Metformin stimulates IGFBP-2 gene expression through PPARalpha in diabetic states

Hye Suk Kang, Ho Chan Cho, Jae Ho Lee, Goo Taeg Oh, Seung-Hoi Koo, Byung Hyun Park, In Kyu Lee, Hueng Sik Choi, Dae Kyu Song, Seung Soon Im

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

The anti-diabetic drug, metformin, exerts its action through AMP-activated protein kinase (AMPK), and Sirtuin (Sirt1) signaling. Insulin-like growth factor (IGF)-binding protein 2 (IGFBP-2) prevents IGF-1 binding to its receptors, thereby contributing to modulate insulin sensitivity. In this study, we demonstrate that metformin upregulates Igfbp-2 expression through the AMPK-Sirt1-PPARα cascade pathway. In the liver of high fat diet, ob/ob, and db/db mice, Igfbp-2 expression was significantly decreased compared to the expression levels in the wild-type mice (p 0.05). Upregulation of Igfbp-2 expression by metformin administration was disrupted by gene silencing of Ampk and Sirt1, and this phenomenon was not observed in Pparα-null mice. Notably, activation of IGF-1 receptor (IGF-1R)-dependent signaling by IGF-1 was inhibited by metformin. Finally, when compared to untreated type 2 diabetes patients, the metformin-treated diabetic patients showed increased IGFBP-2 levels with diminished serum IGF-1 levels. Taken together, these findings indicate that IGFBP-2 might be a new target of metformin action in diabetes and the metformin-AMPK-Sirt1-PPARα-IGFBP-2 network may provide a novel pathway that could be applied to ameliorate metabolic syndromes by controlling IGF-1 bioavailability.

Original languageEnglish
Article number23665
JournalScientific Reports
Volume6
DOIs
Publication statusPublished - 2016 Mar 24

Fingerprint

Insulin-Like Growth Factor Binding Protein 2
PPAR alpha
Metformin
Gene Expression
Somatomedins
AMP-Activated Protein Kinases
Mediator Complex Subunit 1
Up-Regulation
Somatomedin Receptors
Peroxisome Proliferator-Activated Receptors
High Fat Diet
Gene Silencing
Type 2 Diabetes Mellitus
Biological Availability
Insulin Resistance
Liver
Serum

ASJC Scopus subject areas

  • General

Cite this

Kang, H. S., Cho, H. C., Lee, J. H., Oh, G. T., Koo, S-H., Park, B. H., ... Im, S. S. (2016). Metformin stimulates IGFBP-2 gene expression through PPARalpha in diabetic states. Scientific Reports, 6, [23665]. https://doi.org/10.1038/srep23665

Metformin stimulates IGFBP-2 gene expression through PPARalpha in diabetic states. / Kang, Hye Suk; Cho, Ho Chan; Lee, Jae Ho; Oh, Goo Taeg; Koo, Seung-Hoi; Park, Byung Hyun; Lee, In Kyu; Choi, Hueng Sik; Song, Dae Kyu; Im, Seung Soon.

In: Scientific Reports, Vol. 6, 23665, 24.03.2016.

Research output: Contribution to journalArticle

Kang, HS, Cho, HC, Lee, JH, Oh, GT, Koo, S-H, Park, BH, Lee, IK, Choi, HS, Song, DK & Im, SS 2016, 'Metformin stimulates IGFBP-2 gene expression through PPARalpha in diabetic states', Scientific Reports, vol. 6, 23665. https://doi.org/10.1038/srep23665
Kang, Hye Suk ; Cho, Ho Chan ; Lee, Jae Ho ; Oh, Goo Taeg ; Koo, Seung-Hoi ; Park, Byung Hyun ; Lee, In Kyu ; Choi, Hueng Sik ; Song, Dae Kyu ; Im, Seung Soon. / Metformin stimulates IGFBP-2 gene expression through PPARalpha in diabetic states. In: Scientific Reports. 2016 ; Vol. 6.
@article{8079845d8e3347aca3888258878f9b2e,
title = "Metformin stimulates IGFBP-2 gene expression through PPARalpha in diabetic states",
abstract = "The anti-diabetic drug, metformin, exerts its action through AMP-activated protein kinase (AMPK), and Sirtuin (Sirt1) signaling. Insulin-like growth factor (IGF)-binding protein 2 (IGFBP-2) prevents IGF-1 binding to its receptors, thereby contributing to modulate insulin sensitivity. In this study, we demonstrate that metformin upregulates Igfbp-2 expression through the AMPK-Sirt1-PPARα cascade pathway. In the liver of high fat diet, ob/ob, and db/db mice, Igfbp-2 expression was significantly decreased compared to the expression levels in the wild-type mice (p 0.05). Upregulation of Igfbp-2 expression by metformin administration was disrupted by gene silencing of Ampk and Sirt1, and this phenomenon was not observed in Pparα-null mice. Notably, activation of IGF-1 receptor (IGF-1R)-dependent signaling by IGF-1 was inhibited by metformin. Finally, when compared to untreated type 2 diabetes patients, the metformin-treated diabetic patients showed increased IGFBP-2 levels with diminished serum IGF-1 levels. Taken together, these findings indicate that IGFBP-2 might be a new target of metformin action in diabetes and the metformin-AMPK-Sirt1-PPARα-IGFBP-2 network may provide a novel pathway that could be applied to ameliorate metabolic syndromes by controlling IGF-1 bioavailability.",
author = "Kang, {Hye Suk} and Cho, {Ho Chan} and Lee, {Jae Ho} and Oh, {Goo Taeg} and Seung-Hoi Koo and Park, {Byung Hyun} and Lee, {In Kyu} and Choi, {Hueng Sik} and Song, {Dae Kyu} and Im, {Seung Soon}",
year = "2016",
month = "3",
day = "24",
doi = "10.1038/srep23665",
language = "English",
volume = "6",
journal = "Scientific Reports",
issn = "2045-2322",
publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Metformin stimulates IGFBP-2 gene expression through PPARalpha in diabetic states

