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

Title
Metformin stimulates IGFBP-2 gene expression through PPARalpha in diabetic states
Authors
Kang, Hye SukCho, Ho-ChanLee, Jae-HoOh, Goo TaegKoo, Seung-HoiPark, Byung-HyunLee, In-KyuChoi, Hueng-SikSong, Dae-KyuIm, Seung-Soon
Ewha Authors
오구택
SCOPUS Author ID
오구택scopus
Issue Date
2016
Journal Title
SCIENTIFIC REPORTS
ISSN
2045-2322JCR Link
Citation
vol. 6
Publisher
NATURE PUBLISHING GROUP
Indexed
SCI; SCIE; SCOPUS WOS 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-PPAR alpha 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 Ppar alpha-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-PPA alpha-IGFBP-2 network may provide a novel pathway that could be applied to ameliorate metabolic syndromes by controlling IGF-1 bioavailability.
DOI
10.1038/srep23665
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자연과학대학 > 생명과학전공 > Journal papers
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