MECHANISMS OF HYPOGLYCEMIC ACTION OF ANGIOTENSIN PEPTIDES IN DIET-INDUCED DIABETIC MICE WONG YONG CHIAT B.Sc (Hons.), NUS A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY DEPARTMENT OF PHARMACOLOGY NATIONAL UNIVERSITY OF SINGAPORE 2010 ACKNOWLEDGEMENTS I wish to express my sincere gratitude to Associate Professor Sim Meng Kwoon Since knowing him in 2005, he has been an inspiring supervisor, a fantastic mentor and most importantly, a good friend He diligently guided me to successfully complete my PhD degree and showed me the way in becoming a successful researcher I also want to thank him for his patience and words of encouragement that have kept me confident in times of doubts I am deeply impressed with his dedication to Science and research work As a mentor, he shared many of his experiences and positive attitudes to life As a friend, he has put the needs of others before his own and was unstintingly generous with his time I would also like to thank Dr Xu Xiaoguang, my wonderful laboratory officer, for her invaluable assistance and outstanding moral support Working with her has been an enjoyable experience I also wish to express sincere appreciation to National University of Singapore for supporting my PhD full-time research with scholarship Lastly, I am greatly indebted to my loving parents and fiancée Xin Li, who always stand by me with their constant support and unconditional love To them I will always be grateful !"#$%&'(&)'*+%*+,& & & & & & & & -./0& List of publications& List of conference abstracts/ poster presentation& List of figures& List of tables& 31,+&'(&"##4%21"+1'*,& 1! 1! 11! 12! 2! 5677.89& :! );.-!08&:!8?@6)!=?>& A! !"!! #$%%&'()(%&'*+),')-,./&(&+) 0! !"1! 2.(345&'&+,+) 6! !"7! 8'+$9,')+,5'.99,'5)+:+(&;) !1! !"0! &=(4%+) !?! !"@! 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III LIST OF PUBLICATIONS Meng-Kwoon Sim, Xiao-Guang Xu, Yong-Chiat Wong, Sai-Zhen Sim and Kok-Onn Lee, 2007, Des-Aspartate-Angiotensin I Exerts Hypoglycemic Action via Glucose Transporter-4 Translocation in Type Diabetic KKAy Mice and GK Rats Endocrinology, Vol 148, No 12, 5925-5932 Meng-Kwoon Sim, Yong-Chiat Wong, Xiao-Guang Xu, Sai-Zhen Sim and Daniel Tsi, 2009, Hypoglycemic action of chicken meat extract in type diabetic KKAy mice and GK rats, Bioscience, Biotechnology and Biochemistry, Vol 73, 2583-2588 Yong-Chiat Wong and Meng-Kwoon Sim, 2009, Mechanisms of Hypoglycemic Action of Des-Asparate-Angiotensin I in Diet-induced Diabetic Mice, Journal of Diabetes, Vol 1, Issue S1, A230 Yong-Chiat Wong, Meng-Kwoon Sim and Kok-Onn Lee, 2010, Des-aspartateangiotensin I and angiotensin IV attenuate insulin resistance in diet-induced hyperglycaemic mice, [Submitted for Peer Review] LIST OF CONFERENCE ABSTRACTS/ POSTER PRESENTATION Oral presentation, The Inaugural Singapore-Taiwan-Hong Pharmacologists (SINGAPORE, 2007) Kong Meeting of Poster presentation, 3rd International Congress on Prediabetes and the Metabolic Syndrome (Nice, FRANCE, 2009) i LIST OF FIGURES & F=/680& & & & & & !=!30&& & & & & -./0& 1.1 The postulated disease progression of diabetes in developed nations 1.2 The insulin signalling system to metabolic events in the skeletal muscle 14 1.3 The differential of effects on structure and function of IRS-1 17 1.4 The effects of insulin resistance mediating factors in the skeletal muscle 18 1.5 The renin-angiotensin system and its regulating peptidases 21 1.6 The hypothetical IRAP/GLUT4 recycling model 29 1.7 Outline of the experimental strategy 42 2.1 Outline of the experimental protocol of the membrane isolation 54 3.1.1 Effect of DAA-1 on the weight of C57BL/6J mice fed on HFD 62 3.1.2 Effect of Ang-IV on the weight of C57BL/6J mice fed on HFD 63 3.1.3 Effect of DAA-1 on the energy of food consumed by C57BL/6J mice fed on HFD 65 3.1.4 Effect of Ang-IV on the energy of food consumed by C57BL/6J mice fed on HFD 66 3.1.5 Effect of DAA-1 on fasting blood glucose profile in C57BL/6J mice fed on HFD 69 3.1.6 Effect of Ang-IV on fasting blood glucose profile in C57BL/6J mice fed on HFD 70 3.1.7 Effect of DAA-1 on 30-mim OGTT profile in C57BL/6J mice fed on HFD 73 3.1.8 Effect of Ang-IV on 30-mim OGTT profile in C57BL/6J mice fed on HFD 74 3.1.9 Effects of DAA-1 and Ang-IV on the OGTT of C57BL/6J mice fed on HFD 77 3.1.10 Effect of DAA-1 on fasting blood insulin profile in C57BL/6J mice fed on HFD 79 3.1.11 Effect of Ang-IV on fasting blood insulin profile in C57BL/6J mice fed on HFD 80 3.1.12 Effects of DAA-1 and Ang-IV on the serum insulin profile of C57BL/6J mice fed on HFD 82 Effects of DAA-1 and Ang-IV on fasting serum free fatty acid of C57BL/6J mice fed on HFD 84 Experimental outline for the study of the effects of chronic treatment