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 journalArticlepeer-review

22 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

ASJC Scopus subject areas

  • General

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