title: Improved glycemic control in mice lacking Sglt1 and Sglt2.
abstract: Sodium-glucose cotransporter 2 (SGLT2) is the major, and SGLT1 the minor, transporter responsible for renal glucose reabsorption. Increasing urinary glucose excretion (UGE) by selectively inhibiting SGLT2 improves glycemic control in diabetic patients. We generated Sglt1 and Sglt2 knockout (KO) mice, Sglt1/Sglt2 double-KO (DKO) mice, and wild-type (WT) littermates to study their relative glycemic control and to determine contributions of SGLT1 and SGLT2 to UGE. Relative to WTs, Sglt2 KOs had improved oral glucose tolerance and were resistant to streptozotocin-induced diabetes. Sglt1 KOs fed glucose-free high-fat diet (G-free HFD) had improved oral glucose tolerance accompanied by delayed intestinal glucose absorption and increased circulating glucagon-like peptide-1 (GLP-1), but had normal intraperitoneal glucose tolerance. On G-free HFD, Sglt2 KOs had 30%, Sglt1 KOs 2%, and WTs <1% of the UGE of DKOs. Consistent with their increased UGE, DKOs had lower fasting blood glucose and improved intraperitoneal glucose tolerance than Sglt2 KOs. In conclusion, 1) Sglt2 is the major renal glucose transporter, but Sglt1 reabsorbs 70% of filtered glucose if Sglt2 is absent; 2) mice lacking Sglt2 display improved glucose tolerance despite UGE that is 30% of maximum; 3) Sglt1 KO mice respond to oral glucose with increased circulating GLP-1; and 4) DKO mice have improved glycemic control over mice lacking Sglt2 alone. These data suggest that, in patients with type 2 diabetes, combining pharmacological SGLT2 inhibition with complete renal and/or partial intestinal SGLT1 inhibition may improve glycemic control over that achieved by SGLT2 inhibition alone.
authors.affiliation: Lexicon Pharmaceuticals, Inc., 8800 Technology Forest Pl., The Woodlands, TX 77381, USA. dpowell@lexpharma.com
authors.forename: David R
authors.initials: DR
authors.lastname: Powell
authors.forename: Christopher M
authors.initials: CM
authors.lastname: DaCosta
authors.forename: Jason
authors.initials: J
authors.lastname: Gay
authors.forename: Zhi-Ming
authors.initials: ZM
authors.lastname: Ding
authors.forename: Melinda
authors.initials: M
authors.lastname: Smith
authors.forename: Jennifer
authors.initials: J
authors.lastname: Greer
authors.forename: Deon
authors.initials: D
authors.lastname: Doree
authors.forename: Sabrina
authors.initials: S
authors.lastname: Jeter-Jones
authors.forename: Faika
authors.initials: F
authors.lastname: Mseeh
authors.forename: Lawrence A
authors.initials: LA
authors.lastname: Rodriguez
authors.forename: Angela
authors.initials: A
authors.lastname: Harris
authors.forename: Lindsey
authors.initials: L
authors.lastname: Buhring
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Platt
authors.forename: Peter
authors.initials: P
authors.lastname: Vogel
authors.forename: Robert
authors.initials: R
authors.lastname: Brommage
authors.forename: Melanie K
authors.initials: MK
authors.lastname: Shadoan
authors.forename: Arthur T
authors.initials: AT
authors.lastname: Sands
authors.forename: Brian
authors.initials: B
authors.lastname: Zambrowicz
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000235:genetics / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000139:chemically induced / Q000235:genetics / Q000652:urine; D005260:Female; D052216:Glucagon-Like Peptide 1 / Q000494:pharmacology; D005951:Glucose Tolerance Test; D006029:Glycosuria / Q000235:genetics; D007328:Insulin / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051269:Sodium-Glucose Transporter 1 / Q000235:genetics* / Q000502:physiology; D051297:Sodium-Glucose Transporter 2 / Q000235:genetics* / Q000502:physiology; D013311:Streptozocin
chemical_list: D001786:Blood Glucose; D007328:Insulin; C495675:Slc5a1 protein, mouse; C490299:Slc5a2 protein, mouse; D051269:Sodium-Glucose Transporter 1; D051297:Sodium-Glucose Transporter 2; D013311:Streptozocin; D052216:Glucagon-Like Peptide 1