Abstract
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.
Highlights
The Na+/glucose cotransporter 1, is expressed on the brush border membrane of absorptive enterocytes, and is the major route for transport of dietary glucose across the lumen of the intestine [1, 2]
There was a 2.2-fold increase (P = 0.300) in SGLT1 protein abundance compared to the low-carbohydrate diet, which correlated with a 2.7-fold increase (P = 0.0387) in the initial rate of Na+-dependent glucose transport into brush border membrane vesicle (BBMV) (Figures 1B,C) [Rates of Na+-dependent glucose transport were 150.2 ± 28.2 and 55.5 ± 8.0 pmol s−1−1 for two diet groups, respectively]; a similar increase in SGLT1 mRNA abundance and glucose transport was observed in BBMV isolated from the mid small intestine
Whereas wild-type mice are known to respond to increased dietary carbohydrates with enhanced SGLT1 expression [3, 7], glucagon-like peptide-2 (GLP-2) receptor knockout mice did not respond in this manner
Summary
The Na+/glucose cotransporter 1, is expressed on the brush border membrane of absorptive enterocytes, and is the major route for transport of dietary glucose across the lumen of the intestine [1, 2]. The gut epithelium can sense luminal sugars and artificial sweetens via the G-protein coupled sweet taste receptor, T1R2-T1R3, Regulation of Intestinal Glucose Transport expressed in enteroendocrine cells to modulate its Na+dependent glucose absorptive capacity [5,6,7]. Short-term intravenous or serosal administration of GLP-2 leads to an increase in the expression of SGLT1, maximal rate of Na+dependent glucose transport and an associated enhancement in blood glucose concentration [8,9,10,11]. The complete endocrine cell-absorptive enterocyte communication pathway regulating intestinal Na+/glucose cotransport is not known
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