title: 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.affiliation: Department of Physiology, Keimyung University School of Medicine, Daegu 42601, Korea.
authors.forename: Hye Suk
authors.initials: HS
authors.lastname: Kang
authors.affiliation: Department of Internal Medicine, Keimyung University School of Medicine, Daegu 41931, Republic of Korea.
authors.forename: Ho-Chan
authors.initials: HC
authors.lastname: Cho
authors.affiliation: Department of Physiology, Keimyung University School of Medicine, Daegu 42601, Korea.
authors.forename: Jae-Ho
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Life Sciences, Ewha Womans University, Seoul 03760, Republic of Korea.
authors.forename: Goo Taeg
authors.initials: GT
authors.lastname: Oh
authors.affiliation: Division of Life Sciences, Korea University, 145 Anam-Ro, Seongbuk-Gu, Seoul, 02841, Republic of Korea.
authors.forename: Seung-Hoi
authors.initials: SH
authors.lastname: Koo
authors.affiliation: Department of Biochemistry, Chonbuk National University Medical School, Jeonju, Jeonbuk 54896, Republic of Korea.
authors.forename: Byung-Hyun
authors.initials: BH
authors.lastname: Park
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, 41944, Republic of Korea.
authors.forename: In-Kyu
authors.initials: IK
authors.lastname: Lee
authors.affiliation: National 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.
authors.forename: Hueng-Sik
authors.initials: HS
authors.lastname: Choi
authors.affiliation: Department of Physiology, Keimyung University School of Medicine, Daegu 42601, Korea.
authors.forename: Dae-Kyu
authors.initials: DK
authors.lastname: Song
authors.affiliation: Department of Physiology, Keimyung University School of Medicine, Daegu 42601, Korea.
authors.forename: Seung-Soon
authors.initials: SS
authors.lastname: Im
mesh_terms: D000263:Adenylate Kinase / Q000235:genetics; D000368:Aged; D000818:Animals; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000235:genetics*; D008297:Male; D008687:Metformin / Q000008:administration & dosage* / Q000494:pharmacology; D051379:Mice; D008875:Middle Aged; D009765:Obesity / Q000235:genetics*; D047493:PPAR alpha / Q000235:genetics; D056564:Sirtuin 1 / Q000235:genetics
chemical_list: D007004:Hypoglycemic Agents; D018971:Insulin-Like Growth Factor Binding Protein 2; D047493:PPAR alpha; D008687:Metformin; D000263:Adenylate Kinase; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1