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Title: Mechanisms of Hypoglycemic action of angiotensin peptides in Diet-induced diabetic mice
Keywords: Des-aspartate-angiotensin I, Angiotensin IV, Diet-induced diabetes, Insulin resistance, Angiotensin receptor type I, Insulin regulated aminopeptidase
Issue Date: 18-Jun-2010
Citation: WONG YONG CHIAT (2010-06-18). Mechanisms of Hypoglycemic action of angiotensin peptides in Diet-induced diabetic mice. ScholarBank@NUS Repository.
Abstract: Type 2 diabetes mellitus is often associated with obesity and hypertension, with insulin resistance as a hallmark of the prevailing disease. Angiotensin II (Ang-II) is involved in the pathogenesis of insulin resistance by exerting negative modulation on insulin signal transduction. In the current study, we explored the roles of Des-aspartate-angiotensin I (DAA-1) and angiotensin IV (Ang-IV) in the signalling cascades of Ang-II and insulin in diet-induced diabetes. Six to eight-week old male C57BL/6J mice were fed a high-fat-high-sucrose (HFD) or control diet for 52 weeks. The HFD mice were treated with DAA-1 (600 nmole/ kg/ day), Ang-IV (400 nmole/ kg/ day) or drinking water by gavage, starting from week 0 or week 24 of the diet regime. Body weight, blood glucose and blood insulin were measured periodically. Orally-administered DAA-1 and Ang-IV had no effect on body weight and both fasted insulin level but exerted significant hypoglycemic action. At the end of 52 week, the skeletal muscles of HFD animals treated with DAA-1 were found to have (i) decreased levels of ROS, gp91 of NADPH oxidase, pJNK and pIRS-1307 (ii) improved insulin-stimulated pTyr-IR, pTyr-IRS-1, PI3K activation, pAkt and GLUT4 and (iii) reduced level of AT1-JAK-2-IRS-1 complex. Losartan and indomethacin were shown to abolish DAA-1 induced hypoglycemic effect. These findings suggest that DAA-1 exerts its hypoglycaemic effect by acting on AT1 receptor and release of prostaglandins. On the other hand, the skeletal muscles of HFD animals treated with Ang-IV were found to have similar decreased levels of ROS, gp91 of NADPH oxidase, pJNK, pIRS-1307 and AT1-JAK-2-IRS-1 complex, but to a lesser extent compared to the DAA-1 treated animals. Interestingly, the skeletal muscles of Ang-IV treated animals showed significant increased levels of insulin-stimulated pAkt and GLUT4 translocation in the absence of improvement in pTyr-IR, pTyr-IRS-1 and PI3K attachment to IRS-1. These findings suggest that Ang-IV attenuates the insulin signalling via an alternative pathway. This postulation is supported by the observation that the skeletal muscles of Ang-IV treated animals were found to have high levels of pTyr-IRAP and PI3K attachment to IRAP. Divilinal-Ang-IV was shown to abolish Ang-IV induced hypoglycaemic effect. Collectively, the data suggest that Ang-IV exerts its hypoglycaemic action through AT4 receptor. Lastly, the effects of the angiotensin peptides on hyperglycaemic-induced pancreatic beta-cell death were investigated. It was demonstrated that DAA-1, but not Ang-IV attenuated hyperglycaemic-induced beta cell death in a dose dependent manner. In addition, losartan was found to inhibit the actions of DAA-1. This finding suggests that DAA-1 exerts its protective effect via AT1 receptors in hyperglycaemic-induced cell death. Taken together, DAA-1 and Ang-IV are potential prophylactic and acute oral anti-diabetic agents that exert hypoglycemic action through AT1 and AT4 receptors respectively. The study also demonstrates for the first time the protective action of DAA-1 against beta cell death under in vitro hyperglycaemic conditions. In addition to the enhancement of our understanding to the pathogenesis of diet-induced diabetes, the findings in this study reveal novel potential drug targets for the treatment of diabetes.
Appears in Collections:Ph.D Theses (Open)

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