Figure 1. SGLT1 inhibition reduces intestinal glucose absorption and enhances the sustained GLP-1 release from the distal intestine.

In the small intestine, SGLT1 mediates glucose and galactose absorption across the apical cell membrane. Membrane SGLT1 expression is upregulated i) by intracellular glucose which blocks the inhibitory effect of RS1 and ii) by luminal nutrients/glucose that activate luminal taste sensors. This adapts glucose absorption to dietary glucose intake. SGLT1 expression is regulated by multiple signaling cascades and is upregulated in diabetes. SGLT1 in L cells in proximal intestine sense dietary glucose, which subsequently triggers the “acute” release of GLP-1. SGLT1 inhibition in early intestine reduces glucose absorption and thereby increases the glucose delivery to the more distal gut, where glucose is used by the microbiome to form short-chain fatty acids (SCFAs) which enter the distal L-cells through FFAR2 and FFAR3 and trigger a “sustained” release in GLP-1. SGLT1: sodium glucose cotransporter 1; GLP-1: glucagon- like peptide 1; SCFAs: short-chain fatty acids; FFAR2: G-protein-coupled free fatty acid receptor 2; FFAR3: G-protein-coupled free fatty acid receptor 3; GLUT2: glucose transporter 2. T1R3: sweet taste receptor subunit 3;a-gustducin: a-transducin-like Gprotein a-subunit; PKA: protein kinase A; AMPK: AMP-activated protein kinase; SGK1: serum and glucocorticoid inducible kinase 1; SGK3: serum and glucocorticoid inducible kinase 3;PKC: protein kinase C; RS1: gene product of RSC1A1 that blocks release of SGLT1 containing vesicles from the Golgi at low intracellular glucose concentrations; SPAK: ‘with-no-K[Lys] kinases’/STE20/SPS1-related proline/alanine-rich kinase.