title: The TZD insulin sensitizer clue provides a new route into diabetes drug discovery.
abstract: BACKGROUND
  Thiazolidinedione (TZD) insulin sensitizers have a pleotropic pharmacology including reduction of insulin resistance, a root cause of diabetes. Importantly, these agents also preserve pancreatic beta cell function. TZDs are not widely used, especially early on in disease progression when they might have the greatest benefit, because of side effects, principally volume expansion, weight gain, and increased bone reabsorption. Incomplete understanding of their mechanism of action has prevented the development of new agents. Recent studies suggest that these compounds modify mitochondrial metabolism and metabolic signals that coordinate downstream cell function.
  
  
  METHODS
  The author provides a brief history of the development of the first generation insulin sensitizer TZDs, which coincided with the expansion of the concept of insulin resistance in disease. Furthermore, the article summarizes ideas as to how a newly identified mitochondrial target might explain the activity of new clinical candidates.
  
  
  CONCLUSIONS
  Recognition of the pyruvate carrier complex as a mitochondrial target of the TZDs provides a new direction for discovery and development of anti-diabetic agents. Recent clinical studies have suggested that reduction of direct agonism of PPARγ may prove to be useful therapeutically by reducing dose-limiting side effects. The study of the mechanism of insulin resistance produced by metabolic signals (metabolic inflammation) and the counterbalance of these signals by insulin sensitizers is likely to be useful in providing more target and discovery approaches to metabolic diseases.
authors.affiliation: a Metabolic Solutions Development Company, LLC , Kalamazoo , MI , USA.
authors.forename: Jerry R
authors.initials: JR
authors.lastname: Colca
mesh_terms: D000818:Animals; D003920:Diabetes Mellitus / Q000188:drug therapy* / Q000503:physiopathology; D015195:Drug Design; D055808:Drug Discovery / Q000379:methods; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D007333:Insulin Resistance; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*
chemical_list: D007004:Hypoglycemic Agents; D047495:PPAR gamma; D045162:Thiazolidinediones
keywords: diabetes; insulin sensitizers; mTOT; mechanism of action; thiazolidinedione