title: Small molecule glucokinase activators disturb lipid homeostasis and induce fatty liver in rodents: a warning for therapeutic applications in humans.
abstract: OBJECTIVE
  Small-molecule glucokinase activators (GKAs) are currently being investigated as therapeutic options for the treatment of type 2 diabetes (T2D). Because liver overexpression of glucokinase is thought to be associated with altered lipid profiles, this study aimed at assessing the potential lipogenic risks linked to oral GKA administration.
  
  
  METHODS
  Nine GKA candidates were qualified for their ability to activate recombinant glucokinase and to stimulate glycogen synthesis in rat hepatocytes and insulin secretion in rat INS-1E cells. In vivo activity was monitored by plasma glucose and HbA1c measurements after oral administration in rodents. Risk-associated effects were assessed by measuring hepatic and plasma triglycerides and free fatty acids, as well as plasma aminotransferases, and alkaline phosphatase.
  
  
  RESULTS
  GKAs, while efficiently decreasing glycaemia in acute conditions and HbA1c levels after chronic administration in hyperglycemic db/db mice, were potent inducers of hepatic steatosis. This adverse outcome appeared as soon as 4 days after daily oral administration at pharmacological doses and was not transient. GKA treatment similarly increased hepatic triglycerides in diabetic and normoglycaemic rats, together with a pattern of metabolic phenotypes including different combinations of increased plasma triglycerides, free fatty acids, alanine and aspartyl aminotransferases, and alkaline phosphatase. GKAs belonging to three distinct structural families induced hepatic steatosis in db/db mice, arguing in favour of a target-mediated, rather than a chemical class-mediated, effect.
  
  
  CONCLUSIONS
  Given the risks associated with fatty liver disease in the general population and furthermore in patients with T2D, these findings represent a serious warning for the use of GKAs in humans.
  
  
  BACKGROUND
  This article is commented on by Rees and Gloyn, pp. 335-338 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476-5381.2012.02201.x.
authors.affiliation: Division of Metabolic Diseases, Institut de Recherches Servier, Suresnes, France. frederic.deceuninck@fr.netgrs.com
authors.forename: Frédéric
authors.initials: F
authors.lastname: De Ceuninck
authors.forename: Catherine
authors.initials: C
authors.lastname: Kargar
authors.forename: Catherine
authors.initials: C
authors.lastname: Ilic
authors.forename: Audrey
authors.initials: A
authors.lastname: Caliez
authors.forename: Jean-Olivier
authors.initials: JO
authors.lastname: Rolin
authors.forename: Thierry
authors.initials: T
authors.lastname: Umbdenstock
authors.forename: Cédric
authors.initials: C
authors.lastname: Vinson
authors.forename: Murielle
authors.initials: M
authors.lastname: Combettes
authors.forename: Brant
authors.initials: B
authors.lastname: de Fanti
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Harley
authors.forename: Marjorie
authors.initials: M
authors.lastname: Sadlo
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Lefèvre
authors.forename: Olivier
authors.initials: O
authors.lastname: Broux
authors.forename: Michel
authors.initials: M
authors.lastname: Wierzbicki
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Fourquez
authors.forename: Françoise
authors.initials: F
authors.lastname: Perron-Sierra
authors.forename: András
authors.initials: A
authors.lastname: Kotschy
authors.forename: Alain
authors.initials: A
authors.lastname: Ktorza
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism; D020536:Enzyme Activators / Q000494:pharmacology* / Q000627:therapeutic use; D005234:Fatty Liver / Q000139:chemically induced* / Q000378:metabolism; D005941:Glucokinase / Q000378:metabolism*; D006442:Glycated Hemoglobin / Q000032:analysis; D022781:Hepatocytes / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D007408:Intestinal Absorption; D050356:Lipid Metabolism / Q000187:drug effects*; D008297:Male; D051379:Mice; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D011924:Rats, Zucker
chemical_list: D001786:Blood Glucose; D020536:Enzyme Activators; D005941:Glucokinase; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents