Glucagon-Like Peptide 1 Shows Glucose Dependence in Regulating Islet Hormone Secretion

Abstract

Background: GLP-1, glucagon-like peptide 1, is an incretin secreted by intestinal L-cells, responsible for stimulating insulin and decreasing glucagon secretion. Analogs of this hormone such as Liraglutide are approved for treating Type II diabetes (T2D). Despite its clinical success, much about how GLP-1 inhibits the alpha-cell remains unknown. GLP-1 receptor is expressed in both beta and delta cells, but is absent from the alpha-cell. As somatostatin reduces alpha-cell Ca2+ influx, paracrine signaling between delta and alpha cells may contribute to GLP-1 mediated inhibition of glucagon secretion. Therefore, we hypothesize that altered delta-cell activity is involved in the inhibitory effects of GLP-1 on the alpha-cell. Methods: Genetically encoded cAMP indicator cADDIS or a Ca2+ dye together with mouse pancreatic islets that express red fluorescent protein in either alpha or delta cells were used. Islets were perfused in glucose with or without addition of Liraglutide while imaged in real-time on Zeiss LSm780. ImageJ was used for analysis. Results: GLP-1 reduced delta-cell Ca2+ influx in low glucose, possibly by enhancing electrical coupling between beta and delta cells. GLP-1 increased alpha-cell cAMP levels under low glucose, further suggesting that delta cell somatostatin secretion is also reduced in these conditions. In high glucose, we found increased synchronicity and frequency of Ca2+ oscillations between beta and delta cells but decreased alpha-cell cAMP. Conclusion: The data suggests that GLP-1 reduces delta-cell Ca2+ influx in low glucose and increases Ca2+ influx in high glucose, which may provide a mechanism for glucose-dependent modulation of alpha-cell glucagon secretion by GLP-1.