• Titin Andri Wihastuti Department of Biomedicine, Brawijaya University, Malang, Indonesia.
  • Dinda Zahra Putri Andiyani Department of Biomedicine, Brawijaya University, Malang, Indonesia
  • Sri Andarini Department of Biomedicine, Brawijaya University, Malang, Indonesia
  • Teuku Heriansyah Department of Cardiology and Vascular Medicine, Syiah Kuala University, Banda Aceh, Indonesia


Objective: Lipoprotein-associated phospholipase A2 (Lp-PLA2) is an enzyme with several pro-inflammatory properties that involved in pathogenesis of atherosclerosis, but some investigation shows controversial views regarding its biological role. We examined the effect of selective inhibitor of Lp-PLA2 (darapladib) to the inflammation marker, intima-media thickness (IMT), and insulin resistance (IR) of type 2 diabetes mellitus (T2DM) rat model. This study aimed to measure lysophosphatidylcholine (lyso-PC) in serum and aortic tissue, nuclear factor kappa B (NF-κB) expression, IMT, and IR with darapladib treatment in a T2DM rat model.

Methods: 30 Sprague-Dawley rats were randomly divided into normal group, T2DM group and T2DM with darapladib treatment. Induction of T2DM was done by giving high-fat diet and low dose injection of streptozotocin. Blood glucose level and insulin plasma concentration were measured to calculate IR. 8 weeks and 16 weeks after treatment, we compared lyso-PC level, NF-κB expression, and IMT.

Results: Darapladib significantly decreased lyso-PC level, NF-κB expression, and IMT at two serial treatments. Darapladib treatment group exhibited significant reduction of IR (0.64±0.11 vs. 2.07±0.16, at 8 weeks; and 0.93±0.08 vs. 6.48±0.55 at 16 weeks) compared with T2DM group.

Conclusions: These data suggested that Lp-PLA2 played a role in inflammation process, atherosclerosis, and IR occurring in metabolic disorder.

Keywords: Type 2 Diabetes Mellitus, Inflammation, Insulin Resistance, Atherosclerosis Lipoprotein-associated phospholipase A2


