| Type2diabetes is a chronic metabolic disease characterized by the increased peripheral tissue insulin resistance and progressive deterioration of islet cell functions. Insulin resistance from peripheral tissue is one of the most important mechanisms of the onset of type2diabetes. Recently, accumulating evidence showed that endoplasmic reticulum stress plays an important role in the development of insulin resistance in diabetes. Although drug treatment and insulin replacement therapy are still the priority choice for type2diabetes treatments, surgery as a potential treatment for type2diabetes has attracted wide attention in decades.Roux-en-Y gastric bypass surgery (Roux-en-Y gastric bypass, RYGB) is the most commonly performed bariatric operation for the treatment of morbid obesity. RYGB surgery could not only provide significantly long-term weight losing, but also reduce the levels of glucose and glycosylated hemoglobin in80%-100%of type2diabetes patients for many years, indicating that RYGB surgery could be recognized as an effective and long-term treatment for type2diabetes. Weight loss and reduced food intake have significant impact on metabolism. However, more and more data from human and animals established that bariatric surgery has specific effects on type2diabetes independent on weight loss and reduced food intake. Thus, it is very appealing to move from bariatric surgery to metabolic surgery, because the vast majority of type2diabetics are not morbidly obese. The mechanisms of RYGB surgery of ameliorating the type2diabetes are unknown yet. Under the disease conditions such as hypoxia, high glucose, metabolic poisons or mutations, the homeostasis of endoplasmic reticulum is disrupted and lead to the accumulation of misfolded or unfolded protein, leading to activation of the endoplasmic reticulum stress signaling pathway. Therefore, the endoplasmic reticulum stress inhibits the insulin signaling pathway in liver tissue. The current study are designed to find ER stress molecular changes in the antidiabetic effects of gastric bypass independent on weight loss,.GK rat is a model rat of nonobese spontaneous type2diabetes, which has similar characteristics of human type2diabetes and being recognized as one of the best diabetic related laboratory models. In this study, RYGB surgery was performed on GK rats. Experimental methods confirmed by insulin tolerance test and oral glucose tolerance test that both insulin resistance and glucose tolerance improved. In line with this, we found that protein expression of insulin receptor in liver tissue significantly increased after RYGB surgery. We also found that endoplasmic reticulum stress reduced in the liver of GK rat after RYGB surgery, especially the significant decreased protein expression of transcription factor CHOP. The transcription factor FOXO1protein expression increased significantly and the phosphorylation of FOXO1expression was markedly decreased. These results suggest that CHOP and FOXO1may be involved in regulating the expression of insulin receptor and may be also involved in insulin signaling pathway to improve liver insulin resistance in diabetic rat. By transfacting the plasmid expressing full length FOXO1or CHOP siRNA fragments to affect FOXO1or CHOP expression levels in the rat cell line BRL-3A, we found that overexpression FOXO1would reduce the sensitivity of insulin receptor signaling pathway, while knocking down CHOP expression can reverse FOXO-1effects and enhance insulin sensitivity. This study shows that RYGB surgery improving GK rat diabetic state may through reducing endoplasmic reticulum stress, especially CHOP expression, to enhance the insulin sensitivity in liver. This discovery enriches the mechanism of RYGB surgery improving GK rat diabetes. |
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