Document Detail

IRS-1 regulation in health and disease.
MedLine Citation:
PMID:  14584587     Owner:  NLM     Status:  MEDLINE    
The global incidence of diabetes is increasing at epidemic rates. Estimates suggest there are currently 150 million people with diabetes and this number is expected to double in the next 20 years. Type 2 diabetes accounts for 95% of all cases and is characterized in part by impaired sensitivity to insulin or 'insulin resistance'. Defects in the insulin signalling pathways underpin this resistance. In the current article we discuss the regulation of Insulin Receptor Substrate-1 (IRS-1), a protein that plays a pivotal role in insulin signalling and whose function is impaired in subjects with insulin resistance. Coordination of IRS-1 function is multi-faceted, involving phosphorylation of IRS-1 at multiple serine/threonine residues. This controls many aspects of IRS-1, including its interaction with the insulin receptor and subsequent tyrosine phosphorylation, as well as its subcellular distribution and targeting for degradation by the proteasome. Such tight control ensures appropriate transduction and attenuation of the insulin signal, thereby regulating insulin action in healthy individuals. Emerging evidence indicates that 'diabetogenic factors' associated with insulin resistance, such as TNFalpha and elevated circulating fatty acids, impact on insulin signalling at the level of IRS-1 serine/threonine phosphorylation. The expression and/or activity of several kinases, such as IkappaB kinase beta (IKKbeta) and salt-induced kinase 2 (SIK2), and the phosphorylation of IRS-1 at key sites, such as Ser307 and Ser789, are increased in states of insulin resistance. Identifying the pathways by which such factors activate these and other kinases, and defining the precise roles of specific serine/ threonine phosphorylation events in IRS-1 regulation, represent important goals which may eventually provide a rationale for therapeutic intervention.
Carsten Schmitz-Peiffer; Jonathan P Whitehead
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Publication Detail:
Type:  Journal Article; Review    
Journal Detail:
Title:  IUBMB life     Volume:  55     ISSN:  1521-6543     ISO Abbreviation:  IUBMB Life     Publication Date:  2003 Jul 
Date Detail:
Created Date:  2003-10-30     Completed Date:  2004-06-02     Revised Date:  2008-11-21    
Medline Journal Info:
Nlm Unique ID:  100888706     Medline TA:  IUBMB Life     Country:  England    
Other Details:
Languages:  eng     Pagination:  367-74     Citation Subset:  IM    
Cell Signalling Group, Diabetes and Obesity Program, Garvan Institute of Medical Research, Sydney, Australia.
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MeSH Terms
Cysteine Endopeptidases / metabolism
Diabetes Mellitus, Type 2 / metabolism
Gene Expression Regulation*
Insulin / metabolism
Insulin Receptor Substrate Proteins
Insulin Resistance
Models, Biological
Multienzyme Complexes / metabolism
Phosphoproteins / biosynthesis*,  physiology
Proteasome Endopeptidase Complex
Protein Kinase C / metabolism
Serine / chemistry
Signal Transduction
Threonine / chemistry
Reg. No./Substance:
0/IRS1 protein, human; 0/Insulin Receptor Substrate Proteins; 0/Multienzyme Complexes; 0/Phosphoproteins; 11061-68-0/Insulin; 56-45-1/Serine; 72-19-5/Threonine; EC Kinase C; EC 3.4.22.-/Cysteine Endopeptidases; EC Endopeptidase Complex

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