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.
Highlights
It has been demonstrated that obesity and insulin resistance are associated with a proinflammatory state, which may be mediated by cytokines and subsequently cause elevated levels of C-reactive protein (CRP) that might predispose to an increased risk of type 2 diabetes [1,2]
We found that metformin ameliorates insulin resistance and dyslipidemia and exhibit cardioprotective effects by reducing inflammation and tissue oxidative and dicarbonyl stress associated with human CRP
We found that metformin can attenuate inflammation and tissue oxidative and dicarbonyl stress which are all dependent on human CRP
Summary
It has been demonstrated that obesity and insulin resistance are associated with a proinflammatory state, which may be mediated by cytokines and subsequently cause elevated levels of CRP that might predispose to an increased risk of type 2 diabetes [1,2]. Recent data provide evidence that inflammation, oxidative stress, the presence of lipoperoxidation products and hyperglycemia are associated with abnormal cellular accumulation of the reactive dicarbonyl metabolites that induce increased protein and DNA modification, which contribute to cell and tissue dysfunction in ageing and disease [6,7,8]. Increased levels of dicarbonyls are associated with increased levels of triglycerides and free fatty acids, lipid peroxidation and with the degradation of glycated proteins observed in type 1 and 2 diabetes. Dicarbonyls are characterized by their extremely high chemical reactivity They are very reactive and can produce the covalent modification of proteins, lipids and nucleic acids and form advanced glycation end products (AGEs) even at very low levels. Nothing is known about the role of tissue levels of individual dicarbonyls and their relationship to oxidative stress in the pathogenesis of diabetic complications
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