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

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13 Citations (Scopus)


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
Publication statusPublished - 2016 Mar 24

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    Kang, H. S., Cho, H. C., Lee, J. H., Oh, G. T., Koo, S-H., Park, B. H., Lee, I. K., Choi, H. S., Song, D. K., & Im, S. S. (2016). Metformin stimulates IGFBP-2 gene expression through PPARalpha in diabetic states. Scientific Reports, 6, [23665].