<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT04485871</url>
  </required_header>
  <id_info>
    <org_study_id>2020-1035</org_study_id>
    <secondary_id>NUT407816</secondary_id>
    <nct_id>NCT04485871</nct_id>
  </id_info>
  <brief_title>Targeting Risk Factors for Diabetes in Subjects With Normal Blood Cholesterol Using Omega-3 Fatty Acids</brief_title>
  <official_title>White Adipose Tissue LDL Receptors and Omega-3 as Modulators of the Risk for Type 2 Diabetes in Subjects With Normal Plasma LDL Cholesterol</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Institut de Recherches Cliniques de Montreal</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Canadian Institutes of Health Research (CIHR)</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Institut de Recherches Cliniques de Montreal</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Every 3 minutes a new case of diabetes is diagnosed in Canada, mostly type 2 diabetes (T2D)&#xD;
      increasing the risk for heart disease. T2D and heart disease share many common risk factors&#xD;
      such as aging, obesity and unhealthy lifestyle.&#xD;
&#xD;
      Paradoxically however, while lowering blood LDL, commonly known as &quot;bad cholesterol&quot;, is&#xD;
      protective against heart disease, research over the past 10 years have shown that the lower&#xD;
      is blood LDL, the higher is the chance of developing T2D. This phenomena is happening whether&#xD;
      blood LDL is lowered by a common drug against heart disease called Statins, or by being born&#xD;
      with certain variations in genes, some of which are very common (~80% of people have them).&#xD;
&#xD;
      To date, it is unclear why lowering blood LDL is associated with higher risk for diabetes,&#xD;
      and whether this can be treated naturally with certain nutrients.&#xD;
&#xD;
      Investigators believe that lowering blood LDL by forcing LDL entry into the body tissue&#xD;
      through their receptors promotes T2D. This is because investigators have shown that LDL entry&#xD;
      into human fat tissue induces fat tissue dysfunction, which would promote T2D especially in&#xD;
      subjects with excess weight.&#xD;
&#xD;
      On the other hand, investigators have shown that omega-3 fatty acids (omega-3) can directly&#xD;
      treat the same defects induced by LDL entry into fat tissue. Omega-3 is a unique type of fat&#xD;
      that is found mostly in fish oil.&#xD;
&#xD;
      Thus the objectives of this clinical trial to be conducted in 48 subjects with normal blood&#xD;
      LDL are to explore if:&#xD;
&#xD;
        1. Subjects with higher LDL receptors and LDL entry into fat tissue have higher risk&#xD;
           factors for T2D compared to subjects with lower LDL receptors and LDL entry into fat&#xD;
           tissue&#xD;
&#xD;
        2. 6-month supplementation of omega-3 from fish oil can treat subjects with higher LDL&#xD;
           receptors and LDL entry into fat tissue reducing their risk for T2D.&#xD;
&#xD;
      This study will thus explore and attempt to treat a new risk factor for T2D using an&#xD;
      inexpensive and widely accessible nutraceutical, which would aid in preventing T2D in humans.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Type 2 (T2D) and cardiovascular disease (CVD) share many risk factors, whose accumulation&#xD;
      over years lead to disease onset. However, while lowering plasma low-density lipoprotein&#xD;
      cholesterol (LDLC) is cardio-protective, novel evidence over the past 10 years established a&#xD;
      role for common LDLC-lowering variants and widely used hypocholesterolemic Statins in higher&#xD;
      risk for T2D. This diminishes the cardio-protective role of low plasma LDLC. As these&#xD;
      conditions decrease plasma LDLC by increasing tissue-uptake of LDL, a role for LDL receptor&#xD;
      (LDLR) pathway was proposed. However underlying mechanisms fueling higher risk for T2D with&#xD;
      upregulated LDLR pathway, and nutritional approaches to treat them are unclear.&#xD;
&#xD;
      The central hypothesis examined in this trial is that upregulating receptor-mediated uptake&#xD;
      of LDL on white adipose tissue provokes the activation of an innate immunity pathway (the&#xD;
      Nucleotide-binding domain and Leucine-rich repeat Receptor, containing a Pyrin domain 3&#xD;
      (NLRP3) inflammasome) leading to the accumulation of risk factors for T2D in subjects with&#xD;
      normal plasma LDLC. This can be treated by 6-month supplementation of omega-3 fatty acids&#xD;
      (omega-3).&#xD;
&#xD;
      To examine this hypothesis in vivo, ex vivo and in vitro, a clinical trial in conjunction&#xD;
      with mechanistic basic research studies have been initiated at the Montreal Clinical Research&#xD;
      Institute (IRCM). Forty eight volunteers will be recruited through advertisements in&#xD;
      French/English newspapers and online (e.g. Google, Facebook) and placed on a 6-month&#xD;
      supplementation of 3.6 g omega-3 per day. Participants will be stratified into 2 groups&#xD;
      (N=24/group) with higher and lower white adipose tissue surface-expression LDL receptors&#xD;
      (LDLR and CD36) using median plasma PCSK9 (Proprotein Convertase Subtilisin/Kexin type 9) per&#xD;
      sex. Plasma PSCK9 will be used as investigators have shown that it is negatively associated&#xD;
      with white adipose tissue surface-expression of LDLR and CD36.&#xD;
&#xD;
      The duration of this study is about 8 months (33 weeks) divided into 5 parts:&#xD;
&#xD;
      A. Screening and evaluation of eligibility for the study&#xD;
&#xD;
      B. Weight stabilisation (+/- 2 kg change over 4 weeks) and confirmation of eligibility after&#xD;
      a medical examination by IRCM physician collaborators.&#xD;
&#xD;
      C. Baseline testing over 2 days (1- 4 weeks apart) to assess participants risk factors for&#xD;
      T2D: white adipose tissue NLRP3 inflammasome activity, white adipose tissue physiology and&#xD;
      function (ex vivo after a subcutaneous needle biopsy), systemic inflammation, dietary fat&#xD;
      clearance (after a high fat meal), and insulin secretion and sensitivity (by gold-standard&#xD;
      Botnia clamp technique). Participants will also be phenotyped for body composition (by dual&#xD;
      energy x-ray absorptiometry), resting energy expenditure (by indirect calorimetry), dietary&#xD;
      intake (by 3-day dietary journals) and physical activity level (by a questionnaire).&#xD;
&#xD;
      D. 24-week intervention with omega-3 fatty acid supplementation (3.6 g eicosapentaenoic acid&#xD;
      (EPA) and docosahexaenoic (DHA), 2:1)&#xD;
&#xD;
      E. Post intervention testing starting over 2 days (1- 4 weeks apart) to assess risk factors&#xD;
      for T2D that were measured at baseline.&#xD;
&#xD;
      Investigators hypothesize that subjects with low plasma PCSK9 (i.e. with higher white adipose&#xD;
      tissue LDLR and CD36) will have higher risk factors for T2D at baseline and that the omega-3&#xD;
      intervention will eliminate group-differences in these risk factors.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">December 19, 2019</start_date>
