title: Impaired ('diabetic') insulin signaling and action occur in fat cells long before glucose intolerance--is insulin resistance initiated in the adipose tissue?
abstract: This review postulates and presents recent evidence that insulin resistance is initiated in the adipose tissue and also suggests that the adipose tissue may play a pivotal role in the induction of insulin resistance in the muscles and the liver. Marked impairments in insulin's intracellular signaling cascade are present in fat cells from type 2 diabetic patients, including reduced IRS-1 gene and protein expression, impaired insulin-stimulated PI3-kinase and PKB/Akt activities. In contrast, upstream insulin signaling in skeletal muscle from diabetic subjects only shows modest impairments and PKB/Akt activation in vivo by insulin appears normal. However, insulin-stimulated glucose transport and glycogen synthesis are markedly reduced. Similar marked impairments in insulin signaling, including reduced IRS-1 expression, impaired insulin-stimulated PI3-kinase and PKB/Akt activities are also seen in some (approximately 30%) normoglycemic individuals with genetic predisposition for type 2 diabetes. In addition, GLUT4 expression is markedly reduced in these cells, similar to what is seen in diabetic cells. The individuals with reduced cellular expression of IRS-1 and GLUT4 are also markedly insulin resistant and exhibit several characteristics of the Insulin Resistance Syndrome.Thus, a 'diabetic' pattern is seen in the fat cells also in normoglycemic subjects and this is associated with a marked insulin resistance in vivo. It is proposed that insulin resistance and/or its effectors is initiated in fat cells and that this may secondarily encompass other target tissues for insulin, including the impaired glucose transport in the muscles.
authors.affiliation: The Lundberg Laboratory for Diabetes Research, Department of Internal Medicine, Sahlgrenska Academy at Göteborg University, Göteborg, Sweden. ulf.smith@medic.gu.se
authors.forename: U
authors.initials: U
authors.lastname: Smith
mesh_terms: D017667:Adipocytes / Q000378:metabolism*; D003920:Diabetes Mellitus / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2; D018149:Glucose Intolerance; D006801:Humans; D007328:Insulin / Q000494:pharmacology / Q000502:physiology*; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins / Q000502:physiology; D015398:Signal Transduction; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones
chemical_list: C526292:IRS1 protein, human; C526297:IRS2 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D013844:Thiazoles; D045162:Thiazolidinediones; C089946:2,4-thiazolidinedione