title: Effects of Metformin on Tissue Oxidative and Dicarbonyl Stress in Transgenic Spontaneously Hypertensive Rats Expressing Human C-Reactive Protein.
abstract: Inflammation and oxidative and dicarbonyl stress play important roles in the pathogenesis of type 2 diabetes. Metformin is the first-line drug of choice for the treatment of type 2 diabetes because it effectively suppresses gluconeogenesis in the liver. However, its "pleiotropic" effects remain controversial. In the current study, we tested the effects of metformin on inflammation, oxidative and dicarbonyl stress in an animal model of inflammation and metabolic syndrome, using spontaneously hypertensive rats that transgenically express human C-reactive protein (SHR-CRP). We treated 8-month-old male transgenic SHR-CRP rats with metformin (5 mg/kg/day) mixed as part of a standard diet for 4 weeks. A corresponding untreated control group of male transgenic SHR-CRP rats were fed a standard diet without metformin. In a similar fashion, we studied a group of nontransgenic SHR treated with metformin and an untreated group of nontransgenic SHR controls. In each group, we studied 6 animals. Parameters of glucose and lipid metabolism and oxidative and dicarbonyl stress were measured using standard methods. Gene expression profiles were determined using Affymetrix GeneChip Arrays. Statistical significance was evaluated by two-way ANOVA. In the SHR-CRP transgenic strain, we found that metformin treatment decreased circulating levels of inflammatory response marker IL-6, TNFα and MCP-1 while levels of human CRP remained unchanged. Metformin significantly reduced oxidative stress (levels of conjugated dienes and TBARS) and dicarbonyl stress (levels of methylglyoxal) in left ventricles, but not in kidneys. No significant effects of metformin on oxidative and dicarbonyl stress were observed in SHR controls. In addition, metformin treatment reduced adipose tissue lipolysis associated with human CRP. Possible molecular mechanisms of metformin action-studied by gene expression profiling in the liver-revealed deregulated genes from inflammatory and insulin signaling, AMP-activated protein kinase (AMPK) signaling and gluconeogenesis pathways. It can be concluded that in the presence of high levels of human CRP, metformin protects against inflammation and oxidative and dicarbonyl stress in the heart, but not in the kidney. Accordingly, these cardioprotective effects of metformin might be especially effective in diabetic patients with high levels of CRP.
authors.affiliation: Center for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
authors.forename: Hana
authors.initials: H
authors.lastname: Malínská
authors.affiliation: Center for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
authors.forename: Olena
authors.initials: O
authors.lastname: Oliyarnyk
authors.affiliation: Center for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
authors.forename: Vojtěch
authors.initials: V
authors.lastname: Škop
authors.affiliation: Institute of Physiology, Czech Academy of Sciences, Prague, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Šilhavý
authors.affiliation: Institute of Physiology, Czech Academy of Sciences, Prague, Czech Republic.
authors.forename: Vladimír
authors.initials: V
authors.lastname: Landa
authors.affiliation: Institute of Physiology, Czech Academy of Sciences, Prague, Czech Republic.
authors.forename: Václav
authors.initials: V
authors.lastname: Zídek
authors.affiliation: Institute of Physiology, Czech Academy of Sciences, Prague, Czech Republic.
authors.forename: Petr
authors.initials: P
authors.lastname: Mlejnek
authors.affiliation: Institute of Physiology, Czech Academy of Sciences, Prague, Czech Republic.
authors.forename: Miroslava
authors.initials: M
authors.lastname: Šimáková
authors.affiliation: Institute of Molecular Genetics, Czech Academy of Sciences, Prague, Czech Republic.
authors.forename: Hynek
authors.initials: H
authors.lastname: Strnad
authors.affiliation: Center for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
authors.forename: Ludmila
authors.initials: L
authors.lastname: Kazdová
authors.affiliation: Institute of Physiology, Czech Academy of Sciences, Prague, Czech Republic.
authors.forename: Michal
authors.initials: M
authors.lastname: Pravenec
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002097:C-Reactive Protein / Q000096:biosynthesis* / Q000235:genetics; D016207:Cytokines / Q000378:metabolism; D015870:Gene Expression; D005947:Glucose / Q000378:metabolism; D006352:Heart Ventricles / Q000378:metabolism; D006801:Humans; D008066:Lipolysis / Q000187:drug effects* / Q000235:genetics; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D009206:Myocardium / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects* / Q000235:genetics; D011765:Pyruvaldehyde / Q000378:metabolism*; D051381:Rats; D011918:Rats, Inbred SHR; D055647:Rats, Transgenic
chemical_list: D016207:Cytokines; D011765:Pyruvaldehyde; D002097:C-Reactive Protein; D008687:Metformin; D055372:AMP-Activated Protein Kinases; D005947:Glucose