  <completion_date type="Anticipated">October 31, 2025</completion_date>
  <primary_completion_date type="Anticipated">March 31, 2024</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <intervention_model_description>Subjects (N=48) will be recruited with the same inclusion/exclusion criteria and will received the same omega-3 intervention. After completion of recruitment, subjects will be stratified into 2 groups (24/group) based on a baseline plasma PCSK9 for group characterisation and comparison.</intervention_model_description>
    <primary_purpose>Prevention</primary_purpose>
    <masking>None (Open Label)</masking>
    <masking_description>However, subjects will not know into which group they were stratified.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Fasting white adipose tissue NLRP3 inflammasome activation</measure>
    <time_frame>Baseline</time_frame>
    <description>White adipose tissue medium accumulation of interleukin 1 beta (IL-1β) ex vivo over 4 hours (pg/mg tissue by AlphaLISA)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Fasting white adipose tissue NLRP3 inflammasome activation</measure>
    <time_frame>At 24 weeks</time_frame>
    <description>White adipose tissue medium accumulation of interleukin 1 beta (IL-1β) ex vivo over 4 hours (pg/mg tissue by AlphaLISA)</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Fasting plasma PCSK9 concentration</measure>
    <time_frame>Baseline</time_frame>
    <description>Plasma PCSK9 (g/L by ElISA kit)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Fasting plasma PCSK9 concentration</measure>
    <time_frame>At 24 weeks</time_frame>
    <description>Plasma PCSK9 (g/L by ElISA kit)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>White adipose tissue receptors for apoB-lipoproteins</measure>
    <time_frame>Baseline</time_frame>
    <description>Fasting and 4 hour-postprandial change in white adipose tissue surface-expression LDLR and CD36 (% of control by immunohistochemistry in white adipose tissue slides)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>White adipose tissue receptors for apoB-lipoproteins</measure>
    <time_frame>At 24 weeks</time_frame>
    <description>Fasting and 4 hour-postprandial change in white adipose tissue surface-expression LDLR and CD36 (% of control by immunohistochemistry in white adipose tissue slides)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>White adipose tissue inflammation profile</measure>
    <time_frame>Baseline</time_frame>
    <description>Fasting and 4 hour-postprandial change in NLRP3 inflammasome related inflammatory parameters; including gene expression of IL1B, NLRP3 and ADGRE1 (by RT-PCR) and secretion of IL-1β and IL-1Ra (per mg tissue by AlphaLISA)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>White adipose tissue inflammation profile</measure>
    <time_frame>At 24 weeks</time_frame>
    <description>Fasting and 4 hour-postprandial change in NLRP3 inflammasome related inflammatory parameters; including gene expression of IL1B, NLRP3 and ADGRE1 (by RT-PCR) and secretion of IL-1β and IL-1Ra (per mg tissue by AlphaLISA)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>White adipose tissue function ex vivo</measure>
    <time_frame>Baseline</time_frame>
    <description>Fasting and 4 hour postprandial change in situ lipoprotein lipase activity (nmol 3H-triglyceride/mg tissue)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>White adipose tissue function ex vivo</measure>
    <time_frame>At 24 weeks</time_frame>
    <description>Fasting and 4 hour postprandial change in situ lipoprotein lipase activity (nmol 3H-triglyceride/mg tissue)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Postprandial fat metabolism</measure>
    <time_frame>Baseline</time_frame>
    <description>Area under the 6 hour time curve of plasma triglycerides (mmol/hour) after a high-fat meal (66% fat)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Postprandial fat metabolism</measure>
    <time_frame>At 24 week</time_frame>
    <description>Area under the 6 hour time curve of plasma triglycerides (mmol/hour) after a high-fat meal (66% fat)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Systemic inflammation</measure>
    <time_frame>Baseline</time_frame>
    <description>Fasting and 4 hour postprandial change in plasma inflammatory parameters including IL-1Ra and IL-1β (pg/mL by AlphaLISA)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Systemic inflammation</measure>
    <time_frame>At 24 weeks</time_frame>
    <description>Fasting and 4 hour postprandial change in plasma inflammatory parameters including IL-1Ra and IL-1β (pg/mLby AlphaLISA)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Disposition index</measure>
    <time_frame>Baseline</time_frame>
    <description>Calculated as glucose-induced insulin secretion (uU/mL/min) multiplied by insulin sensitivity (glucose infusion rate mg/kg/min) measured by Botnia clamp</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Disposition index</measure>
    <time_frame>At 24 weeks</time_frame>
    <description>Calculated as glucose-induced insulin secretion (uU/mL/min) multiplied by insulin sensitivity (glucose infusion rate mg/kg/min) measured by Botnia clamp</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Fatty acid profile in red blood cell phospholipid fraction</measure>
    <time_frame>Baseline</time_frame>
    <description>(As μmol/L by gas chromatography mass spectrometry)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Fatty acid profile in red blood cell phospholipid fraction</measure>
    <time_frame>At 24 weeks</time_frame>
    <description>(As μmol/L by gas chromatography mass spectrometry)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Body composition</measure>
    <time_frame>Baseline</time_frame>
    <description>Fat and lean body mass (as kg by dual energy x-ray absorptiometry)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Body composition</measure>
    <time_frame>At 24 weeks</time_frame>
    <description>Fat and lean body mass (as kg by dual energy x-ray absorptiometry)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Resting energy expenditure</measure>
    <time_frame>Baseline</time_frame>
    <description>(As kcal/hour by indirect calorimetry)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Resting energy expenditure</measure>
    <time_frame>At 24 weeks</time_frame>
    <description>(As kcal/day by indirect calorimetry)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Energy intake</measure>
    <time_frame>Baseline</time_frame>
    <description>(Average of 3 day energy intake as kcal/day collected by 3-day dietary records)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Energy intake</measure>
    <time_frame>At 24 weeks</time_frame>
    <description>(Average of 3 day energy intake as kcal/day collected by 3-day dietary records)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Physical activity</measure>
    <time_frame>Baseline</time_frame>
