PMID- 24849925
OWN - NLM
STAT- MEDLINE
DCOM- 20140826
LR  - 20220408
IS  - 1521-0103 (Electronic)
IS  - 0022-3565 (Linking)
VI  - 350
IP  - 2
DP  - 2014 Aug
TI  - Effect of LX4211 on glucose homeostasis and body composition in preclinical 
      models.
PG  - 232-42
LID - 10.1124/jpet.114.214304 [doi]
AB  - Treatments that lower blood glucose levels and body weight should benefit 
      patients with type 2 diabetes mellitus (T2DM). We developed LX4211 
      [(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triol], 
      an orally available small molecule that decreases postprandial glucose excursions 
      by inhibiting intestinal sodium/glucose cotransporter 1 (SGLT1) and increases 
      urinary glucose excretion (UGE) by inhibiting renal SGLT2. In clinical studies of 
      patients with T2DM, LX4211 appears to act through dual SGLT1/SGLT2 inhibition to 
      improve glycemic control and promote weight loss. Here, we present preclinical 
      studies that explored the ability of LX4211 to improve glycemic control and 
      promote weight loss. We found that 1) LX4211 inhibited in vitro glucose transport 
      mediated by mouse, rat, and dog SGLT1 and SGLT2; 2) a single daily LX4211 dose 
      markedly increased UGE for >24 hours in mice, rats, and dogs; and 3) in the 
      KK.Cg-Ay/J heterozygous (KKA(y)) mouse model of T2DM, LX4211 lowered A1C and 
      postprandial glucose concentrations while increasing postprandial glucagon-like 
      peptide 1 concentrations. Also, long-term LX4211 treatment 1) decreased oral 
      glucose tolerance test (OGTT) glucose excursions, increased OGTT 30-minute 
      insulin concentrations and increased pancreatic insulin content in KKA(y) mice; 
      and 2) decreased weight gain in dogs and rats but not in KKA(y) mice while 
      increasing food consumption in dogs, rats, and KKA(y) mice; in these KKA(y) mice, 
      calories lost through UGE were completely offset by calories gained through 
      hyperphagia. These findings suggest that LX4211 improves glycemic control by dual 
      SGLT1/SGLT2 inhibition in mice as in humans, and that the LX4211-mediated weight 
      loss observed in patients with T2DM may be attenuated by LX4211-mediated 
      hyperphagia in some of these individuals.
CI  - Copyright (c) 2014 by The American Society for Pharmacology and Experimental 
      Therapeutics.
FAU - Powell, David R
AU  - Powell DR
AD  - Lexicon Pharmaceuticals, Inc., The Woodlands, Texas (D.R.P., C.M.D., M.Sm., D.D., 
      A.H., L.B., A.N., W.X., F.M., A.W., M.Sh., B.Z., Z.-M.D.); and Lexicon 
      Pharmaceuticals, Inc., Princeton, New Jersey (W.H., P.Y.) dpowell@lexpharma.com.
FAU - DaCosta, Christopher M
AU  - DaCosta CM
AD  - Lexicon Pharmaceuticals, Inc., The Woodlands, Texas (D.R.P., C.M.D., M.Sm., D.D., 
      A.H., L.B., A.N., W.X., F.M., A.W., M.Sh., B.Z., Z.-M.D.); and Lexicon 
      Pharmaceuticals, Inc., Princeton, New Jersey (W.H., P.Y.).
FAU - Smith, Melinda
AU  - Smith M
AD  - Lexicon Pharmaceuticals, Inc., The Woodlands, Texas (D.R.P., C.M.D., M.Sm., D.D., 
      A.H., L.B., A.N., W.X., F.M., A.W., M.Sh., B.Z., Z.-M.D.); and Lexicon 
      Pharmaceuticals, Inc., Princeton, New Jersey (W.H., P.Y.).
FAU - Doree, Deon
AU  - Doree D
AD  - Lexicon Pharmaceuticals, Inc., The Woodlands, Texas (D.R.P., C.M.D., M.Sm., D.D., 
      A.H., L.B., A.N., W.X., F.M., A.W., M.Sh., B.Z., Z.-M.D.); and Lexicon 
      Pharmaceuticals, Inc., Princeton, New Jersey (W.H., P.Y.).
FAU - Harris, Angela
AU  - Harris A
AD  - Lexicon Pharmaceuticals, Inc., The Woodlands, Texas (D.R.P., C.M.D., M.Sm., D.D., 
      A.H., L.B., A.N., W.X., F.M., A.W., M.Sh., B.Z., Z.-M.D.); and Lexicon 
      Pharmaceuticals, Inc., Princeton, New Jersey (W.H., P.Y.).
FAU - Buhring, Lindsey
AU  - Buhring L
AD  - Lexicon Pharmaceuticals, Inc., The Woodlands, Texas (D.R.P., C.M.D., M.Sm., D.D., 
      A.H., L.B., A.N., W.X., F.M., A.W., M.Sh., B.Z., Z.-M.D.); and Lexicon 
      Pharmaceuticals, Inc., Princeton, New Jersey (W.H., P.Y.).
FAU - Heydorn, William
AU  - Heydorn W
AD  - Lexicon Pharmaceuticals, Inc., The Woodlands, Texas (D.R.P., C.M.D., M.Sm., D.D., 
      A.H., L.B., A.N., W.X., F.M., A.W., M.Sh., B.Z., Z.-M.D.); and Lexicon 
      Pharmaceuticals, Inc., Princeton, New Jersey (W.H., P.Y.).
