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PMID:20032056

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Citation

Liang, L, Guo, WH, Esquiliano, DR, Asai, M, Rodriguez, S, Giraud, J, Kushner, JA, White, MF and Lopez, MF (2010) Insulin-like growth factor 2 and the insulin receptor, but not insulin, regulate fetal hepatic glycogen synthesis. Endocrinology 151:741-7

Abstract

Whether insulin or IGFs regulate glycogen synthesis in the fetal liver remains to be determined. In this study, we used several knockout mouse strains, including those lacking Pdx-1 (pancreatic duodenal homeobox-1), Insr (insulin receptor), and Igf2 (IGF-II) to determine the role of these genes in the regulation of fetal hepatic glycogen synthesis. Our data show that insulin deficiency does not alter hepatic glycogen stores, whereas Insr and Igf2 deficiency do. We found that both insulin receptor isoforms (IR-A and IR-B) are present in the fetal liver, and their expression is gestationally regulated. IR-B is highly expressed in the fetal liver; nonetheless, the percentage of hepatic IR-A isoform, which binds Igf2, was significantly higher in the fetus than the adult. In vitro experiments demonstrate that Igf2 increases phosphorylation of hepatic Insr, insulin receptor substrate-2, and Akt proteins and also the activity of glycogen synthase. Igf2 ultimately increased glycogen synthesis in fetal hepatocytes. This increase could be blocked by the phosphoinositide 3-kinase inhibitor LY294008. Taken together, we propose Igf2 as a major regulator of fetal hepatic glycogen metabolism, the insulin receptor as its target receptor, and phosphoinositide 3-kinase as the signaling pathway leading to glycogen formation in the fetal liver.

Links

PubMed PMC2817628 Online version:10.1210/en.2009-0705

Keywords

Animals; Cells, Cultured; Crosses, Genetic; DNA Primers; Female; Fetus/drug effects; Fetus/physiology; Glycogen Synthase/metabolism; Hepatocytes/cytology; Hepatocytes/enzymology; Hepatocytes/physiology; Heterozygote; Homeostasis; Insulin/deficiency; Insulin/genetics; Insulin/physiology; Insulin-Like Growth Factor II/deficiency; Insulin-Like Growth Factor II/genetics; Insulin-Like Growth Factor II/physiology; Liver Glycogen/blood; Male; Mice; Mice, Knockout; RNA, Messenger/genetics; Receptor, Insulin/deficiency; Receptor, Insulin/genetics; Receptor, Insulin/physiology

Significance

Annotations

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

MOUSE:INSR

involved_in

GO:0045725: positive regulation of glycogen biosynthetic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:IGF2

enables

GO:0048018: receptor ligand activity

ECO:0000315: mutant phenotype evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:IGF2

involved_in

GO:0001934: positive regulation of protein phosphorylation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:IGF2

involved_in

GO:0043085: positive regulation of catalytic activity

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:IGF2

involved_in

GO:0038028: insulin receptor signaling pathway via phosphatidylinositol 3-kinase

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:IGF2

enables

GO:0043539: protein serine/threonine kinase activator activity

ECO:0000315: mutant phenotype evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:IGF2

involved_in

GO:0045725: positive regulation of glycogen biosynthetic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:IGF2

involved_in

GO:0046628: positive regulation of insulin receptor signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:IGF2

involved_in

GO:0050731: positive regulation of peptidyl-tyrosine phosphorylation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:IGF2

involved_in

GO:2000467: positive regulation of glycogen (starch) synthase activity

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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