The Role of Arachidonic Acid Metabolites, From Patients With Metabolic Syndrome

Type 2 Diabetes Mellitus Clinical Trial

Official title:

The Role of Arachidonic Acid Metabolites, in the Lipid Droplets of Macrophages From Patients With Metabolic Syndrome

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02498119
• Other study ID #: RG291-14AFR
• Status: Recruiting
• Phase: N/A
• First received: May 14, 2015
• Last updated: June 20, 2016
• Start date: November 2014
• Est. completion date: September 2016

Study information

• Verified date: June 2016
• Source: University of Malaya
• Contact: Komathi Perumal
• Phone: 6010-2114913
• Email: komathi_thesis[@]yahoo.com
• Is FDA regulated: No
• Health authority: Malaysia: Institutional Review Board
• Study type: Observational [Patient Registry]

Clinical Trial Summary

The purpose of this study is to determine whether an increase in lipid bodies in leukocytes will lead to an increase in eicosanoid production. The 2nd purpose is to determine if there is a significant correlation between lipid body formation and enhanced generation of both Lipoxygenase (LO) and COX derived eicosanoids. The 3rd purpose is, if lipid bodies are involved in arachidonic acid (AA) metabolism, then AA present in these lipid rich structure must be released by phospholipases and the free Arachidonic Acid (AA) must have access to the eicosanoid forming enzyme. The fourth objective is to determine the compartmentalisation of cPLA2 and MAP kinases including ERK1, ERK2, p85 and p38 are involved in AA liberation within lipid bodies.

Description:

Metabolic syndrome is a cluster of biochemical and physiological abnormalities associated with the development of cardiovascular disease and type 2 diabetes mellitus. The current study focused on type 2 Diabetes Mellitus(T2DM). T2DM is a chronic disease in which people have problems regulating their blood sugar. This disorder consists of an array of dysfunctions characterized by hyperglycemia and resulting from the combination of resistance of insulin action, inadequate insulin secretion and excessive or inappropriate glucagon secretion. Insulin resistance results from a complex interplay between nutrient overload, systemic fatty acid excess, inflammation of the adipose tissue, endoplasmic reticulum and oxidative stress.

At the molecular lever, inflammatory cytokines, fatty acid derivatives such as ceramides, diacylglycerols and reactive oxygen species (ROS), activate several serine/threonine kinases, that have emerged as important negative regulators of insulin signaling. Because of their ability to directly oxidize DNA, protein and lipid damage, ROS are believed to play a key role in the metabolic syndrome and the possible development of T2DM. It is possible that ROS and oxidative stress, induced by elevations in glucose and possibly free fatty acid levels play a key role in causing insulin resistance, and beta cell dysfunction by their ability to activate stress sensitive signaling pathways.

Lipids as signaling intermediates encompass a vast range of molecules with distinct function. The characteristics includes, lipid bodies(LB) are sites for the production of inflammatory mediators and LB within inflammatory cells contain arachidonyl lipids which serve as precursors for eicosanoids. In addition, formation of LB within inflammatory macrophages was positively correlated with augmented increase in prostaglandin E2 (PGE2) in changes. LB also could function as a draining compartment to rapidly uptake and re-acetylate free arachidonic acid with the potentially detrimental outcomes for the host cell.

Macrophage from cells with lipid bodies involves complex and multi step mechanisms that depend on different signaling pathways regulating lipid influx, metabolism storage and mobilization. In view of these clues the investigators have reason to believe that organic anion transporters might be resident or upon stimulation trans located to lipid bodies in order to export the newly synthesized lipid mediators into the cytoplasmic space. Once outside the lipid bodies the eicosanoids can exert intracrine functions or be exported to plasma membrane resident transporters to the extracellular space. Free fatty acids have adverse effects on the mitochondrial function including uncoupling of oxidative phosphorylation and the generation of ROS. Beta cell lipotoxicity has an amplifying effect only if mediated by concurrent hyperglycemia. The association of obesity, fatty acids and oxidative stress with insulin action clearly merits further attention with particular focus on the molecular mechanism.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 12
• Est. completion date: September 2016
• Est. primary completion date: January 2016
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 18 Years to 60 Years

