An Innate Disposition for a Healthier Gut: GLP-1R Signaling in Intestinal Epithelial Lymphocytes

The GLP-1 system affects multiple physiological processes, ranging from potentiation of glucose-stimulated insulin secretion to gut motility, satiety, and even hepatic glucose production (1–3), through distinct mechanisms at separate locations. While there is some debate about whether GLP-1 mediates these actions through the circulation as a hormone (4–6), GLP-1 signaling via its receptor (GLP-1R) on target tissues has been extensively studied and shown to support therapeutic application. As a result, GLP-1 receptor agonists and inhibitors of dipeptidyl peptidase-4 that delay GLP-1 inactivation are now widely used for the treatment of type 2 diabetes and, more recently, obesity (7–10). Thus, there is a substantial and incontrovertible body of evidence supporting a role for GLP-1 in metabolic control.Notable among recent studies is a new direction—interaction between GLP-1 and pathways of inflammation. For example, the enteroendocrine L cells, which are thought to be the primary source of GLP-1, increase their secretion in response to interleukin-6 and lipopolysaccharide, as well as in other settings of systemic inflammation (11–13). At the level of GLP-1 action, satiety effects in the central nervous system seem to be mediated, at least in part, by cytokines (14). A role of GLP-1 in inflammation appears to have some clinical relevance as plasma concentrations are elevated in critically ill patients (12,15). Despite the compelling nature of these findings, the cellular and molecular connections between L cells, GLP-1R, and the immune system are not well understood. Thus, the article by Yusta et al. (16) in this issue of Diabetes is both timely and important as it traces at least one pathway connecting GLP-1 and immune function. Here, the authors show that GLP-1Rs regulate intestinal epithelial lymphocytes (IELs), a novel finding with broad implications that seems likely to advance the understanding in …