Luminal Sweet Sensing and Enteric Nervous System Participate in Regulation of Intestinal Glucose Transporter, GLUT2

Background/Objectives: Dietary glucose is transported across the intestinal absorptive cell into the systemic circulation by the apically located Na⁺-dependent glucose transporter 1 (SGLT1, SLC5A1) and basally residing Na⁺-independent glucose transporter 2 (GLUT2, SLC2A2). Whilst recent experimental evidence has shown that sensing of sweet compounds by the gut-expressed sweet taste receptor T1R2-T1R3 and glucagon-like peptide-2 receptor signalling are components of the pathway controlling SGLT1 expression, little is known about the mechanisms involved in the regulation of GLUT2. In this study, we tested the hypothesis that T1R2-T1R3 and its downstream signalling pathway participate in the regulation of intestinal GLUT2. Methods: We used in vivo and in vitro approaches employing a weaning pig model, a heterologous expression assay, and knockout mice for elucidating the regulation of GLUT2 by luminal sugars. Results: A plant-based sweetener formulation included in piglets' diet led to a marked increase in GLUT2 expression in piglets' intestine, compared to controls. The sweeteners that do not activate pig T1R2-T1R3 failed to upregulate GLUT2. There was a significant increase in GLUT2 expression when the sweetener sucralose, which activates T1R2-T1R3, was included in the drinking water of wild-type mice. However, in knockout mice, in which the genes for the sweet receptor subunit T1R3 and the associated G-protein gustducin were deleted, there was no upregulation of GLUT2 expression in response to sucralose supplementation. There was a notable increase in GLUT2 expression in wild-type mice fed a high-carbohydrate diet compared to when maintained on a low-carbohydrate diet. However, in GLP-2 receptor knockout mice kept on the high-carbohydrate diet, there was no enhancement in GLUT2 expression. Conclusions: The experimental evidence suggests that luminal sweet sensing via T1R2-T1R3 and the enteroendocrine-derived GLP-2 are constituents of the regulatory pathway controlling GLUT2 expression.