The multiple effects of glucagon

Glucagon is canonically viewed as the opposition to insulin action, raising blood glucose through hepatic actions to limit hypoglycemia. However, glucagon also potently stimulates insulin secretion through paracrine interactions between alpha and beta cells in the islet. The mechanism by which glucagon stimulates insulin secretion is similar to incretin peptides; it is mediated by G-protein coupled receptors in beta cells and is glucose dependent. And while intravenous glucose inhibits alpha cell function to decrease circulating glucagon levels, a mixed nutrient meal stimulates alpha cells leading to elevated levels of glucagon. The importance of glucagon in the postprandial state is often overshadowed by the idea that glucagon exists as a counter regulatory hormone to limit hypoglycemia in the fasted state. Here, we demonstrate how glucagon action is necessary for the insulin response to a mixed nutrient meal that resembles the normal feeding pattern of people. We show how the meal induced incretin peptide GIP elicits a direct effect on alpha cells, potentiating amino acid stimulated glucagon secretion and ultimately driving insulin secretion through alpha to beta cell communication. In summary, we provide new ideas that expand the role of glucagon beyond the fasted state, showing that the alpha cell is a critical regulate of metabolism in response to feeding.

Jonathan Campbell is an Associated Profession in the Department of Medicine at Duke University and member of the Duke Molecular Physiology Institute. His group is interested in how incretin peptides regulate metabolism, with a focus on islet endocrine functions. Recently, his group has described the importance of paracrine interactions within the islet, initiated by alpha cell secretion of proglucagon products to regulate beta cell function. The continuation of this work is now aimed at understanding the factors that regulate alpha cell function to initiate this paracrine system, including the interaction between GPCRs expressed on alpha cells and amino acids.