Eligibility

Inclusion Criteria:

• age = 18 to = 60

• Patient diagnosed with Type 2 Diabetes Mellitus within 1 year

Exclusion Criteria:

• Patients < 18 years

• Patients with uncontrolled diabetes, heart failure and sepsis

Study Design

Time Perspective: Prospective

Related Conditions & MeSH terms

• Diabetes Mellitus, Type 2
• Metabolic Syndrome X
• Type 2 Diabetes Mellitus

Locations

Country	Name	City	State
Malaysia	University Malaya Medical Center (UMMC)	Petaling Jaya	Kuala Lumpur

Sponsors (1)

Lead Sponsor	Collaborator
University of Malaya

Country where clinical trial is conducted

Malaysia, 

References & Publications (17)

Beller M, Thiel K, Thul PJ, Jäckle H. Lipid droplets: a dynamic organelle moves into focus. FEBS Lett. 2010 Jun 3;584(11):2176-82. doi: 10.1016/j.febslet.2010.03.022. Epub 2010 Mar 18. Review. — View Citation

Blaner WS, O'Byrne SM, Wongsiriroj N, Kluwe J, D'Ambrosio DM, Jiang H, Schwabe RF, Hillman EM, Piantedosi R, Libien J. Hepatic stellate cell lipid droplets: a specialized lipid droplet for retinoid storage. Biochim Biophys Acta. 2009 Jun;1791(6):467-73. doi: 10.1016/j.bbalip.2008.11.001. Epub 2008 Nov 24. Review. — View Citation

Bozza PT, Bakker-Abreu I, Navarro-Xavier RA, Bandeira-Melo C. Lipid body function in eicosanoid synthesis: an update. Prostaglandins Leukot Essent Fatty Acids. 2011 Nov;85(5):205-13. doi: 10.1016/j.plefa.2011.04.020. Epub 2011 May 12. Review. — View Citation

Brasaemle DL. Thematic review series: adipocyte biology. The perilipin family of structural lipid droplet proteins: stabilization of lipid droplets and control of lipolysis. J Lipid Res. 2007 Dec;48(12):2547-59. Epub 2007 Sep 18. Review. — View Citation

Dichlberger A, Schlager S, Lappalainen J, Käkelä R, Hattula K, Butcher SJ, Schneider WJ, Kovanen PT. Lipid body formation during maturation of human mast cells. J Lipid Res. 2011 Dec;52(12):2198-208. doi: 10.1194/jlr.M019737. Epub 2011 Oct 4. — View Citation

Dvorak AM, Dvorak HF, Peters SP, Shulman ES, MacGlashan DW Jr, Pyne K, Harvey VS, Galli SJ, Lichtenstein LM. Lipid bodies: cytoplasmic organelles important to arachidonate metabolism in macrophages and mast cells. J Immunol. 1983 Dec;131(6):2965-76. — View Citation

Dvorak AM, Hammel I, Schulman ES, Peters SP, MacGlashan DW Jr, Schleimer RP, Newball HH, Pyne K, Dvorak HF, Lichtenstein LM, et al. Differences in the behavior of cytoplasmic granules and lipid bodies during human lung mast cell degranulation. J Cell Biol. 1984 Nov;99(5):1678-87. — View Citation

Goodman JM. The gregarious lipid droplet. J Biol Chem. 2008 Oct 17;283(42):28005-9. doi: 10.1074/jbc.R800042200. Epub 2008 Jul 8. Review. — View Citation

Hapala I, Marza E, Ferreira T. Is fat so bad? Modulation of endoplasmic reticulum stress by lipid droplet formation. Biol Cell. 2011 Jun;103(6):271-85. doi: 10.1042/BC20100144. Review. — View Citation

Krahmer N, Farese RV Jr, Walther TC. Balancing the fat: lipid droplets and human disease. EMBO Mol Med. 2013 Jul;5(7):905-15. doi: 10.1002/emmm.201100671. Epub 2013 Jun 6. Review. — View Citation

