Genistein represses PEPCK-C expression in an insulin-independent manner in HepG2 cells and in alloxan-induced diabetic mice

Barilin Dkhar, Kitboklang Khongsti, Daiahun Thabah, Donkupar Syiem, Kapaettu Satyamoorthy, Bidyadhar Das

Research output: Contribution to journalArticle

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Abstract

Genistein has been reported to exert beneficial effects on type 2 diabetes mellitus (T2DM); however, the underlying molecular mechanisms involved therein have not been clearly elucidated. To address this question, the effect of genistein on the expression of phosphoenolpyruvate carboxykinase (PEPCK), and glucose production in HepG2 cells and in alloxan-induced diabetic mice was investigated. HepG2 cells were exposed to different concentration of genistein in presence or absence of modulators, and the expression of cytosolic PEPCK (PEPCK-C) and the signaling pathways was studied. Further, the biological relevance of the in vitro study was tested in alloxan-induced diabetic mice. Genistein lowered PEPCK-C expression and glucose production in HepG2 cells accompanied with increased in phosphorylation states of AMPK, MEK1/2, ERK1/2, and CRTC2. Treatment with the AMPK inhibitor (compoundC) enhanced genistein-induced MEK1/2 and ERK1/2 activity indicating a potential cross-talk between the two signaling pathways. In vivo, genistein also reduced fasting glucose levels accompanied with reduced PEPCK-C expression and increased in AMPK and ERK1/2 phosphorylation states in the liver of genistein-treated alloxan-induced diabetic mice. Genistein fulfills the criteria of a suitable anti-diabetic agent by reducing glucose production and inhibiting PEPCK-C expression in HepG2 cells and also in alloxan-induced diabetic mice. These results indicate that genistein is an effective candidate for preventing T2DM through the modulation of AMPK-CRTC2 and MEK/ERK signaling pathways, which may allow a novel approach to modulate dysfunction in hepatic gluconeogenesis in T2DM.

Original languageEnglish
JournalJournal of Cellular Biochemistry
DOIs
Publication statusPublished - 2018

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Alloxan
Phosphoenolpyruvate
Genistein
Hep G2 Cells
Insulin
AMP-Activated Protein Kinases
Medical problems
Type 2 Diabetes Mellitus
Glucose
Phosphorylation
Gluconeogenesis
MAP Kinase Signaling System
Liver
Reducing Agents
Mitogen-Activated Protein Kinase Kinases
Modulators
Fasting
Modulation

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

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title = "Genistein represses PEPCK-C expression in an insulin-independent manner in HepG2 cells and in alloxan-induced diabetic mice",
abstract = "Genistein has been reported to exert beneficial effects on type 2 diabetes mellitus (T2DM); however, the underlying molecular mechanisms involved therein have not been clearly elucidated. To address this question, the effect of genistein on the expression of phosphoenolpyruvate carboxykinase (PEPCK), and glucose production in HepG2 cells and in alloxan-induced diabetic mice was investigated. HepG2 cells were exposed to different concentration of genistein in presence or absence of modulators, and the expression of cytosolic PEPCK (PEPCK-C) and the signaling pathways was studied. Further, the biological relevance of the in vitro study was tested in alloxan-induced diabetic mice. Genistein lowered PEPCK-C expression and glucose production in HepG2 cells accompanied with increased in phosphorylation states of AMPK, MEK1/2, ERK1/2, and CRTC2. Treatment with the AMPK inhibitor (compoundC) enhanced genistein-induced MEK1/2 and ERK1/2 activity indicating a potential cross-talk between the two signaling pathways. In vivo, genistein also reduced fasting glucose levels accompanied with reduced PEPCK-C expression and increased in AMPK and ERK1/2 phosphorylation states in the liver of genistein-treated alloxan-induced diabetic mice. Genistein fulfills the criteria of a suitable anti-diabetic agent by reducing glucose production and inhibiting PEPCK-C expression in HepG2 cells and also in alloxan-induced diabetic mice. These results indicate that genistein is an effective candidate for preventing T2DM through the modulation of AMPK-CRTC2 and MEK/ERK signaling pathways, which may allow a novel approach to modulate dysfunction in hepatic gluconeogenesis in T2DM.",
author = "Barilin Dkhar and Kitboklang Khongsti and Daiahun Thabah and Donkupar Syiem and Kapaettu Satyamoorthy and Bidyadhar Das",
year = "2018",
doi = "10.1002/jcb.26356",
language = "English",
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Genistein represses PEPCK-C expression in an insulin-independent manner in HepG2 cells and in alloxan-induced diabetic mice. / Dkhar, Barilin; Khongsti, Kitboklang; Thabah, Daiahun; Syiem, Donkupar; Satyamoorthy, Kapaettu; Das, Bidyadhar.

