Glucagon is the principal counterregulatory hormone that opposes the anabolic effects of insulin, notably on the liver (3), and a relative excess of glucagon is a hallmark of all forms of diabetes. However, failure to secrete adequate quantities of glucagon in response to insulin-induced hypoglycemia characterizes longstanding type 1 diabetes (4) and is an important contributor to mortality in this disease, accounting for 2–4% of all deaths (5). Glucagon is stored alongside insulin in the islet, albeit in a discrete cellular compartment, the pancreatic α-cell. Just as the metabolic actions of glucagon oppose those of insulin, the regulators of insulin’s release (1) tend to exert opposing effects on glucagon secretion (6). Thus, elevated concentrations of glucose suppress glucagon release, while catecholamines stimulate the secretion of this hormone. Acting independently of these mechanisms, neuronal inputs into the islet exert a further important level of control over glucagon release (7). Despite being a subject under investigation for more than 35 years (6), just how the effects of glucose are achieved at the level of individual α-cells is still disputed and has become an area of vigorous research in recent times (Figure 1). As yet, however, a consensus has not been reached. Several laboratories (eg, 8), including the author’s (9), have concluded that glucose acts directly on isolated mouse α-cells to suppress oscillations in intracellular free Ca2+ concentration in the absence of paracrine influences from β-cells (the latter parameter is usually taken in these excitable cells as an adequate surrogate for electrical and secretory activity). The Ca2+ changes were associated with increases in intracellular free ATP concentration (9), which might be “decoded” via 1) the partial closure of ATP-sensitive K+ channels (KATP), resulting in the inactivation of N-type Ca2+ and voltage-gated Na+ channels, suppression of electrical activity, and Ca2+ influx through L-type Ca2+ channels (1, 10); 2) through the activation of Ca2+ uptake by the endoplasmic reticulum, the consequent inactivation of a store-operated current that results in plasma membrane hyperpolarization, and decreased Ca2+ influx through voltage-gated Ca2+ channels (11); and 3) through changes in the activity of nutrient-regulated protein kinases including AMP kinase (12).

An alternative model has become known as the “intraislet” or “switch off” hypothesis. Informed by the strikingly “anti-parallel” regulation of insulin and glucagon secretion, this posits that factors released from the β-cell as glucose levels rise, including insulin itself (13) and cosecreted species such as γ-aminobutyric acid (GABA)(14–16) and Zn2+ ions (1, 17, 18), suppress the release of glucagon in a paracrine manner. This idea is supported by the fact that the intraislet circulation appears to be from β-to α-cell (19) and by the clinical observation that treatment of type 1 diabetic subjects with insulin usually lowers glucagon levels. Finally, purified rat α-cells have been reported to respond to elevated glucose concentrations with enhanced glucagon secretion (20)(though the impact of the fluorescence-activated cell sorting on the functional integrity of these preparations is uncertain). However, the “switch off” hypothesis has been challenged (8, 9) on the grounds that the concentrations of glucose that almost fully inhibit glucagon release from isolated rodent (8) and human islets (3–4 mmol/l) are significantly below those that elicit detectable depolarization of the β-cell or the release of insulin and costored regulators