Linked Life Data

16166093

Source:http://linkedlifedata.com/resource/pubmed/id/16166093

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
45
pubmed:dateCreated
2005-11-7
pubmed:abstractText
Insulin resistance is a cardinal feature of normal pregnancy and excess growth hormone (GH) states, but its underlying mechanism remains enigmatic. We previously found a significant increase in the p85 regulatory subunit of phosphatidylinositol kinase (PI 3-kinase) and striking decrease in IRS-1-associated PI 3-kinase activity in the skeletal muscle of transgenic animals overexpressing human placental growth hormone. Herein, using transgenic mice bearing deletions in p85alpha, p85beta, or insulin-like growth factor-1, we provide novel evidence suggesting that overexpression of p85alpha is a primary mechanism for skeletal muscle insulin resistance in response to GH. We found that the excess in total p85 was entirely accounted for by an increase in the free p85alpha-specific isoform. In mice with a liver-specific deletion in insulin-like growth factor-1, excess GH caused insulin resistance and an increase in skeletal muscle p85alpha, which was completely reversible using a GH-releasing hormone antagonist. To understand the role of p85alpha in GH-induced insulin resistance, we used mice bearing deletions of the genes coding for p85alpha or p85beta, respectively (p85alpha (+/-) and p85beta(-/-)). Wild type and p85beta(-/-) mice developed in vivo insulin resistance and demonstrated overexpression of p85alpha and reduced insulin-stimulated PI 3-kinase activity in skeletal muscle in response to GH. In contrast, p85alpha(+/-)mice retained global insulin sensitivity and PI 3-kinase activity associated with reduced p85alpha expression. These findings demonstrated the importance of increased p85alpha in mediating skeletal muscle insulin resistance in response to GH and suggested a potential role for reducing p85alpha as a therapeutic strategy for enhancing insulin sensitivity in skeletal muscle.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
http://linkedlifedata.com/resource/pubmed/chemical/Growth Hormone, http://linkedlifedata.com/resource/pubmed/chemical/IRS1 protein, human, http://linkedlifedata.com/resource/pubmed/chemical/Insulin, http://linkedlifedata.com/resource/pubmed/chemical/Insulin Receptor Substrate Proteins, http://linkedlifedata.com/resource/pubmed/chemical/Insulin-Like Growth Factor I, http://linkedlifedata.com/resource/pubmed/chemical/Irs1 protein, mouse, http://linkedlifedata.com/resource/pubmed/chemical/Phosphatidylinositol 3-Kinases, http://linkedlifedata.com/resource/pubmed/chemical/Phosphoproteins, http://linkedlifedata.com/resource/pubmed/chemical/Pregnancy Proteins, http://linkedlifedata.com/resource/pubmed/chemical/Protein Subunits, http://linkedlifedata.com/resource/pubmed/chemical/placenta growth factor
pubmed:status
MEDLINE
pubmed:month
Nov
pubmed:issn
0021-9258
pubmed:author
pubmed:issnType
Print
pubmed:day
11
pubmed:volume
280
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
37489-94
pubmed:dateRevised
2011-11-17
pubmed:meshHeading
pubmed-meshheading:16166093-Animals, pubmed-meshheading:16166093-Gene Expression Regulation, Enzymologic, pubmed-meshheading:16166093-Growth Hormone, pubmed-meshheading:16166093-Humans, pubmed-meshheading:16166093-Insulin, pubmed-meshheading:16166093-Insulin Receptor Substrate Proteins, pubmed-meshheading:16166093-Insulin Resistance, pubmed-meshheading:16166093-Insulin-Like Growth Factor I, pubmed-meshheading:16166093-Mice, pubmed-meshheading:16166093-Mice, Knockout, pubmed-meshheading:16166093-Mice, Transgenic, pubmed-meshheading:16166093-Muscle, Skeletal, pubmed-meshheading:16166093-Phosphatidylinositol 3-Kinases, pubmed-meshheading:16166093-Phosphoproteins, pubmed-meshheading:16166093-Pregnancy Proteins, pubmed-meshheading:16166093-Protein Subunits, pubmed-meshheading:16166093-Signal Transduction
pubmed:year
2005
pubmed:articleTitle
Increased P85alpha is a potent negative regulator of skeletal muscle insulin signaling and induces in vivo insulin resistance associated with growth hormone excess.
pubmed:affiliation
Department of Medicine, University Colorado Health Sciences Center, Denver, 80262, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, N.I.H., Extramural