T1R3 and gustducin in gut sense sugars to regulate expression of Na ⁺ -glucose cotransporter 1

TLDR

Sodium‑dependent glucose transporter 1 (SGLT1) mediates intestinal sugar absorption, and its regulation is essential for glucose provision and preventing malabsorption, yet the luminal glucose sensor responsible for this regulation was previously unknown. The study demonstrates that the sweet taste receptor subunit T1R3 and the G protein gustducin in enteroendocrine cells mediate intestinal sugar sensing and regulate SGLT1 expression. Dietary sugars and artificial sweeteners upregulate SGLT1 mRNA, protein, and glucose absorption in wild‑type mice, an effect absent in T1R3 or gustducin knockouts, and sweet‑taste receptor activation stimulates gut hormone secretion that promotes SGLT1 up‑regulation, suggesting new targets for treating malabsorption, diabetes, and obesity.

Abstract

Dietary sugars are transported from the intestinal lumen into absorptive enterocytes by the sodium-dependent glucose transporter isoform 1 (SGLT1). Regulation of this protein is important for the provision of glucose to the body and avoidance of intestinal malabsorption. Although expression of SGLT1 is regulated by luminal monosaccharides, the luminal glucose sensor mediating this process was unknown. Here, we show that the sweet taste receptor subunit T1R3 and the taste G protein gustducin, expressed in enteroendocrine cells, underlie intestinal sugar sensing and regulation of SGLT1 mRNA and protein. Dietary sugar and artificial sweeteners increased SGLT1 mRNA and protein expression, and glucose absorptive capacity in wild-type mice, but not in knockout mice lacking T1R3 or alpha-gustducin. Artificial sweeteners, acting on sweet taste receptors expressed on enteroendocrine GLUTag cells, stimulated secretion of gut hormones implicated in SGLT1 up-regulation. Gut-expressed taste signaling elements involved in regulating SGLT1 expression could provide novel therapeutic targets for modulating the gut's capacity to absorb sugars, with implications for the prevention and/or treatment of malabsorption syndromes and diet-related disorders including diabetes and obesity.