Document Detail


Hyperglycemia inhibits insulin activation of Akt/protein kinase B but not phosphatidylinositol 3-kinase in rat skeletal muscle.
MedLine Citation:
PMID:  10078574     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Sustained hyperglycemia impairs insulin-stimulated glucose utilization in the skeletal muscle of both humans and experimental animals--a phenomenon referred to clinically as glucose toxicity. To study how this occurs, a model was developed in which hyperglycemia produces insulin resistance in vitro. Rat extensor digitorum longus muscles were preincubated for 4 h in Krebs-Henseleit solution containing glucose or glucose + insulin at various concentrations, after which insulin action was studied. Preincubation with 25 mmol/l glucose + insulin (10 mU/ml) led to a 70% decrease in the ability of insulin (10 mU/ml) to stimulate glucose incorporation into glycogen and a 30% decrease in 2-deoxyglucose (2-DG) uptake, compared with muscles incubated with 0 mmol/l glucose. Glucose incorporation into lipid and its oxidation to CO2 were marginally diminished, if at all. The alterations of glycogen synthesis and 2-DG uptake were first evident after 1 h and were maximal after 2 h of preincubation; they were not observed in muscles preincubated with 25 mmol/l glucose + insulin for 5 min. Preincubation for 4 h with 25 mmol/l glucose in the absence of insulin produced a similar although somewhat smaller decrease in insulin-stimulated glycogen synthesis; however, it did not alter 2-DG uptake, glucose oxidation to CO2, or incorporation into lipids. Studies of insulin signaling in the latter muscles revealed that activation of Akt/protein kinase B (PKB) was diminished by 60%, compared with that of muscles preincubated in a glucose-free medium; whereas activation of phosphatidylinositol (PI) 3-kinase, an upstream regulator of Akt/PKB in the insulin-signaling cascade, and of mitogen-activated protein (MAP) kinase, a parallel signal, was unaffected. Immunoblots demonstrated that this was not due to a change in Akt/PKB abundance. The results indicate that hyperglycemia-induced insulin resistance can be studied in rat skeletal muscle in vitro. They suggest that impairment of insulin action in these muscles is related to inhibition of Akt/PKB by events that do not affect PI 3-kinase.
Authors:
T G Kurowski; Y Lin; Z Luo; P N Tsichlis; M G Buse; S J Heydrick; N B Ruderman
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Publication Detail:
Type:  In Vitro; Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Diabetes     Volume:  48     ISSN:  0012-1797     ISO Abbreviation:  Diabetes     Publication Date:  1999 Mar 
Date Detail:
Created Date:  1999-03-30     Completed Date:  1999-03-30     Revised Date:  2012-06-22    
Medline Journal Info:
Nlm Unique ID:  0372763     Medline TA:  Diabetes     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  658-63     Citation Subset:  AIM; IM    
Affiliation:
Department of Microbiology and Immunology, Kimmel Cancer Center, Jefferson Medical College, Philadelphia, Pennsylvania, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Calcium-Calmodulin-Dependent Protein Kinases / metabolism
Deoxyglucose / metabolism
Enzyme Activation
Glucose / pharmacology
Glycogen / biosynthesis
Hyperglycemia / enzymology*
Insulin / pharmacology*
Kinetics
Male
Mitogen-Activated Protein Kinase 1
Muscle, Skeletal / drug effects,  enzymology,  metabolism*
Phosphatidylinositol 3-Kinases / antagonists & inhibitors,  metabolism*
Protein-Serine-Threonine Kinases*
Protein-Tyrosine Kinases / metabolism
Proto-Oncogene Proteins / antagonists & inhibitors,  metabolism*
Proto-Oncogene Proteins c-akt
Rats
Rats, Sprague-Dawley
Grant Support
ID/Acronym/Agency:
DK-19514/DK/NIDDK NIH HHS; DK-42621/DK/NIDDK NIH HHS; DK-49147/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/Insulin; 0/Proto-Oncogene Proteins; 154-17-6/Deoxyglucose; 50-99-7/Glucose; 9005-79-2/Glycogen; EC 2.7.1.-/Phosphatidylinositol 3-Kinases; EC 2.7.10.1/Protein-Tyrosine Kinases; EC 2.7.11.1/Akt1 protein, rat; EC 2.7.11.1/Protein-Serine-Threonine Kinases; EC 2.7.11.1/Proto-Oncogene Proteins c-akt; EC 2.7.11.17/Calcium-Calmodulin-Dependent Protein Kinases; EC 2.7.11.24/Mitogen-Activated Protein Kinase 1

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