Whereas the metabolic regulation of insulin secretion from the β-cell is fairly well understood, the processes that control hormone release from the non-β-cells of the islets (which include the glucagon-producing α-cell and the somatostatin-secreting δ-cell) are less well established. Pancreatic α-cells exhibit many similarities with the β-cells. Like β-cells, α-cells contain ATP-regulated K-channels (KATP-channels) and the metabolic rate as well as ATP production are similarly affected by an elevation of the extracellular glucose concentration in both cell types. Yet, insulin and glucagon secretion are reciprocally regulated by glucose. In β-cells, closure of the KATP-channels leads to membrane depolarization, initiation of electrical activity, opening of voltage-gated Ca-channels and insulin secretion. Work on KATP knockout mice indicates that KATP-channels are involved in the regulation of glucagon secretion by glucose but precisely how these channels participate in the control of glucagon secretion is not unknown. Experiments using increasing concentrations of tolbutamide (a blocker) and diazoxide (an activator) to “titrate” KATP-channel activity in α-cells in intact mouse, rat and human islets suggest that there is a bell-shaped relationship between KATP-channel activity and secretion. Glucagon secretion is only possible within a narrow window of KATP-channel activity and both increases and decreases in channel activity lead to inhibition of secretion (MacDonald et al., 2007). These effects can be dissociated from any concomitant changes in insulin and somatostatin release and are therefore likely to reflect mechanisms intrinsic to the α-cell rather than involving paracrine processes (exerted by factors released from the neighbouring β- and δ-cells). Pharmacological suppression of KATP-channel activity (with high concentrations of tolbutamide) inhibits glucagon secretion as strongly as glucose and the sugar has no further inhibitory action on glucagon secretion in islets already inhibited by tolbutamide. Addition of tolbutamide tis associated with membrane depolarization to ~-35 mV. All voltage-gated ion channels involved in α-cell action potential firing (TTX-sensitive Na-channels, A-type K-channels and N- and T-type Ca-channels) undergo voltage-dependent inactivation. Electrophysiological experiments have estblished that inactivation of these currents is complete at the membrane potential attained in the presence of tolbutamide. It remains unclear whether glucose inhibits glucagon secretion by exerting a tolbutamide-like effect mediated by inhibition of KATP-channels and changes in membrane potential or if it acts by direct modulation of, for example, the N-type Ca-channels that are tightly linked to exocytosis of the glucagon-containing granules. In contrast to the strong effects of the KATP-channel modulators on glucagon secretion, the release of somatostatin is only weakly influenced by these compounds and downstream processes appear quantitatively more important. Among these, Ca-induced Ca-release (CICR) is of particular significance (Zhang et al., 2007). Pancreatic δ-cells express RyR3 at levels comparable to those found in the CNS, whereas RyR1 and RyR2 are present at very low levels in both δ-cell and the other islet cells. CICR is triggered by Ca-influx through R-type (but not L-type) Ca-channels and occurs with a delay as short as <10 ms. Glucose-induces somatostatin secretion is strongly inhibited by ryanodine, dantrolene and thapsigargin and depends on glucose metabolism as suggested by its sensitivity to the glucokinase inhibitor mannoheptulose. The effect of glucose is mediated by elevation of intracellular cAMP with resultant activation of PKA. In capacitance measurements of exocytosis in δ-cell in intact mouse islets, the stimulatory effect of glucose can be mimicked by a low concentration of forskolin (2 µM). Forskolin at this concentration lacked effects when added to cells already exposed to glucose. The involvement of the cAMP/PKA pathway in the control of δ-cell secretion was confirmed by the demonstration that glucose-stimulated somatostatin release was inhibited by the PKA inhibitor 8-Br-Rp-cAMPS. Glucose and/or cAMP stimulate(s) exocytosis of somatostatin-containing secretory granules via a dramatic increase in the amplitude of the cytoplasmic Ca-transient that can be evoked by membrane depolarization or intracellular Ca mobilization. Collectively, these data demonstrate that glucose-sensing involves rather different mechanisms in the three major islet cell types.