Preproglucagon Products and Their Respective Roles Regulating Insulin Secretion

Historically, intracellular function and metabolic adaptation within the alpha-cell has been understudied, with most of the attention being placed on the insulin-producing beta-cells due to their role in the pathophysiology of type 2 diabetes mellitus. However, there is a growing interest in understanding the function of other endocrine cell types within the islet and their paracrine role in regulating insulin secretion. For example, there is greater appreciation for alpha-cell products and their contributions to overall glucose homeostasis. Several recent studies have addressed a paracrine role for alpha-cell-derived glucagon-like peptide-1 (GLP-1) in regulating glucose homeostasis and responses to metabolic stress. Further, other studies have demonstrated the ability of glucagon to impact insulin secretion by acting through the GLP-1 receptor. These studies challenge the central dogma surrounding alpha-cell biology describing glucagon's primary role in glucose counterregulation to one where glucagon is critical in regulating both hyper- and hypoglycemic responses. Herein, this review will update the current understanding of the role of glucagon and alpha-cell-derived GLP-1, placing emphasis on their roles in regulating glucose homeostasis, insulin secretion, and beta-cell mass.