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PMID:16814735

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Citation

Bouzakri, K, Zachrisson, A, Al-Khalili, L, Zhang, BB, Koistinen, HA, Krook, A and Zierath, JR (2006) siRNA-based gene silencing reveals specialized roles of IRS-1/Akt2 and IRS-2/Akt1 in glucose and lipid metabolism in human skeletal muscle. Cell Metab. 4:89-96

Abstract

Type 2 diabetes is associated with defects in insulin signaling and the resulting abnormal glucose and lipid metabolism. The complexity of insulin signaling cascades is highlighted by the existence of multiple isoforms of target proteins implicated in metabolic and gene-regulatory events. We utilized siRNA to decipher the specific role of predominant insulin receptor substrates and Akt isoforms expressed in human skeletal muscle. Gene silencing revealed specialized roles of insulin signaling cascades to metabolic endpoints. IRS-1 and Akt2 were required for myoblast differentiation and glucose metabolism, whereas IRS-2 and Akt1 were dispensable. A key role of IRS-2 and Akt1 in lipid metabolism was revealed, highlighting reciprocal relationships between metabolic pathways. Unraveling the isoform-specific regulation of glucose and lipid metabolism by key elements along insulin signaling cascades through siRNA-mediated gene silencing in human tissues will facilitate the discovery of novel targets for the treatment of diabetes and related metabolic disorders.

Links

PubMed Online version:10.1016/j.cmet.2006.04.008

Keywords

Cells, Cultured; Female; Gene Silencing/physiology; Glucose/metabolism; Humans; Insulin/physiology; Insulin Receptor Substrate Proteins; Intracellular Signaling Peptides and Proteins; Lipids/physiology; Male; Middle Aged; Muscle Fibers, Skeletal/metabolism; Muscle, Skeletal/metabolism; Myoblasts/metabolism; Oxidation-Reduction; Palmitates/metabolism; Phosphoproteins/genetics; Phosphoproteins/physiology; Proto-Oncogene Proteins c-akt/genetics; Proto-Oncogene Proteins c-akt/physiology; RNA, Small Interfering/genetics; Signal Transduction/physiology

Significance

Annotations

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

HUMAN:IRS1

involved_in

GO:0042593: glucose homeostasis

ECO:0000304: author statement supported by traceable reference used in manual assertion

P

Seeded From UniProt

complete

HUMAN:IRS1

involved_in

GO:0010907: positive regulation of glucose metabolic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:IRS1

involved_in

GO:0008286: insulin receptor signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:IRS1

involved_in

GO:0032000: positive regulation of fatty acid beta-oxidation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:IRS1

involved_in

GO:0032869: cellular response to insulin stimulus

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:IRS1

involved_in

GO:0045725: positive regulation of glycogen biosynthetic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:IRS1

involved_in

GO:0046326: positive regulation of glucose import

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:AKT1

involved_in

GO:0046326: positive regulation of glucose import

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:AKT1

involved_in

GO:0045725: positive regulation of glycogen biosynthetic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:AKT1

involved_in

GO:0032869: cellular response to insulin stimulus

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:AKT1

involved_in

GO:0031999: negative regulation of fatty acid beta-oxidation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:AKT1

involved_in

GO:0010907: positive regulation of glucose metabolic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:AKT1

involved_in

GO:0010748: negative regulation of long-chain fatty acid import across plasma membrane

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:IRS2

involved_in

GO:0046326: positive regulation of glucose import

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:IRS2

involved_in

GO:0045725: positive regulation of glycogen biosynthetic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:IRS2

involved_in

GO:0032869: cellular response to insulin stimulus

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:IRS2

involved_in

GO:0032000: positive regulation of fatty acid beta-oxidation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:IRS2

involved_in

GO:0055088: lipid homeostasis

ECO:0000304: author statement supported by traceable reference used in manual assertion

P

Seeded From UniProt

complete

HUMAN:IRS2

involved_in

GO:0019216: regulation of lipid metabolic process

ECO:0000304: author statement supported by traceable reference used in manual assertion

P

Seeded From UniProt

complete

HUMAN:IRS2

involved_in

GO:0010748: negative regulation of long-chain fatty acid import across plasma membrane

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:IRS2

involved_in

GO:0010907: positive regulation of glucose metabolic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:AKT2

involved_in

GO:0008286: insulin receptor signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:AKT2

involved_in

GO:0010748: negative regulation of long-chain fatty acid import across plasma membrane

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:AKT2

involved_in

GO:0010907: positive regulation of glucose metabolic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:AKT2

involved_in

GO:0032000: positive regulation of fatty acid beta-oxidation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:AKT2

involved_in

GO:0032869: cellular response to insulin stimulus

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:AKT2

involved_in

GO:0045725: positive regulation of glycogen biosynthetic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:AKT2

involved_in

GO:0046326: positive regulation of glucose import

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:Q05BV0

involved_in

GO:0046326: positive regulation of glucose import

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:Q05BV0

involved_in

GO:0045725: positive regulation of glycogen biosynthetic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:Q05BV0

involved_in

GO:0032869: cellular response to insulin stimulus

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:Q05BV0

involved_in

GO:0032000: positive regulation of fatty acid beta-oxidation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:Q05BV0

involved_in

GO:0010907: positive regulation of glucose metabolic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:Q05BV0

involved_in

GO:0010748: negative regulation of long-chain fatty acid import across plasma membrane

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:Q05BV0

involved_in

GO:0008286: insulin receptor signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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