Melo RC, D'Avila H, Wan HC, Bozza PT, Dvorak AM, Weller PF. Lipid bodies in inflammatory cells: structure, function, and current imaging techniques. J Histochem Cytochem. 2011 May;59(5):540-56. doi: 10.1369/0022155411404073. Epub 2011 Mar 23. Review. — View Citation

Melo RC, Paganoti GF, Dvorak AM, Weller PF. The internal architecture of leukocyte lipid body organelles captured by three-dimensional electron microscopy tomography. PLoS One. 2013;8(3):e59578. doi: 10.1371/journal.pone.0059578. Epub 2013 Mar 26. — View Citation

Silva AR, Pacheco P, Vieira-de-Abreu A, Maya-Monteiro CM, D'Alegria B, Magalhães KG, de Assis EF, Bandeira-Melo C, Castro-Faria-Neto HC, Bozza PT. Lipid bodies in oxidized LDL-induced foam cells are leukotriene-synthesizing organelles: a MCP-1/CCL2 regulated phenomenon. Biochim Biophys Acta. 2009 Nov;1791(11):1066-75. doi: 10.1016/j.bbalip.2009.06.004. Epub 2009 Jun 30. — View Citation

Tauchi-Sato K, Ozeki S, Houjou T, Taguchi R, Fujimoto T. The surface of lipid droplets is a phospholipid monolayer with a unique Fatty Acid composition. J Biol Chem. 2002 Nov 15;277(46):44507-12. Epub 2002 Sep 6. — View Citation

Triggiani M, Oriente A, Marone G. Differential roles for triglyceride and phospholipid pools of arachidonic acid in human lung macrophages. J Immunol. 1994 Feb 1;152(3):1394-403. — View Citation

Triggiani M, Oriente A, Seeds MC, Bass DA, Marone G, Chilton FH. Migration of human inflammatory cells into the lung results in the remodeling of arachidonic acid into a triglyceride pool. J Exp Med. 1995 Nov 1;182(5):1181-90. — View Citation

Yu W, Bozza PT, Tzizik DM, Gray JP, Cassara J, Dvorak AM, Weller PF. Co-compartmentalization of MAP kinases and cytosolic phospholipase A2 at cytoplasmic arachidonate-rich lipid bodies. Am J Pathol. 1998 Mar;152(3):759-69. — View Citation

* Note: There are 17 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Composite measure of patient physical observations to include weight, height and BMI		six months only (1 time only)	No
Secondary	Reduction of pro - inflammatory cytokines		one year	No
Secondary	The effect of eicosanoids in diabetic complication		One year	No
Secondary	The effect of LTB4 and LTC4 of eicosanoids		One year	No

External Links

•   a dynamic organelle moves into focus
•   Balancing the fat: lipid droplets and human disease
•   Co-compartmentalization of MAP kinases and cytosolic phospholipase A2 at cytoplasmic arachidonate-rich lipid bodies
•   Differences in the behavior of cytoplasmic granules and lipid bodies during human lung mast cell degranulation
•   Differential roles for triglyceride and phospholipid pools of arachidonic acid in human lung macrophages
•   Hepatic stellate cell lipid droplets: a specialized lipid droplet for retinoid storage
•   Is fat so bad? Modulation of endoplasmic reticulum stress by lipid droplet formation
•   Lipid bodies in oxidized LDL-induced foam cells are leukotriene-synthesizing organelles: a monocyte chemotactic protein 1/ chemokine ligand 2 (MCP-1/CCL2) regulated phenomenon
•   Lipid bodies inflammatory cells: structure, function, and current imaging techniques
•   Lipid bodies: cytoplasmic organelles important to arachidonate metabolism in macrophages and mast cells
•   Lipid body formation during maturation of human mast cells
•   Lipid body function in eicosanoids synthesis : An update
•   Migration of human inflammatory cells into the lung results in the remodeling of arachidonic acid into a triglyceride pool
•   The gregarious lipid droplet
•   The internal architecture of leukocyte lipid body organelles captured by three-dimensional electron microscopy tomography
•   The perilipin family of structural lipid droplet proteins: stabilization of lipid droplets and control of lipolysis
•   The surface of lipid droplets is a phospholipid monolayer with a unique Fatty Acid composition