Abstract
Severe burn injury causes hepatic dysfunction that results in major metabolic derangements including insulin resistance and hyperglycemia and is associated with hepatic endoplasmic reticulum (ER) stress. We have recently shown that insulin reduces ER stress and improves liver function and morphology; however, it is not clear whether these changes are directly insulin mediated or are due to glucose alterations. Metformin is an antidiabetic agent that decreases hyperglycemia by different pathways than insulin; therefore, we asked whether metformin affects postburn ER stress and hepatic metabolism. The aim of the present study is to determine the effects of metformin on postburn hepatic ER stress and metabolic markers. Male rats were randomized to sham, burn injury and burn injury plus metformin and were sacrificed at various time points. Outcomes measured were hepatic damage, function, metabolism and ER stress. Burn-induced decrease in albumin mRNA and increase in alanine transaminase (p < 0.01 versus sham) were not normalized by metformin treatment. In addition, ER stress markers were similarly increased in burn injury with or without metformin compared with sham (p < 0.05). We also found that gluconeogenesis and fatty acid metabolism gene expressions were upregulated with or without metformin compared with sham (p < 0.05). Our results indicate that, whereas thermal injury results in hepatic ER stress, metformin does not ameliorate postburn stress responses by correcting hepatic ER stress.
Highlights
Liver dysfunction and endoplasmic reticulum (ER) stress are two major consequences of burn injury [1,2]
There was a significant increase (p < 0.05) in the phosphorylation of AMPactivated protein kinase (AMPK) in metformintreated livers compared with nontreated livers (Figure 1)
Hepatic Function We investigated the effects of metformin on albumin expression and Alanine transaminase (ALT) levels
Summary
Liver dysfunction and endoplasmic reticulum (ER) stress are two major consequences of burn injury [1,2]. We previously published rodent studies that showed that insulin treatment after burn attenuates these processes and enhances hepatic function [6]. We expect that insulin treatment may improve postburn morbidity and mortality in patients; the mechanism of action of insulin in the context of burn injury is unclear. It was reported that metformin reduces burn-induced hyperglycemia and insulin resistance, indicating an improvement in postburn patient outcome [8]. Whereas many studies claim the capacity of metformin to suppress hepatic gluconeogenesis [10,13,14,15], some report that metformin primarily decreases plasma glucose by activating glucose utilization [16]. It is important to this study that metformin decreases blood glucose levels by non–insulin-mediated mechanisms, which allows us to distinguish between insulin- and glucose-mediated effects
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