Development of novel therapeutic approaches to manage metabolic syndrome and prevent type 2 diabetes

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NO FULL TEXT AVAILABLE. Access is restricted indefinitely. ----- The metabolic syndrome and its related disorder, type 2 diabetes, non-alcoholic fatty liver disease, Alzheimer disease have reached epidemic proportions. Early treatment to metabolic syndrome has proven an effective way to prevent or delay type-2 diabetes and its complications. My research project has been focusing on investigating effects and mechanisms of herbal medicine extracts and anti-RBP4 RNA oligonucleotides (oligos) on dietary factor-induced rodent models of metabolic syndrome, including obesity, hyperlipidemia, insulin resistance, hepatic steatosis and elevation of butyrylcholinesterase (BuChE). The results described in Chapter 3, 4 and 5 indicate that the mixture of Chinese herbal extracts, SK0506, and Salvia miltiorrhiza extract (SME) significantly decreased body weight associated with low visceral adiposity. Serum triglycerides and non-esterified fatty acid levels were significantly lower in SK0506 and SME treated rats compared with saline and rosiglitazone (RSG) treated rats. The SK0506 improved glucose intolerance and enhanced whole body insulin sensitivity but RSG exerted more potent effects on fasting glucose concentration and glucose uptake by skeletal muscle than SK0506. These finding suggest the combination of SK0506 and RGS may provide better treatment for obesity associated with insulin resistance. Furthermore, HFD feeding induced fat accumulation in liver and skeletal muscle were also reversed by SME treatment. SME treatment also ameliorated the elevated serum Alanine Transaminase (ALT) and Aspartate Transaminase (AST). The mechanism of SME improved fatty liver disease may be related to inhibition of inflammatory cytokines (TNF-a and IL-6) secretion from adipose tissue in HFD rats.Study in chapter 5 showed SK0506 may be a potential therapy for diabetes associated Alzheimer disease through inhibiting inflammatory cytokines and reducing BuChE activity. Retinol binding protein 4 (RBP4) has recently been described as a candidate gene for treating insulin resistance and diabetes. Study in Chapter 6 showed synthetic RNA oligos significantly block RBP4 mRNA expression in 3T3-L1 cells. In vivo study showed that RNA oligos treatment significantly reduced the weight of abdominal adipose tissues and lowered blood lipids. RNA oligos was capable of decreasing fasting serum glucose and insulin levels in HFD mice. The molecular mechanism of RNA oligos treatment was due to inhibition of over-expression of RBP4 in adipose tissue and down-regulation of hepatic PEPCK expression in HFD mice. In summary, this thesis has demonstrated that Chinese herbal extracts, SK0506 and SME, and anti-RBP4 RNA oligos may be novel therapeutic approaches to manage metabolic syndrome and prevent type-2 diabetes
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