    <description>(using Godin Leisure Time Exercise Questionnaire)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Physical activity</measure>
    <time_frame>At 24 weeks</time_frame>
    <description>(using Godin Leisure Time Exercise Questionnaire)</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">48</enrollment>
  <condition>Type 2 Diabetes</condition>
  <condition>Inflammation</condition>
  <condition>Insulin Sensitivity/Resistance</condition>
  <condition>Fatty Acids, Omega-3</condition>
  <arm_group>
    <arm_group_label>Omega-3 fatty acids</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>3.6 g EPA:DHA / day (2:1)</description>
  </arm_group>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Omega-3 fatty acids</intervention_name>
    <description>Tripple Strength Omega-3 from Webber Naturals; 4 oral softgels (600 mg EPA and 300 mg DHA / softgel)</description>
    <arm_group_label>Omega-3 fatty acids</arm_group_label>
    <other_name>Tripple Strength Omega-3 from Webber Naturals</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        Men and post-menopausal women:&#xD;
&#xD;
          -  Having a body mass index (BMI= 25-40 kg/m2)&#xD;
&#xD;
          -  Aged between 45 and 74 years&#xD;
&#xD;
          -  Having confirmed menopausal status (FSH ≥ 30 U/l)&#xD;
&#xD;
          -  Non-smoker&#xD;
&#xD;
          -  Sedentary (less than 2 hours of structured physical exercise (ex: sports club) per&#xD;
             week)&#xD;
&#xD;
          -  Low alcohol consumption: less than 2 alcoholic drinks/day&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Plasma LDL cholesterol &gt; 3.5 mmol/L (i.e. &gt; 75th percentile in a Canadian population).&#xD;
&#xD;
          -  Elevated risk of cardiovascular disease (≥ 20% of calculated Framingham Risk Score)&#xD;
             who would require immediate medical intervention by lipid-lowering agents.&#xD;
&#xD;
          -  Prior history of cardiovascular events (like stroke, transient ischemic attack,&#xD;
             myocardial infarction, angina, heart failure…)&#xD;
&#xD;
          -  Systolic blood pressure &gt; 140 mmHg or diastolic blood pressure &gt; 90 mmHg&#xD;
&#xD;
          -  Type 1 or 2 diabetes or fasting glucose &gt; 7.0 mmol/L&#xD;
&#xD;
          -  Prior history of cancer within the last 3 years&#xD;
&#xD;
          -  Thyroid disease - untreated or unstable&#xD;
&#xD;
          -  Anemia - Hb &lt; 120 g/L&#xD;
&#xD;
          -  Renal dysfunction or plasma creatinine &gt; 100 µmol/L&#xD;
&#xD;
          -  Hepatic dysfunction - AST/ALT &gt; 3 times normal limit&#xD;
&#xD;
          -  Blood coagulation problems (i.e. bleeding predisposition)&#xD;
&#xD;
          -  Autoimmune and chronic inflammatory disease (i.e. celiac, inflammatory bowel, Graves,&#xD;
             multiple sclerosis, psoriasis, rheumatoid arthritis, and lupus).Known history of&#xD;
             difficulties accessing a vein&#xD;
&#xD;
          -  Claustrophobia&#xD;
&#xD;
          -  Sleep apnea&#xD;
&#xD;
          -  Seizures&#xD;
&#xD;
          -  Concomitant medications: Hormone replacement therapy (except thyroid hormone at a&#xD;
             stable dose), systemic corticosteroids, anti-psychotic medications and psycho-active&#xD;
             medication, anticoagulant or anti-aggregates treatment (Aspirin, NSAIDs, warfarin,&#xD;
             coumadin..), adrenergic agonist, anti-hypertensive drugs, weight-loss medication,&#xD;
             lipid lowering medication&#xD;
&#xD;
          -  Known substance abuse&#xD;
&#xD;
          -  Already taking more than 250 mg of omega-3 supplements (EPA/DHA) per day&#xD;
&#xD;
          -  Allergy to seafood or fish&#xD;
&#xD;
          -  Allergy to Xylocaine&#xD;
&#xD;
          -  Unable to eat the components of the high fat meal (croissant, cheese, bacon, brownies)&#xD;
&#xD;
          -  None compliance to the study requirements (i.e. not being fasting) or cancellation of&#xD;
             the same scheduled testing visit more than once.&#xD;
&#xD;
          -  Lack of time to participate in the full length of the study (33 weeks)&#xD;
&#xD;
          -  Have exceeded the annual total allowed radiation dose (like X-ray scans and/or&#xD;
             tomography in the previous year or in the year to come) according to the physician's&#xD;
             judgement.&#xD;
&#xD;
          -  All other medical or psychological conditions deemed inappropriate according to the&#xD;
             physician&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>45 Years</minimum_age>
    <maximum_age>74 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>May Faraj, PDt, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Montreal Clinical Research Institute/ University of Montreal</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Melanie Burnette, MSc</last_name>
    <phone>514-987-5500</phone>
    <phone_ext>3260</phone_ext>
    <email>melanie.burnette@ircm.qc.ca</email>
  </overall_contact>
  <location>
    <facility>
      <name>Montreal Clinical Research Institute</name>
      <address>
        <city>Montréal</city>
        <state>Quebec</state>
        <zip>H2W 1R7</zip>
        <country>Canada</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Melanie Burnette, MSc</last_name>
      <phone>514-987-5500</phone>
      <phone_ext>3260</phone_ext>
      <email>melanie.burnette@ircm.qc.ca</email>
    </contact>
    <contact_backup>
      <last_name>May Faraj, PDt, PhD</last_name>
      <phone>514-987-5655</phone>
      <email>may.faraj@ircm.qc.ca</email>
    </contact_backup>
    <investigator>
      <last_name>May Faraj, PDt, PhD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>Canada</country>
  </location_countries>
  <link>
    <url>https://ircm.qc.ca/en/clinic/participate-in-a-clinical-study/study-aiming-reducing-risk-diabetes</url>
    <description>IRCM website for recruitment</description>
  </link>
  <reference>
    <citation>Bissonnette S, Salem H, Wassef H, Saint-Pierre N, Tardif A, Baass A, Dufour R, Faraj M. Low density lipoprotein delays clearance of triglyceride-rich lipoprotein by human subcutaneous adipose tissue. J Lipid Res. 2013 May;54(5):1466-76. doi: 10.1194/jlr.P023176. Epub 2013 Feb 17.</citation>
    <PMID>23417739</PMID>
  </reference>
  <reference>
    <citation>Wassef H, Bissonnette S, Saint-Pierre N, Lamantia V, Cyr Y, Chretien M, Faraj M. The apoB-to-PCSK9 ratio: A new index for metabolic risk in humans. J Clin Lipidol. 2015 Sep-Oct;9(5):664-75. doi: 10.1016/j.jacl.2015.06.012. Epub 2015 Jul 2.</citation>
    <PMID>26350813</PMID>
  </reference>
  <reference>
    <citation>Lamantia V, Bissonnette S, Wassef H, Cyr Y, Baass A, Dufour R, Rabasa-Lhoret R, Faraj M. ApoB-lipoproteins and dysfunctional white adipose tissue: Relation to risk factors for type 2 diabetes in humans. J Clin Lipidol. 2017 Jan-Feb;11(1):34-45.e2. doi: 10.1016/j.jacl.2016.09.013. Epub 2016 Oct 3.</citation>
    <PMID>28391908</PMID>
  </reference>
  <reference>
    <citation>Skeldon AM, Faraj M, Saleh M. Caspases and inflammasomes in metabolic inflammation. Immunol Cell Biol. 2014 Apr;92(4):304-13. doi: 10.1038/icb.2014.5. Epub 2014 Feb 11.</citation>
    <PMID>24518981</PMID>
  </reference>
