title: Novel Small Molecule Agonist of TGR5 Possesses Anti-Diabetic Effects but Causes Gallbladder Filling in Mice.
abstract: Activation of TGR5 via bile acids or bile acid analogs leads to the release of glucagon-like peptide-1 (GLP-1) from intestine, increases energy expenditure in brown adipose tissue, and increases gallbladder filling with bile. Here, we present compound 18, a non-bile acid agonist of TGR5 that demonstrates robust GLP-1 secretion in a mouse enteroendocrine cell line yet weak GLP-1 secretion in a human enteroendocrine cell line. Acute administration of compound 18 to mice increased GLP-1 and peptide YY (PYY) secretion, leading to a lowering of the glucose excursion in an oral glucose tolerance test (OGTT), while chronic administration led to weight loss. In addition, compound 18 showed a dose-dependent increase in gallbladder filling. Lastly, compound 18 failed to show similar pharmacological effects on GLP-1, PYY, and gallbladder filling in Tgr5 knockout mice. Together, these results demonstrate that compound 18 is a mouse-selective TGR5 agonist that induces GLP-1 and PYY secretion, and lowers the glucose excursion in an OGTT, but only at doses that simultaneously induce gallbladder filling. Overall, these data highlight the benefits and potential risks of using TGR5 agonists to treat diabetes and metabolic diseases.
authors: Lilly Research Laboratories, Eli Lilly and Co., Indianapolis, Indiana, United States of America.
authors: Daniel A
authors: DA
authors: Briere
authors: Lilly Research Laboratories, Eli Lilly and Co., Indianapolis, Indiana, United States of America.
authors: Xiaoping
authors: X
authors: Ruan
authors: Lilly Research Laboratories, Eli Lilly and Co., Indianapolis, Indiana, United States of America.
authors: Christine C
authors: CC
authors: Cheng
authors: Lilly Research Laboratories, Eli Lilly and Co., Indianapolis, Indiana, United States of America.
authors: Angela M
authors: AM
authors: Siesky
authors: Lilly Research Laboratories, Eli Lilly and Co., Indianapolis, Indiana, United States of America.
authors: Thomas E
authors: TE
authors: Fitch
authors: Centro de Investigación, Eli Lilly and Company, Alcobendas, Spain.
authors: Carmen
authors: C
authors: Dominguez
authors: Centro de Investigación, Eli Lilly and Company, Alcobendas, Spain.
authors: Sonia Gutierrez
authors: SG
authors: Sanfeliciano
authors: Centro de Investigación, Eli Lilly and Company, Alcobendas, Spain.
authors: Carlos
authors: C
authors: Montero
authors: Lilly Research Laboratories, Eli Lilly and Co., Indianapolis, Indiana, United States of America.
authors: Chen S
authors: CS
authors: Suen
authors: Lilly Research Laboratories, Eli Lilly and Co., Indianapolis, Indiana, United States of America.
authors: Yanping
authors: Y
authors: Xu
authors: Lilly Research Laboratories, Eli Lilly and Co., Indianapolis, Indiana, United States of America.
authors: Tamer
authors: T
authors: Coskun
authors: Lilly Research Laboratories, Eli Lilly and Co., Indianapolis, Indiana, United States of America.
authors: M Dodson
authors: MD
authors: Michael
mesh_terms: D000818:Animals; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005704:Gallbladder / Q000187:drug effects* / Q000503:physiopathology; D005786:Gene Expression Regulation; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism; D005951:Glucose Tolerance Test; D057809:HEK293 Cells; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects* / Q000494:pharmacology*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019894:Peptide YY / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000235:genetics; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology; D015431:Weight Loss / Q000187:drug effects
chemical_list: C473772:GPBAR1 protein, human; C513561:Gpbar1 protein, mouse; D007004:Hypoglycemic Agents; D043562:Receptors, G-Protein-Coupled; D054852:Small Molecule Libraries; D019894:Peptide YY; D052216:Glucagon-Like Peptide 1