Document Detail


The "thrifty" gene encoding Ahsg/Fetuin-A meets the insulin receptor: Insights into the mechanism of insulin resistance.
MedLine Citation:
PMID:  21087662     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Ahsg (fetuin-A) is a 55-59kDa phosphorylated glycoprotein synthesized in the adult predominantly by hepatocytes, from which it enters the circulation. When dysregulated, this glycoprotein operates to influence the clinical sequelae of insulin resistance-type 2 diabetes and cardiovascular disease. The pathological sequelae likely arise from two separable molecular "faces" of Ahsg-one acting at the level of the insulin receptor and a second face influencing ectopic biomineralization in the intima. A detailed understanding of these two functional faces of Ahsg is not yet clear for lack of structural studies. Ahsg has a physiological role in the biomineralization of bone, which when dysregulated can lead to ectopic calcification of soft tissues in the vasculature. Ahsg has a second physiological function in regulating how insulin signals through its receptor, a transmembrane tyrosine kinase. Dysregulation of this "face" of Ahsg results in morbid sequelae such as impaired glucose disposal and fatty liver. Ahsg binds to tandem fibronectin type 3 (Fn3) domains present in the 194 amino acid residue extracellular portion of the β-subunit of the insulin receptor, distant from the high-affinity pocket formed by two complementing α-subunits where insulin binds. Only two proteins are known to bind directly to the insulin receptor ectodomain - insulin and Ahsg - the former turns on the receptor's intrinsic tyrosine kinase (TK) activity, and the latter shuts it down. Recent X-ray crystallographic studies of the ectodomain of the insulin receptor now sharpen our understanding of the receptor's extracellular α-subunit and linked β-subunit. Ahsg genotype and its circulating level have been correlated with body morphometrics (obese versus lean and visceral adiposity) in epidemiological studies enrolling thousands of patients. Epidemiological studies from the clinic reveal high levels of circulating Ahsg in insulin resistance and diabetes. This review endeavors to explain how one protein can mediate diverse pathologies, but specifically addresses its metabolic "face" blunting insulin receptor activity, an action leading to insulin resistance.
Authors:
Anton-Scott Goustin; Abdul B Abou-Samra
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Review     Date:  2010-11-16
Journal Detail:
Title:  Cellular signalling     Volume:  23     ISSN:  1873-3913     ISO Abbreviation:  Cell. Signal.     Publication Date:  2011 Jun 
Date Detail:
Created Date:  2011-03-22     Completed Date:  2011-06-27     Revised Date:  2014-09-15    
Medline Journal Info:
Nlm Unique ID:  8904683     Medline TA:  Cell Signal     Country:  England    
Other Details:
Languages:  eng     Pagination:  980-90     Citation Subset:  IM    
Copyright Information:
Copyright © 2010 Elsevier Inc. All rights reserved.
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MeSH Terms
Descriptor/Qualifier:
Amino Acid Sequence
Animals
Blood Proteins / genetics*,  metabolism
Diabetes Mellitus, Type 2 / metabolism
Glycoproteins / physiology
Humans
Insulin / metabolism*
Insulin Resistance*
Molecular Sequence Data
Polymorphism, Single Nucleotide
Protein Binding
Protein Conformation
Receptor, Insulin / antagonists & inhibitors,  metabolism*
Sequence Alignment
Thinness / genetics
alpha-2-HS-Glycoprotein
alpha-Fetoproteins / physiology
Grant Support
ID/Acronym/Agency:
1T32DK080657-01A2/DK/NIDDK NIH HHS; DK062286-06/DK/NIDDK NIH HHS; R01 DK045020/DK/NIDDK NIH HHS; R01 DK045485/DK/NIDDK NIH HHS; R01 DK062286/DK/NIDDK NIH HHS; R01 DK063211/DK/NIDDK NIH HHS; R01KD044382//PHS HHS; T32 DK080657/DK/NIDDK NIH HHS; T32 DK080657-01A2/DK/NIDDK NIH HHS; T32 DK080657-02/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/AHSG protein, human; 0/Ahsg protein, rat; 0/Blood Proteins; 0/Glycoproteins; 0/Insulin; 0/alpha-2-HS-Glycoprotein; 0/alpha-Fetoproteins; EC 2.7.10.1/Receptor, Insulin

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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