Regulation of α-cell glucagon secretion: The role of second messengers

Glucagon is a potent glucose-elevating hormone that is secreted by pancreatic α-cells. While well-controlled glucagon secretion plays an important role in maintaining systemic glucose homeostasis and preventing hypoglycaemia, it is increasingly apparent that defects in the regulation of glucagon secretion contribute to impaired counter-regulation and hyperglycaemia in diabetes. It has therefore been proposed that pharmacological interventions targeting glucagon secretion/signalling can have great potential in improving glycaemic control of patients with diabetes. However, despite decades of research, a consensus on the precise mechanisms of glucose regulation of glucagon secretion is yet to be reached. Second messengers are a group of small intracellular molecules that relay extracellular signals to the intracellular signalling cascade, modulating cellular functions. There is a growing body of evidence that second messengers, such as cAMP and Ca²⁺, play critical roles in α-cell glucose-sensing and glucagon secretion. In this review, we discuss the impact of second messengers on α-cell electrical activity, intracellular Ca²⁺ dynamics and cell exocytosis. We highlight the possibility that the interaction between different second messengers may play a key role in the glucose-regulation of glucagon secretion.