  <reference>
    <citation>Sattar N, Preiss D, Murray HM, Welsh P, Buckley BM, de Craen AJ, Seshasai SR, McMurray JJ, Freeman DJ, Jukema JW, Macfarlane PW, Packard CJ, Stott DJ, Westendorp RG, Shepherd J, Davis BR, Pressel SL, Marchioli R, Marfisi RM, Maggioni AP, Tavazzi L, Tognoni G, Kjekshus J, Pedersen TR, Cook TJ, Gotto AM, Clearfield MB, Downs JR, Nakamura H, Ohashi Y, Mizuno K, Ray KK, Ford I. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet. 2010 Feb 27;375(9716):735-42. doi: 10.1016/S0140-6736(09)61965-6. Epub 2010 Feb 16.</citation>
    <PMID>20167359</PMID>
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    <citation>Ridker PM, Pradhan A, MacFadyen JG, Libby P, Glynn RJ. Cardiovascular benefits and diabetes risks of statin therapy in primary prevention: an analysis from the JUPITER trial. Lancet. 2012 Aug 11;380(9841):565-71. doi: 10.1016/S0140-6736(12)61190-8.</citation>
    <PMID>22883507</PMID>
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  <reference>
    <citation>Lotta LA, Sharp SJ, Burgess S, Perry JRB, Stewart ID, Willems SM, Luan J, Ardanaz E, Arriola L, Balkau B, Boeing H, Deloukas P, Forouhi NG, Franks PW, Grioni S, Kaaks R, Key TJ, Navarro C, Nilsson PM, Overvad K, Palli D, Panico S, Quiros JR, Riboli E, Rolandsson O, Sacerdote C, Salamanca EC, Slimani N, Spijkerman AM, Tjonneland A, Tumino R, van der A DL, van der Schouw YT, McCarthy MI, Barroso I, O'Rahilly S, Savage DB, Sattar N, Langenberg C, Scott RA, Wareham NJ. Association Between Low-Density Lipoprotein Cholesterol-Lowering Genetic Variants and Risk of Type 2 Diabetes: A Meta-analysis. JAMA. 2016 Oct 4;316(13):1383-1391. doi: 10.1001/jama.2016.14568.</citation>
    <PMID>27701660</PMID>
  </reference>
  <reference>
    <citation>Schmidt AF, Swerdlow DI, Holmes MV, Patel RS, Fairhurst-Hunter Z, Lyall DM, Hartwig FP, Horta BL, Hypponen E, Power C, Moldovan M, van Iperen E, Hovingh GK, Demuth I, Norman K, Steinhagen-Thiessen E, Demuth J, Bertram L, Liu T, Coassin S, Willeit J, Kiechl S, Willeit K, Mason D, Wright J, Morris R, Wanamethee G, Whincup P, Ben-Shlomo Y, McLachlan S, Price JF, Kivimaki M, Welch C, Sanchez-Galvez A, Marques-Vidal P, Nicolaides A, Panayiotou AG, Onland-Moret NC, van der Schouw YT, Matullo G, Fiorito G, Guarrera S, Sacerdote C, Wareham NJ, Langenberg C, Scott R, Luan J, Bobak M, Malyutina S, Pajak A, Kubinova R, Tamosiunas A, Pikhart H, Husemoen LL, Grarup N, Pedersen O, Hansen T, Linneberg A, Simonsen KS, Cooper J, Humphries SE, Brilliant M, Kitchner T, Hakonarson H, Carrell DS, McCarty CA, Kirchner HL, Larson EB, Crosslin DR, de Andrade M, Roden DM, Denny JC, Carty C, Hancock S, Attia J, Holliday E, O'Donnell M, Yusuf S, Chong M, Pare G, van der Harst P, Said MA, Eppinga RN, Verweij N, Snieder H; LifeLines Cohort study group; Christen T, Mook-Kanamori DO, Gustafsson S, Lind L, Ingelsson E, Pazoki R, Franco O, Hofman A, Uitterlinden A, Dehghan A, Teumer A, Baumeister S, Dorr M, Lerch MM, Volker U, Volzke H, Ward J, Pell JP, Smith DJ, Meade T, Maitland-van der Zee AH, Baranova EV, Young R, Ford I, Campbell A, Padmanabhan S, Bots ML, Grobbee DE, Froguel P, Thuillier D, Balkau B, Bonnefond A, Cariou B, Smart M, Bao Y, Kumari M, Mahajan A, Ridker PM, Chasman DI, Reiner AP, Lange LA, Ritchie MD, Asselbergs FW, Casas JP, Keating BJ, Preiss D, Hingorani AD; UCLEB consortium; Sattar N. PCSK9 genetic variants and risk of type 2 diabetes: a mendelian randomisation study. Lancet Diabetes Endocrinol. 2017 Feb;5(2):97-105. doi: 10.1016/S2213-8587(16)30396-5. Epub 2016 Nov 29.</citation>
    <PMID>27908689</PMID>
  </reference>
  <reference>
    <citation>Ference BA, Robinson JG, Brook RD, Catapano AL, Chapman MJ, Neff DR, Voros S, Giugliano RP, Davey Smith G, Fazio S, Sabatine MS. Variation in PCSK9 and HMGCR and Risk of Cardiovascular Disease and Diabetes. N Engl J Med. 2016 Dec 1;375(22):2144-2153. doi: 10.1056/NEJMoa1604304.</citation>
    <PMID>27959767</PMID>
  </reference>
  <reference>
    <citation>Faraj M. LDL, LDL receptors, and PCSK9 as modulators of the risk for type 2 diabetes: a focus on white adipose tissue. J Biomed Res. 2020 Mar 12;34(4):251-259. doi: 10.7555/JBR.34.20190124.</citation>
    <PMID>32701068</PMID>
  </reference>
  <reference>
    <citation>Cyr Y, Bissonnette S, Lamantia V, Wassef H, Loizon E, Ngo Sock ET, Vidal H, Mayer G, Chretien M, Faraj M. White Adipose Tissue Surface Expression of LDLR and CD36 is Associated with Risk Factors for Type 2 Diabetes in Adults with Obesity. Obesity (Silver Spring). 2020 Dec;28(12):2357-2367. doi: 10.1002/oby.22985. Epub 2020 Oct 11.</citation>
    <PMID>33043593</PMID>
  </reference>
  <reference>
    <citation>Cyr Y, Lamantia V, Bissonnette S, Burnette M, Besse-Patin A, Demers A, Wabitsch M, Chretien M, Mayer G, Estall JL, Saleh M, Faraj M. Lower plasma PCSK9 in normocholesterolemic subjects is associated with upregulated adipose tissue surface-expression of LDLR and CD36 and NLRP3 inflammasome. Physiol Rep. 2021 Feb;9(3):e14721. doi: 10.14814/phy2.14721.</citation>
    <PMID>33527668</PMID>
  </reference>
  <verification_date>March 2023</verification_date>
  <study_first_submitted>July 16, 2020</study_first_submitted>
  <study_first_submitted_qc>July 21, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 24, 2020</study_first_posted>
  <last_update_submitted>March 21, 2023</last_update_submitted>
  <last_update_submitted_qc>March 21, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">March 23, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Institut de Recherches Cliniques de Montreal</investigator_affiliation>
    <investigator_full_name>May Faraj, PDt, PhD</investigator_full_name>
    <investigator_title>Professor</investigator_title>
  </responsible_party>
  <keyword>Proprotein Convertase Subtilisin / kexin Type 9 (PCSK9)</keyword>
  <keyword>NLRP3 inflammasome</keyword>
  <keyword>Eicosapentaenoic acid (EPA)</keyword>
  <keyword>Docosahexaenoic acid (DHA)</keyword>
  <keyword>White adipose tissue</keyword>
  <keyword>Fat metabolism</keyword>
  <keyword>ApoB-lipoproteins</keyword>
  <keyword>LDL receptors (LDLR)</keyword>
  <keyword>Cluster of differentiation 36 (CD36)</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Diabetes Mellitus</mesh_term>
    <mesh_term>Diabetes Mellitus, Type 2</mesh_term>
    <mesh_term>Insulin Resistance</mesh_term>
    <mesh_term>Inflammation</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
    <ipd_description>Frozen plasma and white adipose tissue samples (when sufficient) can be made available for analysis by other investigators. However data statistical analyses incorporating complete IPD must be conducted by the research team of Dr May Faraj as per subject consent form.</ipd_description>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04485871
org study id: 2020-1035
secondary id: NUT407816
nct id: NCT04485871
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Every 3 minutes a new case of diabetes is diagnosed in Canada, mostly type 2 diabetes (T2D)
      increasing the risk for heart disease. T2D and heart disease share many common risk factors
      such as aging, obesity and unhealthy lifestyle.

