title: GSK256073, a selective agonist of G-protein coupled receptor 109A (GPR109A) reduces serum glucose in subjects with type 2 diabetes mellitus.
abstract: OBJECTIVE
  This clinical trial assessed whether a potent, selective GPR109A agonist, GSK256073, could, through inhibition of lipolysis, acutely improve glucose homeostasis in subjects with type 2 diabetes mellitus.
  
  
  METHODS
  Thirty-nine diabetic subjects were enrolled in the randomized, single-blind, placebo-controlled, three-period crossover trial. Each subject received placebo and two of four regimens of GSK256073 for 2 days. GSK256073 was dosed 5 mg every 12 h before breakfast and supper (BID), 10 mg every 24 h before breakfast (QD), 25 mg BID and 50 mg QD.
  
  
  RESULTS
  The change from baseline weighted mean glucose concentration for an interval from 24 to 48 h after the initial drug dose was significantly reduced for all GSK256073 regimens, reaching a maximum of -0.87 mmol/l (-1.20, -0.52) with the 25 mg BID dose. Sustained suppression of non-esterified fatty acid (NEFA) and glycerol concentrations was observed with all GSK256073 doses throughout the 48-h dosing period. Serum insulin and C-peptide concentrations fell in concert with glucose concentrations and calculated HOMA-IR scores decreased 27-47%, consistent with insulin sensitization. No marked differences were evident between either 10 and 50 mg total daily doses or QD versus BID dosing.
  
  
  CONCLUSIONS
  Administration of a GPR109A agonist for 2 days significantly decreased serum NEFA and glucose concentrations in diabetic subjects. Glucose improvements were associated with decreased insulin concentrations and measures of enhanced insulin sensitivity. Improved glucose control occurred with GSK256073 doses that were generally safe and not associated with events of flushing or gastrointestinal disturbances.
authors.affiliation: GlaxoSmithKline, Drug Discovery, Research Triangle Park, NC, USA.
authors.forename: R L
authors.initials: RL
authors.lastname: Dobbins
authors.forename: S P
authors.initials: SP
authors.lastname: Shearn
authors.forename: R L
authors.initials: RL
authors.lastname: Byerly
authors.forename: F F
authors.initials: FF
authors.lastname: Gao
authors.forename: K M
authors.initials: KM
authors.lastname: Mahar
authors.forename: A
authors.initials: A
authors.lastname: Napolitano
authors.forename: G J
authors.initials: GJ
authors.lastname: Nachbaur
authors.forename: A-C
authors.initials: AC
authors.lastname: Le Monnier de Gouville
mesh_terms: D002096:C-Peptide / Q000097:blood; D018592:Cross-Over Studies; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D015507:Drugs, Investigational / Q000008:administration & dosage / Q000032:analysis / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005260:Female; D005500:Follow-Up Studies; D005990:Glycerol / Q000097:blood; D006801:Humans; D006943:Hyperglycemia / Q000517:prevention & control*; D006946:Hyperinsulinism / Q000517:prevention & control; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000960:Hypolipidemic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D007333:Insulin Resistance; D008297:Male; D008875:Middle Aged; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000378:metabolism; D016037:Single-Blind Method
chemical_list: D002096:C-Peptide; D015507:Drugs, Investigational; D005230:Fatty Acids, Nonesterified; C530636:HCAR2 protein, human; D007004:Hypoglycemic Agents; D000960:Hypolipidemic Agents; D043562:Receptors, G-Protein-Coupled; D011978:Receptors, Nicotinic; D005990:Glycerol
keywords: GPR109A; GSK256073; HM74A; clinical trial; niacin receptor