title: LX4211 increases serum glucagon-like peptide 1 and peptide YY levels by reducing sodium/glucose cotransporter 1 (SGLT1)-mediated absorption of intestinal glucose.
abstract: LX4211 [(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triol], a dual sodium/glucose cotransporter 1 (SGLT1) and SGLT2 inhibitor, is thought to decrease both renal glucose reabsorption by inhibiting SGLT2 and intestinal glucose absorption by inhibiting SGLT1. In clinical trials in patients with type 2 diabetes mellitus (T2DM), LX4211 treatment improved glycemic control while increasing circulating levels of glucagon-like peptide 1 (GLP-1) and peptide YY (PYY). To better understand how LX4211 increases GLP-1 and PYY levels, we challenged SGLT1 knockout (-/-) mice, SGLT2-/- mice, and LX4211-treated mice with oral glucose. LX4211-treated mice and SGLT1-/- mice had increased levels of plasma GLP-1, plasma PYY, and intestinal glucose during the 6 hours after a glucose-containing meal, as reflected by area under the curve (AUC) values, whereas SGLT2-/- mice showed no response. LX4211-treated mice and SGLT1-/- mice also had increased GLP-1 AUC values, decreased glucose-dependent insulinotropic polypeptide (GIP) AUC values, and decreased blood glucose excursions during the 6 hours after a challenge with oral glucose alone. However, GLP-1 and GIP levels were not increased in LX4211-treated mice and were decreased in SGLT1-/- mice, 5 minutes after oral glucose, consistent with studies linking decreased intestinal SGLT1 activity with reduced GLP-1 and GIP levels 5 minutes after oral glucose. These data suggest that LX4211 reduces intestinal glucose absorption by inhibiting SGLT1, resulting in net increases in GLP-1 and PYY release and decreases in GIP release and blood glucose excursions. The ability to inhibit both intestinal SGLT1 and renal SGLT2 provides LX4211 with a novel dual mechanism of action for improving glycemic control in patients with T2DM.
authors.affiliation: Lexicon Pharmaceuticals, Inc., 8800 Technology Forest Place, The Woodlands, TX 77381, USA. dpowell@lexpharma.com
authors.forename: David R
authors.initials: DR
authors.lastname: Powell
authors.forename: Melinda
authors.initials: M
authors.lastname: Smith
authors.forename: Jennifer
authors.initials: J
authors.lastname: Greer
authors.forename: Angela
authors.initials: A
authors.lastname: Harris
authors.forename: Sharon
authors.initials: S
authors.lastname: Zhao
authors.forename: Christopher
authors.initials: C
authors.lastname: DaCosta
authors.forename: Faika
authors.initials: F
authors.lastname: Mseeh
authors.forename: Melanie K
authors.initials: MK
authors.lastname: Shadoan
authors.forename: Arthur
authors.initials: A
authors.lastname: Sands
authors.forename: Brian
authors.initials: B
authors.lastname: Zambrowicz
authors.forename: Zhi-Ming
authors.initials: ZM
authors.lastname: Ding
mesh_terms: D000818:Animals; D019540:Area Under Curve; D001786:Blood Glucose / Q000378:metabolism; D004032:Diet; D005749:Gastric Inhibitory Polypeptide / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000097:blood*; D005947:Glucose / Q000378:metabolism*; D005951:Glucose Tolerance Test; D006027:Glycosides / Q000494:pharmacology*; D006029:Glycosuria / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007408:Intestinal Absorption / Q000187:drug effects*; D008757:Methylglucosides / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019894:Peptide YY / Q000097:blood*; D019518:Postprandial Period / Q000502:physiology; D051269:Sodium-Glucose Transporter 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D051297:Sodium-Glucose Transporter 2 / Q000235:genetics; D000077203:Sodium-Glucose Transporter 2 Inhibitors
chemical_list: D001786:Blood Glucose; D006027:Glycosides; D007004:Hypoglycemic Agents; D008757:Methylglucosides; C495674:SLC5A1 protein, human; C089180:SLC5A2 protein, human; D051269:Sodium-Glucose Transporter 1; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D019894:Peptide YY; D005749:Gastric Inhibitory Polypeptide; C575681:(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triol; D052216:Glucagon-Like Peptide 1; D005947:Glucose