      Paradoxically however, while lowering blood LDL, commonly known as "bad cholesterol", is
      protective against heart disease, research over the past 10 years have shown that the lower
      is blood LDL, the higher is the chance of developing T2D. This phenomena is happening whether
      blood LDL is lowered by a common drug against heart disease called Statins, or by being born
      with certain variations in genes, some of which are very common (~80% of people have them).

      To date, it is unclear why lowering blood LDL is associated with higher risk for diabetes,
      and whether this can be treated naturally with certain nutrients.

      Investigators believe that lowering blood LDL by forcing LDL entry into the body tissue
      through their receptors promotes T2D. This is because investigators have shown that LDL entry
      into human fat tissue induces fat tissue dysfunction, which would promote T2D especially in
      subjects with excess weight.

      On the other hand, investigators have shown that omega-3 fatty acids (omega-3) can directly
      treat the same defects induced by LDL entry into fat tissue. Omega-3 is a unique type of fat
      that is found mostly in fish oil.

      Thus the objectives of this clinical trial to be conducted in 48 subjects with normal blood
      LDL are to explore if:

        1. Subjects with higher LDL receptors and LDL entry into fat tissue have higher risk
           factors for T2D compared to subjects with lower LDL receptors and LDL entry into fat
           tissue

        2. 6-month supplementation of omega-3 from fish oil can treat subjects with higher LDL
           receptors and LDL entry into fat tissue reducing their risk for T2D.

