Regulation of islet glucagon secretion: Beyond calcium

Abstract

The islet of Langerhans plays a key role in glucose homeostasis through regulated secretion of the hormones insulin and glucagon. Islet research has focused on the insulin-secreting β-cells, even though aberrant glucagon secretion from α-cells also contributes to the aetiology of diabetes. Despite its importance, the mechanisms controlling glucagon secretion remain controversial. Proper α-cell function requires the islet milieu, where β- and δ-cells drive and constrain α-cell dynamics. The response of glucagon to glucose is similar between isolated islets and that measured in vivo, so it appears that the glucose dependence requires only islet-intrinsic factors and not input from blood flow or the nervous system. Elevated intracellular free Ca²⁺ is needed for α-cell exocytosis, but interpreting Ca²⁺ data is tricky since it is heterogeneous among α-cells at all physiological glucose levels. Total Ca²⁺ activity in α-cells increases slightly with glucose, so Ca²⁺ may serve a permissive, rather than regulatory, role in glucagon secretion. On the other hand, cAMP is a more promising candidate for controlling glucagon secretion and is itself driven by paracrine signalling from β- and δ-cells. Another pathway, juxtacrine signalling through the α-cell EphA receptors, stimulated by β-cell ephrin ligands, leads to a tonic inhibition of glucagon secretion. We discuss potential combinations of Ca²⁺ , cAMP, paracrine and juxtacrine factors in the regulation of glucagon secretion, focusing on recent data in the literature that might unify the field towards a quantitative understanding of α-cell function.

Keywords: EphA receptor; cAMP; calcium; cellular heterogeneity; ephrin; glucagon; insulin; islet of Langerhans; microscopy; somatostatin; α-cell.

Figure 1

Schematic of representative Ca²⁺ kymographs in 5 hypothetical β- and α-cells. The thickness of the line represents longer oscillatory duration. β-cells are electrically coupled and show synchronous behavior, triggered by glucose stimulation (A). In α-cells, cells show some synchronous activity, others stop oscillating, others remain unperturbed by the glucose stimulation (B). The different amplitudes and periodicity of these oscillations further contribute to the heterogeneity of the α-cell populations.

Figure 2

Isolated islets from a 27-year-old nondiabetic human donor. A) Tight junctions (arrows) between an alpha and beta cell. B) Multihormonal cell containing alpha cell granules (arrows), beta cell granules (arrowheads), and delta cell granules (*). Scale bar = 1 μm.