Content area
Full Text
The a-cell of the pancreatic islet modulates glucose homeostasis by secreting glucagon that acts primarily by driving hepatic glucose production. Glucose sensing of the a-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 a-cell. Glucagon secretion has been linked to several triggers: the a-cell detecting a fall in circulating glucose levels directly, a paracrine response to signal(s) from the islet ß-cell (e.g., insulin, 7-aminobutyric acid [GABA], or Zn2+ ions) or the islet d-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 a-cell electrical activity and Ca2+ influx and fundamentally resembles the excitation-secretion coupling seen in many secretory cell types (9). Stimulus-induced a-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 a-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 a-cell electrical activity and Ca2+ entry. In islet ß-cells, elevations in glucose increase the ATP-toADP ratio, resulting in the closure of ATP-sensitive K+ (KATP) channels and causing action potential firing. a-Cell electrical activity is also sensitive to modulators of the KATP channel; thus, glucose responsiveness has been linked to the activity of KATP, which sets the resting membrane potential of pancreatic ß-cells. In contrast to ß-cells, KATI, channel closure in a-cells has been linked to the termination of action potential firing (10). KATP channels can affect human glucagon secretion as evidenced in carriers of the E23K variant of KATP, which is linked to an increased incidence in adult-onset diabetes and perturbations in glucose regulation of glucagon secretion (13). Similarly, a mouse model with a defective KATP channel...