      This study will thus explore and attempt to treat a new risk factor for T2D using an
      inexpensive and widely accessible nutraceutical, which would aid in preventing T2D in humans.
Type 2 (T2D) and cardiovascular disease (CVD) share many risk factors, whose accumulation
      over years lead to disease onset. However, while lowering plasma low-density lipoprotein
      cholesterol (LDLC) is cardio-protective, novel evidence over the past 10 years established a
      role for common LDLC-lowering variants and widely used hypocholesterolemic Statins in higher
      risk for T2D. This diminishes the cardio-protective role of low plasma LDLC. As these
      conditions decrease plasma LDLC by increasing tissue-uptake of LDL, a role for LDL receptor
      (LDLR) pathway was proposed. However underlying mechanisms fueling higher risk for T2D with
      upregulated LDLR pathway, and nutritional approaches to treat them are unclear.

      The central hypothesis examined in this trial is that upregulating receptor-mediated uptake
      of LDL on white adipose tissue provokes the activation of an innate immunity pathway (the
      Nucleotide-binding domain and Leucine-rich repeat Receptor, containing a Pyrin domain 3
      (NLRP3) inflammasome) leading to the accumulation of risk factors for T2D in subjects with
      normal plasma LDLC. This can be treated by 6-month supplementation of omega-3 fatty acids
      (omega-3).

      To examine this hypothesis in vivo, ex vivo and in vitro, a clinical trial in conjunction
      with mechanistic basic research studies have been initiated at the Montreal Clinical Research
      Institute (IRCM). Forty eight volunteers will be recruited through advertisements in
      French/English newspapers and online (e.g. Google, Facebook) and placed on a 6-month
      supplementation of 3.6 g omega-3 per day. Participants will be stratified into 2 groups
      (N=24/group) with higher and lower white adipose tissue surface-expression LDL receptors
      (LDLR and CD36) using median plasma PCSK9 (Proprotein Convertase Subtilisin/Kexin type 9) per
      sex. Plasma PSCK9 will be used as investigators have shown that it is negatively associated
      with white adipose tissue surface-expression of LDLR and CD36.

      The duration of this study is about 8 months (33 weeks) divided into 5 parts:

      A. Screening and evaluation of eligibility for the study

      B. Weight stabilisation (+/- 2 kg change over 4 weeks) and confirmation of eligibility after
      a medical examination by IRCM physician collaborators.

      C. Baseline testing over 2 days (1- 4 weeks apart) to assess participants risk factors for
      T2D: white adipose tissue NLRP3 inflammasome activity, white adipose tissue physiology and
      function (ex vivo after a subcutaneous needle biopsy), systemic inflammation, dietary fat
      clearance (after a high fat meal), and insulin secretion and sensitivity (by gold-standard
      Botnia clamp technique). Participants will also be phenotyped for body composition (by dual
      energy x-ray absorptiometry), resting energy expenditure (by indirect calorimetry), dietary
      intake (by 3-day dietary journals) and physical activity level (by a questionnaire).

      D. 24-week intervention with omega-3 fatty acid supplementation (3.6 g eicosapentaenoic acid
      (EPA) and docosahexaenoic (DHA), 2:1)

      E. Post intervention testing starting over 2 days (1- 4 weeks apart) to assess risk factors
      for T2D that were measured at baseline.