FAU - Nouraldeen, Amr
AU  - Nouraldeen A
AD  - Lexicon Pharmaceuticals, Inc., The Woodlands, Texas (D.R.P., C.M.D., M.Sm., D.D., 
      A.H., L.B., A.N., W.X., F.M., A.W., M.Sh., B.Z., Z.-M.D.); and Lexicon 
      Pharmaceuticals, Inc., Princeton, New Jersey (W.H., P.Y.).
FAU - Xiong, Wendy
AU  - Xiong W
AD  - Lexicon Pharmaceuticals, Inc., The Woodlands, Texas (D.R.P., C.M.D., M.Sm., D.D., 
      A.H., L.B., A.N., W.X., F.M., A.W., M.Sh., B.Z., Z.-M.D.); and Lexicon 
      Pharmaceuticals, Inc., Princeton, New Jersey (W.H., P.Y.).
FAU - Yalamanchili, Padmaja
AU  - Yalamanchili P
AD  - Lexicon Pharmaceuticals, Inc., The Woodlands, Texas (D.R.P., C.M.D., M.Sm., D.D., 
      A.H., L.B., A.N., W.X., F.M., A.W., M.Sh., B.Z., Z.-M.D.); and Lexicon 
      Pharmaceuticals, Inc., Princeton, New Jersey (W.H., P.Y.).
FAU - Mseeh, Faika
AU  - Mseeh F
AD  - Lexicon Pharmaceuticals, Inc., The Woodlands, Texas (D.R.P., C.M.D., M.Sm., D.D., 
      A.H., L.B., A.N., W.X., F.M., A.W., M.Sh., B.Z., Z.-M.D.); and Lexicon 
      Pharmaceuticals, Inc., Princeton, New Jersey (W.H., P.Y.).
FAU - Wilson, Alan
AU  - Wilson A
AD  - Lexicon Pharmaceuticals, Inc., The Woodlands, Texas (D.R.P., C.M.D., M.Sm., D.D., 
      A.H., L.B., A.N., W.X., F.M., A.W., M.Sh., B.Z., Z.-M.D.); and Lexicon 
      Pharmaceuticals, Inc., Princeton, New Jersey (W.H., P.Y.).
FAU - Shadoan, Melanie
AU  - Shadoan M
AD  - Lexicon Pharmaceuticals, Inc., The Woodlands, Texas (D.R.P., C.M.D., M.Sm., D.D., 
      A.H., L.B., A.N., W.X., F.M., A.W., M.Sh., B.Z., Z.-M.D.); and Lexicon 
      Pharmaceuticals, Inc., Princeton, New Jersey (W.H., P.Y.).
FAU - Zambrowicz, Brian
AU  - Zambrowicz B
AD  - Lexicon Pharmaceuticals, Inc., The Woodlands, Texas (D.R.P., C.M.D., M.Sm., D.D., 
      A.H., L.B., A.N., W.X., F.M., A.W., M.Sh., B.Z., Z.-M.D.); and Lexicon 
      Pharmaceuticals, Inc., Princeton, New Jersey (W.H., P.Y.).
FAU - Ding, Zhi-Ming
AU  - Ding ZM
AD  - Lexicon Pharmaceuticals, Inc., The Woodlands, Texas (D.R.P., C.M.D., M.Sm., D.D., 
      A.H., L.B., A.N., W.X., F.M., A.W., M.Sh., B.Z., Z.-M.D.); and Lexicon 
      Pharmaceuticals, Inc., Princeton, New Jersey (W.H., P.Y.).
LA  - eng
PT  - Journal Article
DEP - 20140521
PL  - United States
TA  - J Pharmacol Exp Ther
JT  - The Journal of pharmacology and experimental therapeutics
JID - 0376362
RN  - 0 (Glycosides)
RN  - 0 (Hypoglycemic Agents)
RN  - 0 (Sodium-Glucose Transporter 1)
RN  - 0 (Sodium-Glucose Transporter 2 Inhibitors)
RN  - 6B4ZBS263Y 
      ((2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triol)
RN  - IY9XDZ35W2 (Glucose)
SB  - IM
MH  - Animals
MH  - Body Composition/*drug effects
MH  - Dogs
MH  - Glucose/*metabolism
MH  - Glycosides/pharmacokinetics/*pharmacology
MH  - Glycosuria/drug therapy
MH  - Homeostasis/*drug effects
MH  - Humans
MH  - Hypoglycemic Agents/*pharmacology
MH  - Intestinal Absorption/drug effects
MH  - Mice
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Sodium-Glucose Transporter 1/*antagonists & inhibitors
MH  - *Sodium-Glucose Transporter 2 Inhibitors
EDAT- 2014/05/23 06:00
MHDA- 2014/08/27 06:00
CRDT- 2014/05/23 06:00
PHST- 2014/05/23 06:00 [entrez]
PHST- 2014/05/23 06:00 [pubmed]
PHST- 2014/08/27 06:00 [medline]
AID - jpet.114.214304 [pii]
AID - 10.1124/jpet.114.214304 [doi]
PST - ppublish
SO  - J Pharmacol Exp Ther. 2014 Aug;350(2):232-42. doi: 10.1124/jpet.114.214304. Epub 
      2014 May 21.