Abstract

LX4211, a dual SGLT1/SGLT2 inhibitor, is designed to block renal glucose (G) reabsorption by inhibiting SGLT2 and intestinal (GI) G absorption by inhibiting SGLT1. Increased GI G levels secondary to SGLT1 inhibition should trigger release of GI hormones such as glucagon-like peptide (GLP)-1 and peptide YY (PYY). We asked if oral G increases levels of cecal G and serum GLP-1 and PYY in mice treated with LX4211, and if these findings are recapitulated in SGLT1 or SGLT2 knock out (KO) mice. Wild-type (WT) mice raised on G-containing diet received vehicle or LX4211 (60 mg/kg) by gavage; 30 min later these mice, along with SGLT1 and SGLT2 KO and WT littermate mice raised on G-free diet, received a G-containing meal (9.2 g G/kg, 2.5 g protein/kg, 0.6 g fat/kg) by gavage and were studied 3 hr later. Also, 30 min after receiving vehicle or LX4211 (60 mg/kg) by gavage, WT mice were gavaged at different G doses; total GLP-1 AUC was then estimated over the next 6 hrs. Oral G increased levels of GI G and serum GLP-1 and PYY in LX4211-treated mice, findings that were recapitulated in SGLT1, but not SGLT2, KO mice. These data suggest that LX4211 increases serum GLP-1 and PYY levels after an oral G challenge by inhibiting GI SGLT1.