Effects of Glutamine on Inflammatory Response and Organ Injury in Diabetic Condition with Sepsis

Diabetes mellitus (DM) is the fourth leading causes of death in Taiwan. Diabetic patients have accelerated atherosclerosis and peripheral artery occlusive disease, which predispose them to worse organ perfusion and poor wound healing. Once infected may result in not only local inflammatory response but also overwhelming systemic inflammatory response syndrome, even to septic shock or death. Hyperglycemia or sepsis may induce inflammatory response by way of increasing expression of adhesion molecules such as intercellular adhesion molecule-1(ICAM-1)、LAF-1 and Mac-1 etc. Reducing the production of these adhesion molecules may modulate and attenuate inflammatory response and prevent endothelium dysfunction. Studies showed that sepsis provokes the activation of NF-κB and its downstream proinflammatory cytokines. Peroxisome proliferators- activated receptor (PPAR)-γ, an anti-inflammatory factor, has been reported to play a major role in the treatment of some inflammatory diseases such as diabetes. Besides, oxidative stress and mitochondrial dysfunction are thought to play important roles in the pathogenesis of septic-induced multiple organs failure. Down-regulation of mitochondrial membrane potential and enzyme activity of electronic transport chain (ETC) are proposed as the basis of mitochondrial dysfunction. Sepsis may decrease the ETC enzyme activities by increasing nitric oxide (NO) content from over-expression of inducible nitric oxide synthase (iNOS) in mitochondria. Several studies have shown that increasing mitochondrial NO content will release cytochrome c into cytosol and activate caspase 3, which may consequently result in mitochondrial apoptosis and cell death. Therefore, improving mitochondrial function may attenuate multiple organ dysfunction in sepsis. L-Glutamine (GLN) is a conditional amino acid. The GLN requirement is increased in certain situations such as trauma, infection and surgery etc. Many studies have showed the role of GLN in regulating inflammatory response. Attenuation of adhesion molecules, decreasing cytokines secretion and NF-κB expression and enhanced PPAR-γ activation could be the possible mechanisms. GLN is also a precursor of glutathione (GSH). GLN administration could attenuate iNOS expression by increasing GSH synthesis and reducing oxidative stress. It may also increase the insulin sensitivity and help balance blood sugar. However, few studies were performed with co-morbidities as diabetes and sepsis; we have established the diabetes with septic animal model. Therefore, this 3-year-study will be carried out to investigate the effect of GLN on inflammatory response and organ injury in diabetic condition with sepsis. In the first year, diabetes will be induced by a streptozotocin injection. We will induce polymicrobial sepsis after treating diabetic mice with GLN to investigate the effect of GLN on adhesion molecules, cytokines and PPAR-γ expression in diabetic mice complicated with sepsis. In the second year, we will assess whether GLN administration may alleviate organs injury in the same animal model and define the role of GLN on mitochondrial morphology and enzyme activity. Because our animal studies can not explore the mechanism of endothelial function and leukocyte transmigration directly. Thus, in the third year we will cultivate human umbilical vein endothelial cells with GLN under high concentration of glucose. After stimulation with endotoxin we will further characterize the mechanisms of GLN on adhesion molecule excretion and leukocyte transmigration as well as NO expression. The results of this proposal will lead to a better knowledge to understand the effect of GLN on inflammatory response and organ injury in diabetic condition with sepsis for clinical applications.