      Investigators hypothesize that subjects with low plasma PCSK9 (i.e. with higher white adipose
      tissue LDLR and CD36) will have higher risk factors for T2D at baseline and that the omega-3
      intervention will eliminate group-differences in these risk factors.
allocation: N/A
intervention model: Single Group Assignment
intervention model description: Subjects (N=48) will be recruited with the same inclusion/exclusion criteria and will received the same omega-3 intervention. After completion of recruitment, subjects will be stratified into 2 groups (24/group) based on a baseline plasma PCSK9 for group characterisation and comparison.
primary purpose: Prevention
masking: None (Open Label)
masking description: However, subjects will not know into which group they were stratified.
measure: Fasting white adipose tissue NLRP3 inflammasome activation
time frame: Baseline
description: White adipose tissue medium accumulation of interleukin 1 beta (IL-1β) ex vivo over 4 hours (pg/mg tissue by AlphaLISA)
measure: Fasting white adipose tissue NLRP3 inflammasome activation
time frame: At 24 weeks
description: White adipose tissue medium accumulation of interleukin 1 beta (IL-1β) ex vivo over 4 hours (pg/mg tissue by AlphaLISA)
measure: Fasting plasma PCSK9 concentration
time frame: Baseline
description: Plasma PCSK9 (g/L by ElISA kit)
measure: Fasting plasma PCSK9 concentration
time frame: At 24 weeks
description: Plasma PCSK9 (g/L by ElISA kit)
measure: White adipose tissue receptors for apoB-lipoproteins
time frame: Baseline
description: Fasting and 4 hour-postprandial change in white adipose tissue surface-expression LDLR and CD36 (% of control by immunohistochemistry in white adipose tissue slides)
measure: White adipose tissue receptors for apoB-lipoproteins
time frame: At 24 weeks
description: Fasting and 4 hour-postprandial change in white adipose tissue surface-expression LDLR and CD36 (% of control by immunohistochemistry in white adipose tissue slides)
measure: White adipose tissue inflammation profile
time frame: Baseline
description: Fasting and 4 hour-postprandial change in NLRP3 inflammasome related inflammatory parameters; including gene expression of IL1B, NLRP3 and ADGRE1 (by RT-PCR) and secretion of IL-1β and IL-1Ra (per mg tissue by AlphaLISA)
measure: White adipose tissue inflammation profile
time frame: At 24 weeks
description: Fasting and 4 hour-postprandial change in NLRP3 inflammasome related inflammatory parameters; including gene expression of IL1B, NLRP3 and ADGRE1 (by RT-PCR) and secretion of IL-1β and IL-1Ra (per mg tissue by AlphaLISA)
measure: White adipose tissue function ex vivo
time frame: Baseline
description: Fasting and 4 hour postprandial change in situ lipoprotein lipase activity (nmol 3H-triglyceride/mg tissue)
measure: White adipose tissue function ex vivo
time frame: At 24 weeks
description: Fasting and 4 hour postprandial change in situ lipoprotein lipase activity (nmol 3H-triglyceride/mg tissue)
measure: Postprandial fat metabolism
time frame: Baseline
description: Area under the 6 hour time curve of plasma triglycerides (mmol/hour) after a high-fat meal (66% fat)
measure: Postprandial fat metabolism
time frame: At 24 week
description: Area under the 6 hour time curve of plasma triglycerides (mmol/hour) after a high-fat meal (66% fat)
measure: Systemic inflammation
time frame: Baseline
description: Fasting and 4 hour postprandial change in plasma inflammatory parameters including IL-1Ra and IL-1β (pg/mL by AlphaLISA)
measure: Systemic inflammation
time frame: At 24 weeks
description: Fasting and 4 hour postprandial change in plasma inflammatory parameters including IL-1Ra and IL-1β (pg/mLby AlphaLISA)
measure: Disposition index
time frame: Baseline
description: Calculated as glucose-induced insulin secretion (uU/mL/min) multiplied by insulin sensitivity (glucose infusion rate mg/kg/min) measured by Botnia clamp
measure: Disposition index
time frame: At 24 weeks
description: Calculated as glucose-induced insulin secretion (uU/mL/min) multiplied by insulin sensitivity (glucose infusion rate mg/kg/min) measured by Botnia clamp
measure: Fatty acid profile in red blood cell phospholipid fraction
time frame: Baseline
description: (As μmol/L by gas chromatography mass spectrometry)
measure: Fatty acid profile in red blood cell phospholipid fraction
time frame: At 24 weeks
description: (As μmol/L by gas chromatography mass spectrometry)
measure: Body composition
time frame: Baseline
description: Fat and lean body mass (as kg by dual energy x-ray absorptiometry)
measure: Body composition
time frame: At 24 weeks
description: Fat and lean body mass (as kg by dual energy x-ray absorptiometry)
measure: Resting energy expenditure
time frame: Baseline
description: (As kcal/hour by indirect calorimetry)
measure: Resting energy expenditure
time frame: At 24 weeks
description: (As kcal/day by indirect calorimetry)
measure: Energy intake
time frame: Baseline
description: (Average of 3 day energy intake as kcal/day collected by 3-day dietary records)
measure: Energy intake
time frame: At 24 weeks
description: (Average of 3 day energy intake as kcal/day collected by 3-day dietary records)
measure: Physical activity
time frame: Baseline
description: (using Godin Leisure Time Exercise Questionnaire)
measure: Physical activity
time frame: At 24 weeks
description: (using Godin Leisure Time Exercise Questionnaire)
arm group label: Omega-3 fatty acids
arm group type: Experimental
description: 3.6 g EPA:DHA / day (2:1)
intervention type: Dietary Supplement
intervention name: Omega-3 fatty acids
description: Tripple Strength Omega-3 from Webber Naturals; 4 oral softgels (600 mg EPA and 300 mg DHA / softgel)
arm group label: Omega-3 fatty acids
other name: Tripple Strength Omega-3 from Webber Naturals
criteria: 
gender: All
minimum age: 45 Years
maximum age: 74 Years
healthy volunteers: Accepts Healthy Volunteers
last name: May Faraj, PDt, PhD
role: Principal Investigator
affiliation: Montreal Clinical Research Institute/ University of Montreal
last name: Melanie Burnette, MSc
phone: 514-987-5500
phone ext: 3260
email: melanie.burnette@ircm.qc.ca
facility: 
status: Recruiting
contact: 
contact backup: 
investigator: 
country: Canada
url: https://ircm.qc.ca/en/clinic/participate-in-a-clinical-study/study-aiming-reducing-risk-diabetes
