensitive Potassium Channels in Hyperinsulinism and Type 2 Diabetes: Inconvenient Paradox or New Paradigm?

Secretion of insulin from pancreatic b-cells is complex, but physiological glucose-dependent secretion is domi-nated by electrical activity, in turn controlled by ATP-sen-sitive potassium (K_ATP) channel activity. Accordingly, loss-of-function mutations of the K_ATP channel Kir6.2 (KCNJ11) or SUR1 (ABCC8) subunit increase electrical excitability and secretion, resulting in congenital hyperinsulinism (CHI), whereas gain-of-function mutations cause under-excitability and undersecretion, resulting in neonatal diabetes mellitus (NDM). Thus, diazoxide, which activates K_ATP channels, and sulfonylureas, which inhibit K_ATP channels, have dramatically improved therapies for CHI and NDM, respectively. However, key findings do not fit within this simple paradigm: mice with complete absence of b-cell K_ATP activity are not hyperinsulinemic; instead, they are paradoxically glucose intolerant and prone to dia-betes, as are older human CHI patients. Critically, despite these advances, there has been little insight into any role of K_ATP channel activity changes in the development of type 2 diabetes (T2D). Intriguingly, the CHI progression from hypersecretion to undersecretion actually mirrors the classical response to insulin resistance in the progression of T2D. In seeking to explain the progression of CHI, multiple lines of evidence lead us to propose that underlying mechanisms are also similar and that development of T2D may involve loss of K_ATP activity.