title: Inhibition of apical sodium-dependent bile acid transporter as a novel treatment for diabetes.
abstract: Bile acids are recognized as metabolic modulators. The present study was aimed at evaluating the effects of a potent Asbt inhibitor (264W94), which blocks intestinal absorption of bile acids, on glucose homeostasis in Zucker Diabetic Fatty (ZDF) rats. Oral administration of 264W94 for two wk increased fecal bile acid concentrations and elevated non-fasting plasma total Glp-1. Treatment of 264W94 significantly decreased HbA1c and glucose, and prevented the drop of insulin levels typical of ZDF rats in a dose-dependent manner. An oral glucose tolerance test revealed up to two-fold increase in plasma total Glp-1 and three-fold increase in insulin in 264W94 treated ZDF rats at doses sufficient to achieve glycemic control. Tissue mRNA analysis indicated a decrease in farnesoid X receptor (Fxr) activation in small intestines and the liver but co-administration of a Fxr agonist (GW4064) did not attenuate 264W94 induced glucose lowering effects. In summary, our results demonstrate that inhibition of Asbt increases bile acids in the distal intestine, promotes Glp-1 release and may offer a new therapeutic strategy for type 2 diabetes mellitus.
authors.affiliation: Department of Biology, Quantitative Science, Metabolic Drug Discovery, GlaxoSmithKline Inc., Five Moore Dr., Research Triangle Park, NC 27709, USA. lihong.z.chen@gsk.com
authors.forename: Lihong
authors.initials: L
authors.lastname: Chen
authors.forename: Xiaozhou
authors.initials: X
authors.lastname: Yao
authors.forename: Andrew
authors.initials: A
authors.lastname: Young
authors.forename: Judi
authors.initials: J
authors.lastname: McNulty
authors.forename: Don
authors.initials: D
authors.lastname: Anderson
authors.forename: Yaping
authors.initials: Y
authors.lastname: Liu
authors.forename: Christopher
authors.initials: C
authors.lastname: Nystrom
authors.forename: Dallas
authors.initials: D
authors.lastname: Croom
authors.forename: Sean
authors.initials: S
authors.lastname: Ross
authors.forename: Jon
authors.initials: J
authors.lastname: Collins
authors.forename: Deepak
authors.initials: D
authors.lastname: Rajpal
authors.forename: Kimberly
authors.initials: K
authors.lastname: Hamlet
authors.forename: Chari
authors.initials: C
authors.lastname: Smith
authors.forename: Bronislava
authors.initials: B
authors.lastname: Gedulin
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000032:analysis / Q000097:blood / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005243:Feces / Q000737:chemistry; D005765:Gastrointestinal Agents / Q000627:therapeutic use*; D005786:Gene Expression Regulation / Q000187:drug effects; D052216:Glucagon-Like Peptide 1 / Q000097:blood; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D007408:Intestinal Absorption / Q000187:drug effects*; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism; D007555:Isoxazoles / Q000008:administration & dosage / Q000627:therapeutic use; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D029363:Organic Anion Transporters, Sodium-Dependent / Q000037:antagonists & inhibitors*; D012333:RNA, Messenger / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D011924:Rats, Zucker; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D027981:Symporters / Q000037:antagonists & inhibitors*; D013841:Thiazepines / Q000008:administration & dosage / Q000627:therapeutic use*; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D001647:Bile Acids and Salts; D005765:Gastrointestinal Agents; D052216:Glucagon-Like Peptide 1; D007004:Hypoglycemic Agents; D007555:Isoxazoles; D029363:Organic Anion Transporters, Sodium-Dependent; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D027981:Symporters; D013841:Thiazepines; D000099150:Receptor, Farnesoid X-Activated; C119986:264W 94; C071908:sodium-bile acid cotransporter; C412815:GW 4064