description: IRCM website for recruitment
citation: Bissonnette S, Salem H, Wassef H, Saint-Pierre N, Tardif A, Baass A, Dufour R, Faraj M. Low density lipoprotein delays clearance of triglyceride-rich lipoprotein by human subcutaneous adipose tissue. J Lipid Res. 2013 May;54(5):1466-76. doi: 10.1194/jlr.P023176. Epub 2013 Feb 17.
PMID: 23417739
citation: Wassef H, Bissonnette S, Saint-Pierre N, Lamantia V, Cyr Y, Chretien M, Faraj M. The apoB-to-PCSK9 ratio: A new index for metabolic risk in humans. J Clin Lipidol. 2015 Sep-Oct;9(5):664-75. doi: 10.1016/j.jacl.2015.06.012. Epub 2015 Jul 2.
PMID: 26350813
citation: Lamantia V, Bissonnette S, Wassef H, Cyr Y, Baass A, Dufour R, Rabasa-Lhoret R, Faraj M. ApoB-lipoproteins and dysfunctional white adipose tissue: Relation to risk factors for type 2 diabetes in humans. J Clin Lipidol. 2017 Jan-Feb;11(1):34-45.e2. doi: 10.1016/j.jacl.2016.09.013. Epub 2016 Oct 3.
PMID: 28391908
citation: Skeldon AM, Faraj M, Saleh M. Caspases and inflammasomes in metabolic inflammation. Immunol Cell Biol. 2014 Apr;92(4):304-13. doi: 10.1038/icb.2014.5. Epub 2014 Feb 11.
PMID: 24518981
citation: Sattar N, Preiss D, Murray HM, Welsh P, Buckley BM, de Craen AJ, Seshasai SR, McMurray JJ, Freeman DJ, Jukema JW, Macfarlane PW, Packard CJ, Stott DJ, Westendorp RG, Shepherd J, Davis BR, Pressel SL, Marchioli R, Marfisi RM, Maggioni AP, Tavazzi L, Tognoni G, Kjekshus J, Pedersen TR, Cook TJ, Gotto AM, Clearfield MB, Downs JR, Nakamura H, Ohashi Y, Mizuno K, Ray KK, Ford I. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet. 2010 Feb 27;375(9716):735-42. doi: 10.1016/S0140-6736(09)61965-6. Epub 2010 Feb 16.
PMID: 20167359
citation: Ridker PM, Pradhan A, MacFadyen JG, Libby P, Glynn RJ. Cardiovascular benefits and diabetes risks of statin therapy in primary prevention: an analysis from the JUPITER trial. Lancet. 2012 Aug 11;380(9841):565-71. doi: 10.1016/S0140-6736(12)61190-8.
PMID: 22883507
citation: Lotta LA, Sharp SJ, Burgess S, Perry JRB, Stewart ID, Willems SM, Luan J, Ardanaz E, Arriola L, Balkau B, Boeing H, Deloukas P, Forouhi NG, Franks PW, Grioni S, Kaaks R, Key TJ, Navarro C, Nilsson PM, Overvad K, Palli D, Panico S, Quiros JR, Riboli E, Rolandsson O, Sacerdote C, Salamanca EC, Slimani N, Spijkerman AM, Tjonneland A, Tumino R, van der A DL, van der Schouw YT, McCarthy MI, Barroso I, O'Rahilly S, Savage DB, Sattar N, Langenberg C, Scott RA, Wareham NJ. Association Between Low-Density Lipoprotein Cholesterol-Lowering Genetic Variants and Risk of Type 2 Diabetes: A Meta-analysis. JAMA. 2016 Oct 4;316(13):1383-1391. doi: 10.1001/jama.2016.14568.
PMID: 27701660
citation: Schmidt AF, Swerdlow DI, Holmes MV, Patel RS, Fairhurst-Hunter Z, Lyall DM, Hartwig FP, Horta BL, Hypponen E, Power C, Moldovan M, van Iperen E, Hovingh GK, Demuth I, Norman K, Steinhagen-Thiessen E, Demuth J, Bertram L, Liu T, Coassin S, Willeit J, Kiechl S, Willeit K, Mason D, Wright J, Morris R, Wanamethee G, Whincup P, Ben-Shlomo Y, McLachlan S, Price JF, Kivimaki M, Welch C, Sanchez-Galvez A, Marques-Vidal P, Nicolaides A, Panayiotou AG, Onland-Moret NC, van der Schouw YT, Matullo G, Fiorito G, Guarrera S, Sacerdote C, Wareham NJ, Langenberg C, Scott R, Luan J, Bobak M, Malyutina S, Pajak A, Kubinova R, Tamosiunas A, Pikhart H, Husemoen LL, Grarup N, Pedersen O, Hansen T, Linneberg A, Simonsen KS, Cooper J, Humphries SE, Brilliant M, Kitchner T, Hakonarson H, Carrell DS, McCarty CA, Kirchner HL, Larson EB, Crosslin DR, de Andrade M, Roden DM, Denny JC, Carty C, Hancock S, Attia J, Holliday E, O'Donnell M, Yusuf S, Chong M, Pare G, van der Harst P, Said MA, Eppinga RN, Verweij N, Snieder H; LifeLines Cohort study group; Christen T, Mook-Kanamori DO, Gustafsson S, Lind L, Ingelsson E, Pazoki R, Franco O, Hofman A, Uitterlinden A, Dehghan A, Teumer A, Baumeister S, Dorr M, Lerch MM, Volker U, Volzke H, Ward J, Pell JP, Smith DJ, Meade T, Maitland-van der Zee AH, Baranova EV, Young R, Ford I, Campbell A, Padmanabhan S, Bots ML, Grobbee DE, Froguel P, Thuillier D, Balkau B, Bonnefond A, Cariou B, Smart M, Bao Y, Kumari M, Mahajan A, Ridker PM, Chasman DI, Reiner AP, Lange LA, Ritchie MD, Asselbergs FW, Casas JP, Keating BJ, Preiss D, Hingorani AD; UCLEB consortium; Sattar N. PCSK9 genetic variants and risk of type 2 diabetes: a mendelian randomisation study. Lancet Diabetes Endocrinol. 2017 Feb;5(2):97-105. doi: 10.1016/S2213-8587(16)30396-5. Epub 2016 Nov 29.
PMID: 27908689
citation: Ference BA, Robinson JG, Brook RD, Catapano AL, Chapman MJ, Neff DR, Voros S, Giugliano RP, Davey Smith G, Fazio S, Sabatine MS. Variation in PCSK9 and HMGCR and Risk of Cardiovascular Disease and Diabetes. N Engl J Med. 2016 Dec 1;375(22):2144-2153. doi: 10.1056/NEJMoa1604304.
PMID: 27959767
citation: Faraj M. LDL, LDL receptors, and PCSK9 as modulators of the risk for type 2 diabetes: a focus on white adipose tissue. J Biomed Res. 2020 Mar 12;34(4):251-259. doi: 10.7555/JBR.34.20190124.
PMID: 32701068
citation: Cyr Y, Bissonnette S, Lamantia V, Wassef H, Loizon E, Ngo Sock ET, Vidal H, Mayer G, Chretien M, Faraj M. White Adipose Tissue Surface Expression of LDLR and CD36 is Associated with Risk Factors for Type 2 Diabetes in Adults with Obesity. Obesity (Silver Spring). 2020 Dec;28(12):2357-2367. doi: 10.1002/oby.22985. Epub 2020 Oct 11.
PMID: 33043593
citation: Cyr Y, Lamantia V, Bissonnette S, Burnette M, Besse-Patin A, Demers A, Wabitsch M, Chretien M, Mayer G, Estall JL, Saleh M, Faraj M. Lower plasma PCSK9 in normocholesterolemic subjects is associated with upregulated adipose tissue surface-expression of LDLR and CD36 and NLRP3 inflammasome. Physiol Rep. 2021 Feb;9(3):e14721. doi: 10.14814/phy2.14721.
PMID: 33527668
responsible party type: Principal Investigator
investigator affiliation: Institut de Recherches Cliniques de Montreal
investigator full name: May Faraj, PDt, PhD
investigator title: Professor
mesh term: Diabetes Mellitus
mesh term: Diabetes Mellitus, Type 2
mesh term: Insulin Resistance
mesh term: Inflammation
sharing ipd: No
ipd description: Frozen plasma and white adipose tissue samples (when sufficient) can be made available for analysis by other investigators. However data statistical analyses incorporating complete IPD must be conducted by the research team of Dr May Faraj as per subject consent form.