Conflicting Views About Interactions Between Pancreatic α-Cells and β-Cells

In type 1 diabetes, the reduced glucagon response to insulin-induced hypoglycemia has been used to argue that beta-cell secretion of insulin is required for the full glucagon counterregulatory response. For years, the concept has been that insulin from the beta-cell core flows downstream to suppress glucagon secretion from the alpha-cells in the islet mantle. This core-mantle relationship has been supported by perfused pancreas studies that show marked increases in glucagon secretion when insulin was neutralized with antisera. Additional support comes from a growing number of studies focused on vascular anatomy and blood flow. However, in recent years this core-mantle view has generated less interest than the argument that optimal insulin secretion is due to paracrine release of glucagon from alpha-cells stimulating adjacent beta-cells. This mechanism has been evaluated by knockout of beta-cell receptors and impairment of alpha-cell function by inhibition of Gi designer receptors exclusively activated by designer drugs. Other studies that support this mechanism have been obtained by pharmacological blocking of glucagon-like peptide 1 receptor in humans. While glucagon has potent effects on beta-cells, there are concerns with the suggested paracrine mechanism, since some of the supporting data are from isolated islets. The study of islets in static incubation or perifusion systems can be informative, but the normal paracrine relationships are disrupted by the isolation process. While this complicates interpretation of data, arguments supporting paracrine interactions between alpha-cells and beta-cells have growing appeal. We discuss these conflicting views of the relationship between pancreatic alpha-cells and beta-cells and seek to understand how communication depends on blood flow and/or paracrine mechanisms.