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  • Type diabetes mellitus T DM causes vascular complications an


    Type 2 NSC 14613 (T2DM) causes vascular complications and is a major public health problem associated with lifestyle diseases such as obesity, liver steatosis, hypertension, and so on. Although serum lactate is reportedly elevated in diabetic patients [12], [13], the physiological effects remain unclear. This study aimed to identify the significance of serum lactate elevation in T2DM patients, which may facilitate developing diabetes treatment strategies and new approaches to health promotion.
    Materials and methods
    Discussion Fatty liver is associated with metabolic risk factors such as obesity, diabetes, and dyslipidemia [16] and has been reported as a risk factor for atherosclerosis [17], [18]. It can also progress to severe related diseases such as liver steatosis, cirrhosis and hepatocellular carcinoma [19]. The gold standard for assessment of fatty liver is liver biopsy but this is an invasive procedure, and quantitative and useful biomarkers of early-stage diseases might contribute to treatment strategies aimed at suppressing the progression of such liver disorders. Lactate is a major substrate for gluconeogenesis and serum lactate elevation may serve as an indicator of impaired glucose production and lipid synthesis in states of obesity [20]. In addition, a positive correlation between serum lactate levels and lipid oxidation, suggesting that increasing gluconeogenesis from lactate is related to the promotion of lipid oxidation, has been reported in obese children [21]. Furthermore, in vivo magnetic resonance spectroscopy of non-alcoholic fatty liver disease (NAFLD) animal models, has suggested [1-13C] lactate to be a potential biomarker of liver steatosis [22]. It has also been shown that the Warburg shift from mitochondrial respiration to cytosolic glycolysis contributes to lactate production in the early phase of liver steatosis [23]. Some previous studies have already shown that lactate is metabolized primarily by the liver [24], [25], [26] and also have suggested that liver dysfunction is associated with higher lactate levels in the acutely ill patients [27], [28], [29]. To our knowledge, however, no study has considered examined serum lactate levels in human subjects with T2DM with various serum markers and anthropometric parameters. In our study, serum lactate levels correlated positively with ALT and negatively with total bilirubin. Furthermore, serum lactate was elevated in patients with ALT-predominant liver dysfunction not attributable to either alcohol-induced damage or viral infections. The serum lactate levels of patients with high serum total bilirubin levels (normal range: 0.4–1.5 mg/dL) were lower than those in patients with normal serum total bilirubin levels (n = 4 and 92, respectively, 0.73 ± 0.08 vs 1.07 ± 0.10 mmol/L, P = 0.05). However, further investigation of this issue is necessary since the number of target patients in our study was small. In recent studies, ALT elevation was found to be a risk factor related to new onset of diabetes [30], and was related to markers of inflammation and oxidative stress in NAFLD [31]. In addition, bilirubin which has antioxidant and cell-protective functions, is related to a reduced incidence of metabolic diseases and lower risk of cardiovascular disease, with an inverse correlation having been demonstrated between serum total bilirubin levels and the NAFLD incidence rate [32]. Our hypothesis, that serum lactate might serve as a biomarker of liver dysfunction, is further supported by these previously reported findings. Lactate has an effect as a metabolic mediator suppressing lipolysis by insulin in adipose tissue. The mechanisms involve direct activation of GPR81, which is an orphan G-protein-coupled receptor. After being stimulated by lactate in adipocytes, intracellular adenylyl cyclase activity is decreased, resulting in reduced cyclic adenosine monophosphate (cAMP) production and, ultimately, the suppression of lipolysis [6], [7]. GPR81 was reported to be highly expressed in adipose tissue, as well as in the brain, liver, kidney, skeletal muscle, spleen and testicles [15]. In the present study, serum lactate levels correlated negatively with the body muscle ratio (r = −0.277, P = 0.004), suggesting that lactate is a metabolite secreted from adipose tissues rather than a waste product of metabolic activities in muscles. In a past study, lactate was shown to suppress inflammatory reactions induced by Toll-like receptors and inflammasomes through activation of GPR81 in a model of acute hepatitis and acute pancreatitis [11]. Like these prior reports, our results support the hypothesis that the anti-inflammatory actions of NSC 14613 lactate might also function in fatty liver with chronic inflammation. It has also been shown that chronic obesity due to a high fat diet can suppress GPR81 gene expression in adipose tissues [33]. It is not unreasonable to theorize that expression of the GPR81 gene might be suppressed in fatty liver as well, possibly inducing a state of “lactate resistance” with a resultant rise in serum lactate levels. In addition, it has been found that sufficient serum lactate enhances UCP1 gene expression through mono-carboxylate transport proteins and promotes browning of white adipose tissues independently of GPR81 [10]. White adipose tissues undergoing increased fat deposition are thought to change into brown adipose tissues via the metabolism of lactate. This mechanism is regarded as a compensatory response to insulin resistance, mediated by lactate, and a similar mechanism might exist in fatty liver.