Data_Sheet_1_Glucagon-Like Peptide-2 and the Enteric Nervous System Are Components of Cell-Cell Communication Pathway Regulating Intestinal Na+/Glucose Co-transport.docx

The Na+/glucose cotransporter 1, SGLT1 is the major route for transport of dietary glucose from the lumen of the intestine into absorptive enterocytes. Sensing of dietary sugars and artificial sweeteners by the sweet taste receptor, T1R2-T1R3, expressed in the enteroendocrine L-cell regulates SGLT1 expression in neighboring absorptive enterocytes. However, the mechanism by which sugar sensing by the enteroendocrine cell is communicated to the absorptive enterocytes is not known. Here, we show that glucagon-like peptide-2 (GLP-2) secreted from the enteroendocrine cell in response to luminal sugars regulates SGLT1 mRNA and protein expression in absorptive enterocytes, via the enteric neurons. Glucose and artificial sweeteners induced secretion of GLP-2 from mouse small intestine, which was inhibited by the sweet-taste receptor inhibitor, gurmarin. In wild type mice there was an increase in sugar-induced SGLT1 mRNA and protein abundance that was not observed in GLP-2 receptor knockout mice. GLP-2 receptor is expressed in enteric neurons, and not in absorptive enterocytes ruling out a paracrine effect of GLP-2. Electric field stimulation of the intestine resulted in upregulation of SGLT1 expression that was abolished by the nerve blocking agent tetrodotoxin. We conclude that GLP-2 and the enteric nervous system are components of the enteroendocrine-absorptive enterocyte communication pathway regulating intestinal glucose transport.