Figure 10. A Model for the Suppression of Glucagon Secretion by an Intrinsic α-Cell Pathway.

Schematic representation of the effects of glucose, tolbutamide, and diazoxide on α-cell K_ATP, Na⁺, and N-type Ca²⁺ (VDCC) channel activities and glucagon secretion is shown. The insulin response is also shown for comparison with our experimental results (dashed lines, lower panels). The grey gradient represents a “window” of α-cell K_ATP channel activity that supports the activation of Ca²⁺ and Na⁺ channels. Above this window, the cell is hyperpolarized and Ca²⁺ and Na⁺ channel activation is prevented, whereas K_ATP channel activity below this window depolarizes the cell and causes voltage-dependent inactivation of Ca²⁺ and Na⁺ channels.

(A) High-glucose concentration reduces α-cell K_ATP channel activity, reducing glucagon secretion.

(B) Graded application of tolbutamide (in zero glucose) transiently increases glucagon secretion as K_ATP channel activity is reduced through, and eventually below, the window supporting glucagon release.

(C) The graded application of diazoxide in high-glucose conditions increases α-cell K_ATP channel activity into, and then above the window supporting glucagon secretion. The result is a transient “re-activation” of glucagon secretion at low-diazoxide concentrations.

(D) In low-glucose (1–2 mM) conditions, graded application of diazoxide increases K_ATP channel activity above the window supporting glucagon secretion, causing a monotonic inhibition of glucagon release.