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Studies on the Preparation and Anti-type 2 Diabetes Mechanisms of Marine Oligosaccharide Derivatives

Author: HaoCui
Tutor: YuGuangLi
School: Ocean University of China
Course: Medicinal Chemistry
Keywords: Marine oligosaccharide chromium complex Type 2 diabetes mellitus Insulin sensitivity Skeletal muscle cells db / db mice
CLC: R587.1
Type: PhD thesis
Year: 2011
Downloads: 113
Quote: 0
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Abstract


Diabetes (Diabetes Mellitus, DM) is a common metabolic disease, and its incidence is on the rise in both developed and developing countries, China has become the the World Diabetes incidence largest number of countries. Diabetes is mainly divided into type 1 (insulin-dependent diabetes mellitus, IDDM) and type 2 (non-insulin-independent diabetes mellitus, NIDDM). Wherein the type 2 diabetes accounts for more than 90% of diabetic patients, as a typical multi-gene disorders. Type 2 diabetes is mainly related to two physiological defects, defects in insulin secretion and insulin resistance. Insulin resistance occurs mainly in fat, liver and muscle, containing a large number of insulin receptors in the cells of these organizations, they are capable of binding to the insulin which play an important role in the regulation of glucose metabolism homeostasis, especially insulin resistance in skeletal muscle major risk factor for diabetes. Prevention and treatment of type 2 diabetes insulin resistance caused by metabolic disorders, and improve insulin resistance or increased insulin sensitivity in drug research and development has an important significance. However, the existing anti-type 2 diabetes drugs and more secondary failure, side effects and defects are likely to cause hypoglycemia, so the research and development of low toxicity and can improve insulin resistance, the long-acting drugs are very necessary. Unique marine environment created many diverse and unique features of the active substance, marine polysaccharide compounds its resource-rich, low toxicity and activity of a broad and concern. Numerous studies show that a variety of complex organic chromium improve glucose metabolism and regulation of blood lipids. In a previous study on the basis of this study, various of marine oligosaccharides and chromium ion with prepared the series marine oligosaccharides chromium derivatives, oligosaccharides chromium compounds OM2 obtained by screening a better increase insulin sensitivity, and the molecular mechanism of its anti role of type 2 diabetes. First use acid degradation as raw material, alginate and carrageenan, successfully prepared by a different degree of polymerization of brown algae and carrageenan oligosaccharides, then with the Cr3 prepared the series marine oligosaccharides chromium derivatives. Using the orthogonal experimental mannuronic acid oligosaccharides chromium complex matter and carrageenan oligosaccharides chromium, complexes preparation conditions were optimized to determine the optimum reaction conditions. The resulting oligosaccharides chromium compounds were characterized by UV wavelength scanning and infrared spectroscopy analysis means. C2C12 skeletal muscle cell model and Thioflavin fluorescence method for a variety of marine oligosaccharides derivatives activity screening. Found that the oceans acidic oligosaccharides chromium complexes OM2 can not only blocked the amylin fibrosis in vitro activation of AMPK signaling pathway, has the potential to improve insulin resistance activity. On this basis, the use of hereditary diabetes transgenic db / db mice model to further evaluate its effect in vivo anti-type 2 diabetes. The study, of marine oligosaccharides OM2 no acute hypoglycemic role, there is no risk of transient lower blood sugar; not only be able to effectively lower blood sugar, improve lipid metabolism and reduce insulin resistance in mice, but also has the role of enhanced insulin sensitivity. In determining the the OM2 has the anti type 2 diabetes role based on the further use of the C2C12 cells and db / db mouse model mechanism OM2 improve insulin sensitivity in cells and animals on the overall level of system. The results, OM2 can significantly increase insulin-stimulated glucose transport, and the results are better than the positive control drug metformin. ELISA and real-time quantitative RT-PCR results showed that, OM2 not only be able to activate the insulin signaling pathway critical proteins IR, Akt and PI3K phosphorylation to increase the quantity of the insulin receptor and GLUT4 also able to increase the AMPK signaling pathway critical protein AMPK and ACC phosphorylation levels, regulate fat metabolism, so as to play its role of the insulin-sensitizing. Western blot findings, OM2 can also be through the insulin signaling pathway is activated in the liver, regulation of glycogen synthesis and gluconeogenesis process, thus reducing hyperglycemia in mice. OM2 FITC fluorescence labeling using live cell imaging technology research found, OM2 into C2C12 cells and located in the mitochondria, indicating that its role may improve mitochondrial function. In summary, this study successfully in vitro and in vivo have better resistance to type 2 diabetes, the role of marine oligosaccharides chromium complexes OM2; clear through the mechanisms by activation of the insulin signaling pathway and AMPK signaling pathway to regulate sugar lipid metabolism, increased insulin sensitivity, thereby improving insulin resistance, and provides a theoretical basis for its development as a new anti-type 2 diabetes marine drugs.

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CLC: > Medicine, health > Internal Medicine > Endocrine diseases and metabolic diseases > Islet disease > Diabetes
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