Role of 12-lipoxygenase in Platelet Reactivity and Type 2 Diabetes Mellitus

Study Overview
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Brief Summary
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This study investigates the potential protective effects of fatty acid supplementation through inhibition of platelet activation. fatty acids (omega-3 and omega-6) will be evaluated for protection from agonist-mediated platelet activation in platelets from type 2 diabetics and healthy controls. Post-menopausal women with type 2 diabetes mellitus and healthy post-menopausal women will be treated with omega-3 and omega-6 fatty acid supplements to determine protection from platelet activation and thrombosis in this high risk population.

Detailed Description
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Essential fatty acids such as omega-3 and omega-6 have been shown to play important roles in regulating platelet activation, but the underlying mechanisms have not been fully elucidated as well as their true protection from thrombosis. 12-lipoxygenase oxidized fatty acids are known to play both a pro- and anti-thrombotic effect on platelets depending on the fatty acid. oxidation of arachidonic acid by 12-lipoxygenase resuts in a pro-thrombotic bioactive lipid whereas oxidation of the omega-6 fatty acid DGLA found in plant oil results in formation of a potent anti-thrombotic bioactive lipid. Determining the extent of protection from this and other bioactive lipids produced through oxygenase activity will allow for a better understanding of which fatty acid supplementation may best protect from thrombosis. Essential fatty acids such as omega-3 (DHA/EPA) and omega-6 (DGLA) appear to be protective. However the underlying mechanism for this potential protection is not well understood. Identifying the mechanism by which these supplements protect from platelet activation may identify new approaches to preventing thrombotic events in this high risk population.

Official Title
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Role of 12-lipoxygenase in Platelet Reactivity and Type 2 Diabetes Mellitus

Conditions
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Thrombosis, Type 2 Diabetes Mellitus

Intervention / Treatment
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* Dietary Supplement: Primrose oil
* Dietary Supplement: Fish Oil


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy subjects and T2DM patients Postmenopausal women with T2DM All races and ethnicities T2DM patients taking 1st line diabetic treatment (i.e. Metformin) Exclusion Criteria: Fish and plant oil supplements 2 months prior to enrollment NSAIDS and aspirin 1 week prior to enrollment Cardiovascular event within 6 months prior to enrollment Other anti-platelet treatment including PDE and P2Y12 inhibitors

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Healthy subjects for Omega-6 protection<br>Platelets from healthy donors will be assessed for regulation by Primrose Oil (omega-6 fatty acid). | Dietary Supplement: Primrose oil<br>* T2DM patients and matched controls subjects will be given Primrose oil for 2 months, followed by 2-week washout. Blood will be drawn at the beginning, during, and following treatments and platelet function will be assessed.<br>|
| Experimental: T2DM patients for Omega-6 protection<br>platelets from Type 2 diabetes mellitus (T2DM) patients will be assessed for regulation by Primrose Oil (omega-6 fatty acid). | Dietary Supplement: Primrose oil<br>* T2DM patients and matched controls subjects will be given Primrose oil for 2 months, followed by 2-week washout. Blood will be drawn at the beginning, during, and following treatments and platelet function will be assessed.<br>|
| Active Comparator: Healthy control for Omega-3 protection<br>Platelets from healthy donors will be assessed for regulation by Fish Oil (omega-3 fatty acid). | Dietary Supplement: Fish Oil<br>* T2DM patients and matched controls subjects will be given Fish oil for 2 months, followed by 2-week washout. Blood will be drawn at the beginning, during, and following treatments and platelet function will be assessed.<br>* Other names: DHA/EPA;|
| Active Comparator: T2DM for Omega-3 protection<br>platelets from Type 2 diabetes mellitus (T2DM) patients will be assessed for regulation by Fish Oil (omega-3 fatty acid). | Dietary Supplement: Fish Oil<br>* T2DM patients and matched controls subjects will be given Fish oil for 2 months, followed by 2-week washout. Blood will be drawn at the beginning, during, and following treatments and platelet function will be assessed.<br>* Other names: DHA/EPA;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| platelet reactivity | decreased platelet activity ex vivo translating to protection from clot formation in vivo | through study completion, an average of 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| fatty acid incorporation | measure altered levels of essential fatty acids in blood and platelets following treatment | through study completion, an average of 1 year | 
| Oxylipin production | determine the oxylipin products formed following each intervention | through study completion, an average of 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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platelets, 12-lipoxygenase, fatty acids, DGLA, DHA, EPA, 12-LOX