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PMID:17569761

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Citation

Ciaraldi, TP, Nikoulina, SE, Bandukwala, RA, Carter, L and Henry, RR (2007) Role of glycogen synthase kinase-3 alpha in insulin action in cultured human skeletal muscle cells. Endocrinology 148:4393-9

Abstract

An association between glycogen synthase kinase-3 (GSK3) in skeletal muscle and insulin resistance has been demonstrated in type 2 diabetic patients. In addition, inhibition of GSK3 improves insulin action. The aim of the present study was to elucidate the role of the alpha-isoform of GSK3 in insulin resistance in human skeletal muscle cells from nondiabetic subjects maintained in culture. Transfection of muscle cells with specific antisense oligonucleotides resulted in a 30-50% decrease of GSK3alpha protein expression (P < 0.05). Whereas neither the basal fractional velocity of glycogen synthase (GS FV) (an indicator of the activation state of the enzyme) nor glucose uptake (GU) were altered, reducing GSK3alpha expression resulted in increases in insulin stimulation of both GS FV and GU. GSK3alpha overexpression (60-100% increase over control) did not alter basal GS FV or GU but impaired insulin stimulation of both responses. Knockdown of GSK alpha also led to an increase in insulin receptor substrate-1 protein expression but did not alter insulin stimulation of pS473-Akt phosphorylation. However, GSK3alpha overexpression impaired insulin action on pS473-Akt. In summary, we concluded the following: 1) modulation of GSK3alpha expression has no effect on basal GU and glycogen synthase activities; 2) reduction of GSK3alpha expression results in improvements in insulin action; and 3) elevation of GSK3alpha in human skeletal muscle cells can induce insulin resistance for several responses. We conclude that GSK3alpha is an important regulator of muscle insulin action.

Links

PubMed Online version:10.1210/en.2006-0932

Keywords

Biopsy; Cells, Cultured; Down-Regulation/drug effects; Gene Expression Regulation, Enzymologic/drug effects; Glucose/metabolism; Glycogen Synthase/drug effects; Glycogen Synthase/metabolism; Glycogen Synthase Kinase 3/genetics; Glycogen Synthase Kinase 3/metabolism; Hemoglobin A, Glycosylated/metabolism; Humans; Insulin/pharmacology; Insulin Resistance; Muscle, Skeletal/cytology; Muscle, Skeletal/drug effects; Muscle, Skeletal/enzymology; Reference Values; Transfection

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:GSK3A

involved_in

GO:1904227: negative regulation of glycogen synthase activity, transferring glucose-1-phosphate

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:GSK3A

involved_in

GO:0046627: negative regulation of insulin receptor signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:GSK3A

involved_in

GO:0046325: negative regulation of glucose import

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:GSK3A

involved_in

GO:0032869: cellular response to insulin stimulus

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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