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.

• Authors: 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
• Journal: Scientific reports (Sci Rep) Vol. 6 Pg. 23665 (Mar 24 2016) ISSN: 2045-2322 [Electronic] England
• PMID: 27009398 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Hypoglycemic Agents
• Insulin-Like Growth Factor Binding Protein 2
• PPAR alpha
• Metformin
• Adenylate Kinase
• Sirt1 protein, mouse
• Sirtuin 1

Topics

• Adenylate Kinase (genetics)
• Aged
• Animals
• Cells, Cultured
• Diabetes Mellitus, Experimental
• Diabetes Mellitus, Type 2 (drug therapy, genetics)
• Female
• Gene Expression Regulation (drug effects)
• Humans
• Hypoglycemic Agents (administration & dosage, pharmacology)
• Insulin-Like Growth Factor Binding Protein 2 (genetics)
• Male
• Metformin (administration & dosage, pharmacology)
• Mice
• Middle Aged
• Obesity (genetics)
• PPAR alpha (genetics)
• Sirtuin 1 (genetics)