| Summary: | 博士 === 國立臺灣大學 === 園藝暨景觀學系 === 101 === Diabetes is the world''s fastest growing chronic disease that has caused many serious complications, resulting in a heavy burden of medical care. Recently studies have shown that causes of diabetes are all related to advanced glycation end products (AGEs) as well as the production and accumulation of its precursor-methylglyoxal (MG). Disorders of carbohydrate metabolism are among the most significant features of diabetes which is often accompanied by insulin resistance. Hyperglycemia will cause the production of the two endogenous – MG and AGEs. MG is a dicarbonyl produced during glycation which higher levels in the human body result in faster reactive oxygen species (ROS) which causes oxidative stress and inflammation. The nuclear factor erythroid 2-related factor 2 (Nrf2) is a defense mechanism against oxidative damage in cells. Because of this, it is especially important that we find the natural antioxidants via the activation of Nrf2 and evaluate its potential for the prevention of diabetes. It is known that the dry rhizomes of Plygonum cuspidatum Sieb. et. Zucc. (knotweed) contain a higher level of resveratrol, a phytoalexin which through various pathways can improve insulin sensitivity. The resveratrol rich knotweed plant was planted in the mountains of the Mei-Feng Area, Ren-Ai Township, Nantou County for two years. Via asexual reproduction, the final product of the selected strain produced ‘no.051111’. The rhizomes of the knotweed were converted into dry powder (100 g) and were then purified to produce a high yield of resveratrol (230 mg). The aim of this study is to evaluate the use of resveratrol in the activation of nuclear factor erythroid 2-related factor 2 (Nrf2) to attenuate MG-induced oxidative damage in cell lines. The results suggested that MG-induced insulin resistance in Hep G2 cells. However, resveratrol activated via the extracellular signal regulated kinase (ERK) pathway lead to Nrf2 nuclear translocation as well as the elevation of HO-1 and glyoxalase expression levels. Moreover, resveratrol significantly elevated glucose uptake and protected against MG-induced insulin resistance in Hep G2 cells. Furthermore, MG treatment induced the expression of apoptotic signaling molecules and decreased insulin production. Pretreatment with resveratrol increased insulin synthesis via upregulation of peroxisome proliferator-activated receptor γ (PPARγ) and pancreatic-duodenal homeobox-1 (PDX-1), while inhibiting MG-mediated expression of CCAAT/enhancer-binding protein β (C/EBPβ), a negative regulator of insulin production. Resveratrol strongly activated Nrf2 expression, which resulted in the attenuation of oxidative stress and increased insulin secretion. In conclusion, dietary antioxidants inhibit glycoxidative stress generated by protein modification, an important and significant property in research regarding diabetes pathophysiology. This study demonstrated that resveratrol upregulates Nrf2 expression to attenuate methylglyoxal-induced insulin resistance in Hep G2 cells, and protects RINm5F pancreatic cells from methylglyoxal-induced apoptosis. It has been made clear that resveratrol upregulates Nrf2 to promote MG metabolism, causing relative inhibition of AGEs formation and accumulation, which ultimately attenuates cellular oxidative damage, thereby improving the symptoms of diabetes.
|
|---|
