title: Insulin-receptor substrate-2 (irs-2) is required for maintaining glucokinase and glucokinase regulatory protein expression in mouse liver.
abstract: Insulin receptor substrate (IRS) proteins play important roles in hepatic nutrient homeostasis. Since glucokinase (GK) and glucokinase regulatory protein (GKRP) function as key glucose sensors, we have investigated the expression of GK and GKRP in liver of Irs-2 deficient mice and Irs2(-/-) mice where Irs2 was reintroduced specifically into pancreatic β-cells [RIP-Irs-2/IRS-2(-/-)]. We observed that liver GK activity was significantly lower (p<0.0001) in IRS-2(-/-) mice. However, in RIP-Irs-2/IRS-2(-/-) mice, GK activity was similar to the values observed in wild-type animals. GK activity in hypothalamus was not altered in IRS-2(-/-) mice. GK and GKRP mRNA levels in liver of IRS-2(-/-) were significantly lower, whereas in RIP-Irs-2/IRS-2(-/-) mice, both GK and GKRP mRNAs levels were comparable to wild-type animals. At the protein level, the liver content of GK was reduced in IRS-2(-/-) mice as compared with controls, although GKRP levels were similar between these experimental models. Both GK and GKRP levels were lower in RIP-Irs-2/IRS-2(-/-) mice. These results suggest that IRS-2 signalling is important for maintaining the activity of liver GK. Moreover, the differences between liver and brain GK may be explained by the fact that expression of hepatic, but not brain, GK is controlled by insulin. GK activity was restored by the β-cell compensation in the RIP-Irs-2/IRS-2 mice. Interestingly, GK and GKRP protein expression remained low in RIP-Irs-2/IRS-2(-/-) mice, perhaps reflecting different mRNA half-lives or alterations in the process of translation and post-translational regulation.
authors.affiliation: The Center for Biomedical Research in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Roncero
authors.forename: Elvira
authors.initials: E
authors.lastname: Alvarez
authors.forename: Carlos
authors.initials: C
authors.lastname: Acosta
authors.forename: Carmen
authors.initials: C
authors.lastname: Sanz
authors.forename: Pedro
authors.initials: P
authors.lastname: Barrio
authors.forename: Veronica
authors.initials: V
authors.lastname: Hurtado-Carneiro
authors.forename: Deborah
authors.initials: D
authors.lastname: Burks
authors.forename: Enrique
authors.initials: E
authors.lastname: Blázquez
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D005816:Genetic Complementation Test; D005941:Glucokinase / Q000235:genetics* / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D007031:Hypothalamus / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins / Q000172:deficiency / Q000235:genetics*; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D008099:Liver / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009928:Organ Specificity; D012333:RNA, Messenger / Q000235:genetics; D015398:Signal Transduction; D014162:Transfection
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C499483:Gckr protein, mouse; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; C526298:Irs2 protein, mouse; D012333:RNA, Messenger; D005941:Glucokinase; D005947:Glucose
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