of DAA-1 and Ang-IV on insulin signal transduction in the skeletal muscles of HFD animals 89 3.1.13 3.2.1 ii 3.2.2 Effects of DAA-1 and Ang-IV on basal and insulin-stimulated serine phosphorylation of IR in skeletal muscle of C57BL/ 6J mice fed on HFD 91 3.2.3 Effects of DAA-1 and Ang-IV on basal and insulin-stimulated tyrosine phosphorylation of IR in skeletal muscle of C57BL/6J mice fed on HFD 93 3.2.4 Effects of DAA-1 and Ang-IV on basal and insulin-stimulated serine phosphorylation of IRS-1 in skeletal muscle of C57BL/6J mice fed on HFD 95 3.2.5 Effects of DAA-1 and Ang-IV on basal and insulin-stimulated tyrosine phosphorylation of IRS-1 in skeletal muscle of C57BL/6J mice fed on HFD 97 3.2.6 Effects of DAA-1 and Ang-IV on basal and insulin-stimulated attachment of PI3K to IRS-1 in skeletal muscle of C57BL/6J mice fed on HFD 99 Effects of DAA-1 and Ang-IV on basal and insulin-stimulated phosphorylation of Akt in skeletal muscle of C57BL/6J mice fed on HFD 101 Distribution of GLUT4 protein and enzymatic activity of alkaline phosphodiesterase-1 in membranes of different sucrose gradient fractions 104 Effects of DAA-1 and Ang-IV on insulin-induced GLUT4 translocation in skeletal Muscle of C57BL/6J mice fed on HFD 105 Experimental outline for the study of the effects of chronic treatment of DAA-1 and Ang-IV on oxidative stress and Ang-II signaling induced JNK activation in the skeletal muscle of HFD animals 107 3.2.7 3.2.8 3.2.9 3.3.1 3.3.2 Effects of DAA-1 and Ang-IV on superoxide formation in skeletal muscle of C57BL/6J mice fed on HFD 109 3.3.3 Effects of DAA-1 and Ang-IV on the expression of gp91 NADPH oxidase in skeletal muscle of C57BL/6J mice fed on HFD 110 Effects of DAA-1 and Ang-IV on basal and insulin-stimulated level of phosphorylated JNK in skeletal muscle of C57BL/6J mice fed on HFD 112 Effects of DAA-1 and Ang-IV on the coupling of JAK-2, IRS-1 and PI3K to the angiotensin AT1 receptor in skeletal muscle of C57BL/6J mice fed on HFD 114 Effects of DAA-1 and Ang-IV on basal and insulin-stimulated IRAP-PI3K interaction in skeletal muscle of C57BL/6J mice fed on HFD 116 Effects of AT1 and AT4 receptor blockers on hypoglycaemic actions of DAA-I and Ang-IV in C57BL/6J mice 118 3.6.2 Effect of losartan on the hypoglycemic action of DAA-I in C57BL/6J mice 119 3.7.1 Effects of Ang-IV and its metabolites on blood glucose of C57BL/6J mice 121 3.8.1 Effect of hyperglycaemia condition on the survival of pancreatic beta-TC-6 cells 123 3.8.2 Effect of DAA-1 on the survival of pancreatic beta-TC-6 cells cultured in high glucose concentration 124 3.3.4 3.4.1 3.5.1 3.6.1 iii 3.8.3 3.8.4 Effect of Ang-IV on the survival of pancreatic beta-TC-6 cells cultured in high glucose concentration 125 Effect of losartan on the survival of pancreatic beta-TC-6 cells cultured in high glucose concentration 126 3.8.5 Effect of DAA-1 in the presence of losartan on the survival of pancreatic beta-TC-6 cells cultured in high glucose concentration 127 3.8.6 Effects of DAA-1, Ang-IV and losartan on the survival of pancreatic beta-TC-6 cells cultured in basal medium 128 4.1 Early events of the Ang-II and insulin signalling cross-talk 137 4.2 Putative mechanism of hypoglycaemic action of DAA-1 136 4.3 Putative mechanism of hypoglycaemic action of Ang-IV 141 LIST OF TABLES & !.I30& & & & & !=!30&& & & & & -./0& 1.1 Summary of evidences of Ang-II as mediator in obesity related diseases 33 1.2 Current medications available for glycemic control 39 2.1 Diet composition of normal diet and high-fat high-sucrose diet 44 2.2 List of antibodies 57 3.1.1 Animal characteristics 87 4.1 Summary of various protein expressions in tissues of the test animals 131 & iv 31,+&'(&.##4%21"+1'*,& ACE ACD Akt Ang-I Ang-II Ang-III Ang-IV ANOVA ARB AT1 AT2 AT4 BSA DAA-1 DAG DHE DMEM ELISA FFA GLUT4 GLP GK GPCR h HFD IB IR IRAP IRS-1 IP i.p JAK2 JNK kg MAPK mg MTT !g mM !M NADPH ND Angiotensin converting enzyme Acyl-coenzyme A dehydrogenase Protein kinase B Angiotensin I Angiotensin II Angiotensin III Angiotensin IV One-way analysis of variance Angiotensin receptor blocker 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serine phosphorylation of insulin receptor and IRS-1, which inhibits the insulin signalling 14 IRS-1 plays a pivotal role in insulin signalling In its N-terminus, contains... protein kinase C induces serine phosphorylation of insulin receptor and IRS-1, which inhibits the insulin signalling (Figure 1.2) 13 Figure 1.2 Insulin signalling system in skeletal muscle Insulin... NADPH ND Angiotensin converting enzyme Acyl-coenzyme A dehydrogenase Protein kinase B Angiotensin I Angiotensin II Angiotensin III Angiotensin IV One-way analysis of variance Angiotensin receptor