title: Selective small-molecule agonists of G protein-coupled receptor 40 promote glucose-dependent insulin secretion and reduce blood glucose in mice.
abstract: OBJECTIVE
  Acute activation of G protein-coupled receptor 40 (GPR40) by free fatty acids (FFAs) or synthetic GPR40 agonists enhances insulin secretion. However, it is still a matter of debate whether activation of GPR40 would be beneficial for the treatment of type 2 diabetes, since chronic exposure to FFAs impairs islet function. We sought to evaluate the specific role of GPR40 in islets and its potential as a therapeutic target using compounds that specifically activate GPR40.
  
  
  METHODS
  We developed a series of GPR40-selective small-molecule agonists and studied their acute and chronic effects on glucose-dependent insulin secretion (GDIS) in isolated islets, as well as effects on blood glucose levels during intraperitoneal glucose tolerance tests in wild-type and GPR40 knockout mice (GPR40(-/-)).
  
  
  RESULTS
  Small-molecule GPR40 agonists significantly enhanced GDIS in isolated islets and improved glucose tolerance in wild-type mice but not in GPR40(-/-) mice. While a 72-h exposure to FFAs in tissue culture significantly impaired GDIS in islets from both wild-type and GPR40(-/-) mice, similar exposure to the GPR40 agonist did not impair GDIS in islets from wild-type mice. Furthermore, the GPR40 agonist enhanced insulin secretion in perfused pancreata from neonatal streptozotocin-induced diabetic rats and improved glucose levels in mice with high-fat diet-induced obesity acutely and chronically.
  
  
  CONCLUSIONS
  GPR40 does not mediate the chronic toxic effects of FFAs on islet function. Pharmacological activation of GPR40 may potentiate GDIS in humans and be beneficial for overall glucose control in patients with type 2 diabetes.
authors.affiliation: Department of Metabolic Disorders-Diabetes, Merck Research Laboratories, Rahway, New Jersey, USA.
authors.forename: Carina P
authors.initials: CP
authors.lastname: Tan
authors.forename: Yue
authors.initials: Y
authors.lastname: Feng
authors.forename: Yun-Ping
authors.initials: YP
authors.lastname: Zhou
authors.forename: George J
authors.initials: GJ
authors.lastname: Eiermann
authors.forename: Aleksandr
authors.initials: A
authors.lastname: Petrov
authors.forename: Changyou
authors.initials: C
authors.lastname: Zhou
authors.forename: Songnian
authors.initials: S
authors.lastname: Lin
authors.forename: Gino
authors.initials: G
authors.lastname: Salituro
authors.forename: Peter
authors.initials: P
authors.lastname: Meinke
authors.forename: Ralph
authors.initials: R
authors.lastname: Mosley
authors.forename: Taro E
authors.initials: TE
authors.lastname: Akiyama
authors.forename: Monica
authors.initials: M
authors.lastname: Einstein
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Kumar
authors.forename: Joel P
authors.initials: JP
authors.lastname: Berger
authors.forename: Sander G
authors.initials: SG
authors.lastname: Mills
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Thornberry
authors.forename: Lihu
authors.initials: L
authors.lastname: Yang
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Howard
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001786:Blood Glucose / Q000378:metabolism*; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000378:metabolism / Q000473:pathology; D004041:Dietary Fats / Q000008:administration & dosage; D005227:Fatty Acids / Q000494:pharmacology; D005230:Fatty Acids, Nonesterified / Q000494:pharmacology; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000097:blood / Q000209:etiology / Q000378:metabolism; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000235:genetics / Q000502:physiology
chemical_list: D001786:Blood Glucose; D004041:Dietary Fats; D005227:Fatty Acids; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D043562:Receptors, G-Protein-Coupled; D015544:Inositol 1,4,5-Trisphosphate