AU - Kang, Hye Suk

AU - Cho, Ho Chan

AU - Lee, Jae Ho

AU - Oh, Goo Taeg

AU - Koo, Seung-Hoi

AU - Park, Byung Hyun

AU - Lee, In Kyu

AU - Choi, Hueng Sik

AU - Song, Dae Kyu

AU - Im, Seung Soon

PY - 2016/3/24

Y1 - 2016/3/24

N2 - The anti-diabetic drug, metformin, exerts its action through AMP-activated protein kinase (AMPK), and Sirtuin (Sirt1) signaling. Insulin-like growth factor (IGF)-binding protein 2 (IGFBP-2) prevents IGF-1 binding to its receptors, thereby contributing to modulate insulin sensitivity. In this study, we demonstrate that metformin upregulates Igfbp-2 expression through the AMPK-Sirt1-PPARα cascade pathway. In the liver of high fat diet, ob/ob, and db/db mice, Igfbp-2 expression was significantly decreased compared to the expression levels in the wild-type mice (p 0.05). Upregulation of Igfbp-2 expression by metformin administration was disrupted by gene silencing of Ampk and Sirt1, and this phenomenon was not observed in Pparα-null mice. Notably, activation of IGF-1 receptor (IGF-1R)-dependent signaling by IGF-1 was inhibited by metformin. Finally, when compared to untreated type 2 diabetes patients, the metformin-treated diabetic patients showed increased IGFBP-2 levels with diminished serum IGF-1 levels. Taken together, these findings indicate that IGFBP-2 might be a new target of metformin action in diabetes and the metformin-AMPK-Sirt1-PPARα-IGFBP-2 network may provide a novel pathway that could be applied to ameliorate metabolic syndromes by controlling IGF-1 bioavailability.

AB - The anti-diabetic drug, metformin, exerts its action through AMP-activated protein kinase (AMPK), and Sirtuin (Sirt1) signaling. Insulin-like growth factor (IGF)-binding protein 2 (IGFBP-2) prevents IGF-1 binding to its receptors, thereby contributing to modulate insulin sensitivity. In this study, we demonstrate that metformin upregulates Igfbp-2 expression through the AMPK-Sirt1-PPARα cascade pathway. In the liver of high fat diet, ob/ob, and db/db mice, Igfbp-2 expression was significantly decreased compared to the expression levels in the wild-type mice (p 0.05). Upregulation of Igfbp-2 expression by metformin administration was disrupted by gene silencing of Ampk and Sirt1, and this phenomenon was not observed in Pparα-null mice. Notably, activation of IGF-1 receptor (IGF-1R)-dependent signaling by IGF-1 was inhibited by metformin. Finally, when compared to untreated type 2 diabetes patients, the metformin-treated diabetic patients showed increased IGFBP-2 levels with diminished serum IGF-1 levels. Taken together, these findings indicate that IGFBP-2 might be a new target of metformin action in diabetes and the metformin-AMPK-Sirt1-PPARα-IGFBP-2 network may provide a novel pathway that could be applied to ameliorate metabolic syndromes by controlling IGF-1 bioavailability.

UR - http://www.scopus.com/inward/record.url?scp=84961669709&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84961669709&partnerID=8YFLogxK

U2 - 10.1038/srep23665

DO - 10.1038/srep23665

M3 - Article

C2 - 27009398

AN - SCOPUS:84961669709

VL - 6

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

M1 - 23665

ER -