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.
Highlights
Creative Research Initiatives Center for Nuclear Receptor Signals, Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, 61186, Republic of Korea. *These authors contributed to this work
Igfbp-2 gene expression is decreased in diabetic condition and increased when insulin resistance was improved in diabetic animal model[10]
Igfbp-2 expression was markedly increased by metformin compared to untreated control (p < 0.05); Igfbp-1 expression was not induced by metformin treatment (Fig. 1C). These findings demonstrate that metformin upregulates Igfbp-2 expression in vitro
Summary
Creative Research Initiatives Center for Nuclear Receptor Signals, Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, 61186, Republic of Korea. *These authors contributed to this work. PPARα is known to suppress inflammation and to preserve insulin sensitivity[17] It interacts with the retinoid X receptor, and the resulting heterodimer promotes the transcriptional activation of target genes by binding to the consensus PPAR response element (PPRE) on target gene promoters[18]. Because AMPK functions as a potential intracellular energy sensor and a master regulator of metabolic homeostasis, understanding the mechanisms of its activation by various physiological stimuli or therapeutic drugs and several hormones including adiponectin and leptin[25] are of utmost importance in developing anti-diabetic drugs. Our results demonstrated that metformin controls Igfbp-2 gene transcription through the AMPK-Sirt1-PPARα signaling pathway. We showed that regulation of the Sirt1-PPARα -IGFBP-2 signaling cascade by AMPK activator represents a novel pathway that could be applied to ameliorate metabolic syndromes by controlling IGF-1 homeostasis
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