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

Abstract

Secretion of insulin from pancreatic β-cells is complex, but physiological glucose-dependent secretion is dominated by electrical activity, in turn controlled by ATP-sensitive potassium (KATP) channel activity. Accordingly, loss-of-function mutations of the KATP channel Kir6.2 (KCNJ11) or SUR1 (ABCC8) subunit increase electrical excitability and secretion, resulting in congenital hyperinsulinism (CHI), whereas gain-of-function mutations cause underexcitability and undersecretion, resulting in neonatal diabetes mellitus (NDM). Thus, diazoxide, which activates KATP channels, and sulfonylureas, which inhibit KATP 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 β-cell KATP activity are not hyperinsulinemic; instead, they are paradoxically glucose intolerant and prone to diabetes, as are older human CHI patients. Critically, despite these advances, there has been little insight into any role of KATP 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 KATP activity.

Figure 1

Canonical and paradoxical consequences of reduced K_ATP activity. A cartoon representation of the relationship between K_ATP levels, excitability, and secretory response is shown. Supranormal K_ATP activity (>100%) reduces excitability and secretion, resulting in NDM. Conversely, reduced K_ATP activity causes hyperexcitability, hypersecretion, and HI. However, when K_ATP density is reduced substantially, there is a paradoxical crossover to an undersecreting phenotype (the inverse-U relationship [101]), resulting in HI remission or development of diabetes. We propose that increased excitability in response to insulin resistance (IR) will result in hypersecretion but that further reduction of K_ATP and enhanced excitability may underlie progression to undersecretion in T2D.