In: Journal of Cellular Biochemistry, 2018.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Genistein represses PEPCK-C expression in an insulin-independent manner in HepG2 cells and in alloxan-induced diabetic mice

AU - Dkhar, Barilin

AU - Khongsti, Kitboklang

AU - Thabah, Daiahun

AU - Syiem, Donkupar

AU - Satyamoorthy, Kapaettu

AU - Das, Bidyadhar

PY - 2018

Y1 - 2018

N2 - Genistein has been reported to exert beneficial effects on type 2 diabetes mellitus (T2DM); however, the underlying molecular mechanisms involved therein have not been clearly elucidated. To address this question, the effect of genistein on the expression of phosphoenolpyruvate carboxykinase (PEPCK), and glucose production in HepG2 cells and in alloxan-induced diabetic mice was investigated. HepG2 cells were exposed to different concentration of genistein in presence or absence of modulators, and the expression of cytosolic PEPCK (PEPCK-C) and the signaling pathways was studied. Further, the biological relevance of the in vitro study was tested in alloxan-induced diabetic mice. Genistein lowered PEPCK-C expression and glucose production in HepG2 cells accompanied with increased in phosphorylation states of AMPK, MEK1/2, ERK1/2, and CRTC2. Treatment with the AMPK inhibitor (compoundC) enhanced genistein-induced MEK1/2 and ERK1/2 activity indicating a potential cross-talk between the two signaling pathways. In vivo, genistein also reduced fasting glucose levels accompanied with reduced PEPCK-C expression and increased in AMPK and ERK1/2 phosphorylation states in the liver of genistein-treated alloxan-induced diabetic mice. Genistein fulfills the criteria of a suitable anti-diabetic agent by reducing glucose production and inhibiting PEPCK-C expression in HepG2 cells and also in alloxan-induced diabetic mice. These results indicate that genistein is an effective candidate for preventing T2DM through the modulation of AMPK-CRTC2 and MEK/ERK signaling pathways, which may allow a novel approach to modulate dysfunction in hepatic gluconeogenesis in T2DM.

AB - Genistein has been reported to exert beneficial effects on type 2 diabetes mellitus (T2DM); however, the underlying molecular mechanisms involved therein have not been clearly elucidated. To address this question, the effect of genistein on the expression of phosphoenolpyruvate carboxykinase (PEPCK), and glucose production in HepG2 cells and in alloxan-induced diabetic mice was investigated. HepG2 cells were exposed to different concentration of genistein in presence or absence of modulators, and the expression of cytosolic PEPCK (PEPCK-C) and the signaling pathways was studied. Further, the biological relevance of the in vitro study was tested in alloxan-induced diabetic mice. Genistein lowered PEPCK-C expression and glucose production in HepG2 cells accompanied with increased in phosphorylation states of AMPK, MEK1/2, ERK1/2, and CRTC2. Treatment with the AMPK inhibitor (compoundC) enhanced genistein-induced MEK1/2 and ERK1/2 activity indicating a potential cross-talk between the two signaling pathways. In vivo, genistein also reduced fasting glucose levels accompanied with reduced PEPCK-C expression and increased in AMPK and ERK1/2 phosphorylation states in the liver of genistein-treated alloxan-induced diabetic mice. Genistein fulfills the criteria of a suitable anti-diabetic agent by reducing glucose production and inhibiting PEPCK-C expression in HepG2 cells and also in alloxan-induced diabetic mice. These results indicate that genistein is an effective candidate for preventing T2DM through the modulation of AMPK-CRTC2 and MEK/ERK signaling pathways, which may allow a novel approach to modulate dysfunction in hepatic gluconeogenesis in T2DM.

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