title: Insulin resistance and improvements in signal transduction.
abstract: Type 2 diabetes and obesity are common metabolic disorders characterized by resistance to the actions of insulin to stimulate skeletal muscle glucose disposal. Insulin-resistant muscle has defects at several steps of the insulin-signaling pathway, including decreases in insulin-stimulated insulin receptor and insulin receptor substrate-1 tyrosine phosphorylation, and phosphatidylinositol 3-kinase (PI 3-kinase) activation. One approach to increase muscle glucose disposal is to reverse/improve these insulin-signaling defects. Weight loss and thiazolidinediones (TZDs) improve glucose disposal, in part, by increasing insulin-stimulated insulin receptor and IRS-1 tyrosine phosphorylation and PI 3-kinase activity. In contrast, physical training and metformin improve whole-body glucose disposal but have minimal effects on proximal insulin-signaling steps. A novel approach to reverse insulin resistance involves inhibition of the stress-activated protein kinase Jun N-terminal kinase (JNK) and the protein tyrosine phosphatases (PTPs). A different strategy to increase muscle glucose disposal is by stimulating insulin-independent glucose transport. AMP-activated protein kinase (AMPK) is an enzyme that works as a fuel gauge and becomes activated in situations of energy consumption, such as muscle contraction. Several studies have shown that pharmacologic activation of AMPK increases glucose transport in muscle, independent of the actions of insulin. AMPK activation is also involved in the mechanism of action of metformin and adiponectin. Moreover, in the hypothalamus, AMPK regulates appetite and body weight. The effect of AMPK to stimulate muscle glucose disposal and to control appetite makes it an important pharmacologic target for the treatment of type 2 diabetes and obesity.
authors.affiliation: Texas Diabetes Institute and University of Texas Health Science Center at San Antonio, USA.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Musi
authors.forename: Laurie J
authors.initials: LJ
authors.lastname: Goodyear
mesh_terms: D055372:AMP-Activated Protein Kinases; D052242:Adiponectin / Q000494:pharmacology; D001069:Appetite Regulation / Q000187:drug effects / Q000502:physiology; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000503:physiopathology; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D015444:Exercise / Q000502:physiology; D005947:Glucose / Q000378:metabolism; D051246:Glucose Transport Proteins, Facilitative / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007328:Insulin / Q000502:physiology*; D007333:Insulin Resistance / Q000502:physiology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology; D008687:Metformin / Q000494:pharmacology / Q000627:therapeutic use; D009097:Multienzyme Complexes / Q000502:physiology; D018482:Muscle, Skeletal / Q000378:metabolism; D009765:Obesity / Q000188:drug therapy / Q000503:physiopathology*; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D017027:Protein Tyrosine Phosphatases / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D045162:Thiazolidinediones / Q000494:pharmacology / Q000627:therapeutic use; D015431:Weight Loss / Q000502:physiology
chemical_list: D052242:Adiponectin; D051246:Glucose Transport Proteins, Facilitative; D007328:Insulin; D009097:Multienzyme Complexes; D045162:Thiazolidinediones; D008687:Metformin; D017346:Protein Serine-Threonine Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D055372:AMP-Activated Protein Kinases; D017027:Protein Tyrosine Phosphatases; D005947:Glucose