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The Giucose-lowering Effect of Stilbenoids E2 and Its Mechanism

Author: ChenJinLong
Tutor: WuZuZe
School: PLA Military Academy of Medical Sciences
Course: Pathology and Pathophysiology
Keywords: Stilbene compounds E2 Diabetes Insulin receptor Sphingosine kinase Glucose metabolism
CLC: R96
Type: PhD thesis
Year: 2007
Downloads: 289
Quote: 1
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Abstract


Diabetes is characterized by hyperglycemia, which results from impaired insulin secretion and/or insulin action. It is also the leading cause of many clinical chronic complications, which lead to a markedly increased morbidity and mortality. Drugs currently used in clinical practices could not correct the abnormality of diabetes with satisfaction. Therefore, it is still an important mission in the world to find a more effective agent in the treatment and prophylaxis of diabetes.Stilbenoids E2, a derivate from rheum officinal rootstock, is a kind of glucose-lowering agent owned by our laboratory. However, we know little about its glucose-lowering mechanism and complication improving effects. In order to evaluate its glucose-lowering effects and clarify the underlying mechanisms, we performed a systemic research using several experimental diabetic animal models.. Meantime, we investigated the role of SPK in the regulation of glucose metabolism, and tested the possibility of taking it as a new target in managing the diabetes mellitus..First, we observed the functions of Stilbenoids E2 on glucose-lowering and complication controlling by using 5 kind experimental animal models The results showed that Stilbenoids E2 could decrease the serum glucose, triglyceride and cholesterol levels, and could markedly improve the oral glucose tolerance of the diabetic animals. Stilbenoids E2 could not promote the secretion of insulin but protect the islet cells. Stilbenoids E2 showed a potent ability to protect and reconstruct many organs, such as the heart, kidney, liver and spleen. Glucogen synthesis in the rat liver and heart was accelerated after the administration of Stilbenoids E2. Stilbenoids E2 could also improve the rat’s heart output through the decomposing glycosylating terminal products-AGEs, decreasing the distal resistance of blood vessels, and improving the compliances of the arteries. Western Blot results showed that stilbenoids E2 could increase the expression of insulin receptor in the liver and activate the signaling pathways of Akt、GSK-3βin the liver and heart tissues. we then probed the molecular and cellular mechanisms of stilbenoids E2 for its abilities to decrease the serum levels of triglyceride and cholesterol, and its controlling on the related complications. Stilbenoids E2 enhanced the consumption of hepatin in the L0-2 liver cells but not in the C2C12 muscle cells, impling that the liver cells might be a target of stilbenoids E2. We found that stilbenoids E2 could not induce insulin secretion of theβTC3 islet cells, but could active the phosphorylation of Akt and GSK-3βin the SMMC-7721 hepatoma cells. We also found that stilbenoids E2 could activate the SPK, another important lipid kinase as PI3K. To clarify whether SPK is really a key molecule involved in the glucose metabolism, we prepared the Ad-SPK1, the recombinant adenovirus harboring SPK1 gene, then transfected the SMMC-7721 hepatoma cells and C2C12 myoblasts with Ad-SPK1. We found that SPK1 gene tranfer could significantly increase both basal and insulin-induced glucose uptake, and DMS, a potent inhibitor of SPK1, inhibited both basal and insulin-induced glucose uptake. We further investigated the role of SPK1 in glucose metabolism in the spontaneous KK-Ay type 2 diabetic mice model using a adenoviral-mediated gene transfer approach. It was found that the adenoviral-mediated gene transfer of SPK1 markedly decreased blood glucose levels and alleviated their insulin-resistance of the animals. All these findings strongly suggest that SPK1 is a key molecule in modulating the glucose metabolism, and stimulating activation of SPK may be an important mechanism of the anti-diabetic action of stilbenoids E2.In conclusion, our results demonstrate that: (1) Stilbenoids E2 can decrease the blood glucose and lipid levels, improve the structures and functions of the heart, liver, spleen and kidney, so it is a new and effective agent in the treatment of diabete. (2) The glucose-lowering mechanism of Stilbenoids E2 are:①Protect the islet cells but do not stimulate the secretion of insulin;②Increase the expression of insulin receptors;③Accelerate the glycogen synthesis in the liver and the heart through activating Akt and GSK-3βsignaling;④stimulating activation of SPK is an important mechanism of the anti-diabetic action of stilbenoids E2. (3) SPK is a another lipid kinase involved in the regulation of glucose metabolism and homeostasis.

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