The α-Cell Conundrum: ATP-Sensitive K+ Channels and Glucose Sensing
- From the Department of Medicine, Section of Endocrinology, Diabetes and Metabolism, The University of Chicago, Chicago, Illinois
- Corresponding author: Louis H. Philipson,
The α-cell of the pancreatic islet modulates glucose homeostasis by secreting glucagon that acts primarily by driving hepatic glucose production. Glucose sensing of the α-cell becomes defective in both type 1 and type 2 diabetes, resulting in hyperglucagonemia that likely contributes to hyperglycemia (1). Thus, it is important to elucidate the signals that trigger glucagon secretion and the transduction of these signals within the α-cell. Glucagon secretion has been linked to several triggers: the α-cell detecting a fall in circulating glucose levels directly, a paracrine response to signal(s) from the islet β-cell (e.g., insulin, γ-aminobutyric acid [GABA], or Zn2+ ions) or the islet δ-cell (somatostatin), or a response to neural signals (2–8). In all likelihood, an interaction of several signals regulates glucagon secretion in vivo.
There is good reason to believe that glucagon release, like insulin release, is influenced by physiological α-cell electrical activity and Ca2+ influx and fundamentally resembles the excitation-secretion coupling seen in many secretory cell types (9). Stimulus-induced α-cell electrical activity results from depolarization-induced opening of voltage-gated Ca2+ and K+ channels (2,9–11). The depolarization first activates the low voltage–activated T-type Ca2+ channels, which have been implicated in action potential initiation (10). Activation of K+ channels then shapes the α-cell action potential upstroke. The resulting depolarization activates high voltage–activated Ca2+ channels including the N-type and L-type Ca2+ channels, which coordinate Ca2+-induced glucagon release (11). Action potential repolarization then follows with the activation of voltage-gated potassium (N) channels (12).
Hypoglycemic conditions can promote glucagon secretion by stimulating α-cell electrical activity and Ca2+ entry. …