| 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: 2011-09-22 |
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. |
Affiliation:
|
Department of Internal Medicine and Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201, USA. asg@genetics.wayne.edu |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| 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-Fetoproteins / physiology |
| Grant Support | |
ID/Acronym/Agency:
|
1T32DK080657-01A2/DK/NIDDK NIH HHS; DK062286-06/DK/NIDDK NIH HHS; R01 DK045020-07/DK/NIDDK NIH HHS; R01 DK045485-07/DK/NIDDK NIH HHS; R01 DK045485-08/DK/NIDDK NIH HHS; R01 DK062286-01A2/DK/NIDDK NIH HHS; R01 DK062286-02/DK/NIDDK NIH HHS; R01 DK062286-03/DK/NIDDK NIH HHS; R01 DK062286-04/DK/NIDDK NIH HHS; R01 DK062286-05/DK/NIDDK NIH HHS; R01 DK062286-06/DK/NIDDK NIH HHS; R01 DK063211-01A1/DK/NIDDK NIH HHS; R01 DK063211-02/DK/NIDDK NIH HHS; R01 DK063211-03/DK/NIDDK NIH HHS; R01 DK063211-04/DK/NIDDK NIH HHS; R01 DK063211-05/DK/NIDDK NIH HHS; R01KD044382//PHS HHS; T32 DK080657-01A2/DK/NIDDK NIH HHS; T32 DK080657-02/DK/NIDDK NIH HHS |
| Chemical | |
Reg. No./Substance:
|
0/Ahsg protein, rat; 0/Blood Proteins; 0/Glycoproteins; 0/alpha-Fetoproteins; 0/alpha2HS glycoprotein; 11061-68-0/Insulin; EC 2.7.10.1/Receptor, Insulin |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: Distribution of catecholaminergic and peptidergic cells in the gerbil medial amygdala, caudal preopt...
Next Document: Assemblage of drug release modules: effect of module shape and position in the assembled systems on ...