Repositioning the Alpha Cell in Postprandial Metabolism

Glucose homeostasis is maintained in large part due to the actions of the pancreatic islet hormones insulin and glucagon, secreted from beta- and alpha-cells, respectively. The historical narrative positions these hormones in opposition, with insulin primarily responsible for glucose-lowering and glucagon-driving elevations in glucose. Recent progress in this area has revealed a more complex relationship between insulin and glucagon, highlighted by data demonstrating that alpha-cell input is essential for beta-cell function and glucose homeostasis. Moreover, the common perception that glucagon levels decrease following a nutrient challenge is largely shaped by the inhibitory effects of glucose administration alone on the alpha-cell. Largely overlooked is that a mixed nutrient challenge, which is more representative of typical human feeding, actually stimulates glucagon secretion. Thus, postprandial metabolism is associated with elevations, not decreases, in alpha-cell activity. This review discusses the recent advances in our understanding of how alpha-cells regulate metabolism, with a particular focus on the postprandial state. We highlight alpha- to beta-cell communication, a term that describes how alpha-cell input into beta-cells is a critical axis that regulates insulin secretion and glucose homeostasis. Finally, we discuss the open questions that have the potential to advance this field and continue to evolve our understanding of the role that alpha-cells play in postprandial metabolism.