1. Ozougwu JC, Obimba KC, Belonwu CD, Unakalamba CB. The pathogenesis and pathophysiology of Type 1 and Type 2 diabetes mellitus. J Physiol Pathophysiol 2013;4(4):46-57.
2. Niskanen L, Turpeinen A, Penttilä I, Uusitupa MI. Hyperglycemia and compositional lipoprotein abnormalities as predictors of cardiovascular mortality in Type 2 diabetes: A 15-year follow-up from the time of diagnosis. Diabetes Care 1998;21(11):1861-9.
3. Kim TN, Kim S, Yang SJ, Yoo HJ, Seo JA, Kim SG, et al. Vascular inflammation in patients with impaired glucose tolerance and Type 2 diabetes: Analysis with 18F-fluorodeoxyglucose positron emission tomography. Circ Cardiovasc Imaging 2010;39(2):142-8.
4. Patel S, Santani D. Role of NF-kappa B in the pathogenesis of diabetes and its associated complications. Pharmacol Rep 2009;61(4):595-603.
5. Hameed I, Masoodi SR, Mir SA, Nabi M, Ghazanfar K, Ganai BA. Type 2 diabetes mellitus: From a metabolic disorder to an inflammatory condition. World J Diabetes 2015;6(4):598-612.
6. Stafforini DM, Zimmerman GA. Unraveling the PAF-AH/Lp-PLA2 controversy. J Lipid Res 2014;55(9):1811-4.
7. Hassan M. Stability and SOLID-TIMI 52: Lipoprotein associated phopholipase A2 (Lp-PLA2) as a biomarker or risk factor for cardiovascular disease. Glob Cardiol Sci Pract 2015;2015:6.
8. van Dijk TH, Laskewitz AJ, Grefhorst A, Boer TS, Bloks VW, Kuipers F, et al. A novel approach to monitor glucose metabolism using stable isotopically labelled glucose in longitudinal studies in mice. Lab Anim 2013;47(2):79-88.
9. Takatera A, Takeuchi A, Saiki K, Morioka I. Blood lysophosphatidylcholine (LPC) levels and characteristic molecular species in neonates: Prolonged low blood LPC levels in very low birth weight infants. Pediatr Res 2007;62:477-82.
10. Ziegler D. Type 2 diabetes as an inflammatory cardiovascular disorder. Curr Mol Med 2005;5(3):309-22.
11. Mazzone T, Chait A, Plutzky J. Cardiovascular disease risk in Type 2 diabetes mellitus: Insights from mechanistic studies. Lancet 2008;371(9629):1800-9.
12. Subhapriya S, Tomi L, Padmanaban VC. Atherosclerosis: Critical role of oxidation and inflammation. Int J Pharm Pharm Sci 2013;5:6-8.
13. Skovsø S. Modeling Type 2 diabetes in rats using high fat diet and streptozotocin. J Diabetes Investig 2014;5(4):349-58.
14. Shaw JE, Sicree RA, Zimmet PZ. Global estimates of the prevalence of diabetes for 2010 and 2030. Diabetes Res Clin Pract 2010;87(1):4-14.
15. Reaven G. Insulin resistance, Type 2 diabetes mellitus, and cardiovascular disease: The end of the beginning. Circulation 2005;112(20):3030-2.
16. Zhang M, Lv XY, Li J, Xu ZG, Chen L. The characterization of high-fat diet and multiple low-dose streptozotocin induced Type 2 diabetes rat model. Exp Diabetes Res 2008;2008:704045.
17. Muwarni S, Ali M, Muliartha K. Diet aterogenik pada tikus putih (Rattus novergicus strain Wistar) sebagai model hewan aterosklerosis. J Kedokteran Brawijaya 2006;22:6-9.
18. Rohman MS, Lukitasari M, Nugroho DA, Nashi W, Nugraheini NI, Sardjono TW. Development of an experiment model of metabolic syndrome in Sprague dawley rat. Res J Life Sci 2017;4:76-86.
19. Nelson TL, Biggs ML, Kizer JR, Cushman M, Hokanson JE, Furberg CD, et al. Lipoprotein-associated phospholipase A2 (Lp-PLA2) and future risk of Type 2 diabetes: Results from the Cardiovascular Health Study. J Clin Endocrinol Metab 2012;97(5):1695-701.
20. Hajra L, Evans AI, Chen M, Hyduk SJ, Collins T, Cybulsky MI. The NF-κB signal transduction pathway in aortic endothelial cells is primed for activation in regions predisposed to athersclerotic lesion formation. Proc Natl Acad Sci 2000;97(16):9052-7.
21. Navale AM, Paranjape AN, Role of inflammation in development of diabetic complications and commonly used inflammatory markers with respect to diabetic complications. Int J Pharm Pharm Sci 2013;5:1-5.
22. Patel S, Santani D. Role of NF-kappa B in the pathogenesis of diabetes and its associated complications. Pharmacol Rep 2009;61(4):595-603.
23. Indira M, Abhilash PA. Role of NF-κappa B (NF-κB) in diabetes. For Immunopathol Dis Therap J 2013 4(2):111-32.
24. Tilstra JS, Clauson CL, Niedernhofer LJ, Robbins PD. NF-?B in Aging and Disease. Aging Dis 2011;2(6):449-65.
25. Wihastuti TA, Heriansyah T, Soraya M, Wijayanti MD, Firani NK, Iskandar A et al. Inhibition of oxidative stress in hypercholesterolemic rats by soy milk. J Cardiovasc Disease Res 2016;7(2):74-82.
26. Wihastuti TA, Sargowo D, Tjokroprawiro A, Permatasari N, Widodo MA, Soeharto S. Vasa vasorum anti-angiogenesis through H2O2, HIF-1a, NF-kB and iNOS inhibition by mangosteen pericarp ethanolic extract (Garcinia mangostana Linn) in hypercholesterol-diet-given Rattus norvegicus Wistar strain. Vasc Health Risk Manag 2014;10:523-31.
27. Heriansyah T, Adam AA, Wihastuti TA, Rohman MS. Elaborate evaluation of serum and tissue oxidized LDL level with darapladib therapy: A feasible diagnostic marker for early atherogenesis. Asian Pac J Trop Biomed 2016. DOI: 10.1016/j.apjtb.2016.11.014.
28. Tabit CE, Chung WB, Hamburg NM, Vita JA. Endothelial dysfunction in diabetes mellitus: Molecular mechanisms and clinical implications. Rev Endocr Metab Disord 2010;11(1):61-74.
29. Zhu HA. Lp-PLA2, a novel potential biomarker predicting cardiovascular disease in Type 2 diabetes mellitus. Med Clin Rev 2016;2(2):20.
30. Han X, Wang T, Zhang J, Liu X, Li Z, Wang G. Apolipoprotein CIII regulates lipoprotein-associated phospholipase A2 expression via the MAPK and NFkB pathways. Biol Open 2015;4:661-5.
31. Esser N, Paquot N, Scheen AJ. Anti-inflammatory agents to treat or prevent Type 2 diabetes, metabolic syndrome and cardiovascular disease. Expert Opin Investig Drugs 2015;24(3):283-307.
172 Views | 288 Downloads
How to Cite
Wihastuti, T. A., D. Z. P. Andiyani, S. Andarini, and T. Heriansyah. “DECREASEMENT OF LYSOPHOSPHATIDYLCHOLINE LEVEL, NF-KB EXPRESSION, INTIMA MEDIA THICKNESS AND IMPROVEMENT OF INSULIN RESISTANCE BY DARAPLADIB TREATMENT: IN VIVO STUDIES OF TYPE 2 DIABETES MELLITUS SPRAGUE-DAWLEY RAT MODEL”. Asian Journal of Pharmaceutical and Clinical Research, Vol. 10, no. 12, Dec. 2017, pp. 362-5, doi:10.22159/ajpcr.2017.v10i12.19022.
Original Article(s)