title: Knockout models are useful tools to dissect the pathophysiology and genetics of insulin resistance.
abstract: OBJECTIVE
  The development of type 2 diabetes is linked to insulin resistance coupled with a failure of pancreatic beta-cells to compensate by adequate insulin secretion.
  
  
  METHODS
  Here, we review studies obtained from genetically engineered mice that provide novel insights into the pathophysiology of insulin resistance.
  
  
  RESULTS
  Knockout models with monogenic impairment in insulin action have highlighted the potential role for insulin signalling molecules in insulin resistance at a tissue-specific level. Polygenic models have strengthened the idea that minor defects in insulin secretion and insulin action, when combined, can lead to diabetes, emphasizing the importance of interactions of different genetic loci in the production of diabetes. Knockout models with tissue-specific alterations in glucose or lipid metabolism have dissected the individual contributions of insulin-responsive organs to glucose homeostasis. They have demonstrated the central role of fat as an endocrine tissue in the maintenance of insulin sensitivity and the development of insulin resistance. Finally, these models have shown the potential role of impaired insulin action in pancreatic beta-cells and brain in the development of insulin deficiency and obesity.
authors.affiliation: Department of Endocrinology and Diabetes, Saint-Louis Hospital and University of Paris VII Medical School, France. FMauvais_jarvis@aol.com
authors.forename: Franck
authors.initials: F
authors.lastname: Mauvais-Jarvis
authors.forename: Rohit N
authors.initials: RN
authors.lastname: Kulkarni
authors.forename: C Ronald
authors.initials: CR
authors.lastname: Kahn
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology*; D007515:Islets of Langerhans / Q000378:metabolism; D020738:Leptin / Q000502:physiology; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D018482:Muscle, Skeletal / Q000378:metabolism; D009765:Obesity / Q000378:metabolism; D011972:Receptor, Insulin / Q000235:genetics* / Q000378:metabolism; D017451:Receptors, Somatomedin / Q000235:genetics; D012107:Research Design
chemical_list: D020738:Leptin; D017451:Receptors, Somatomedin; D011972:Receptor, Insulin; D005947:Glucose