Targeting Risk Factors for Diabetes in Subjects With Normal Blood Cholesterol Using Omega-3 Fatty Acids

NCT04485871 | Recruiting

• 2 other identifiers: 2020-1035NUT407816
• Study Type: interventional
• Target: 48
• Locations: 1 country
• Sites: 1

Brief Summary

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. 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. 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.

Conditions

Type 2 Diabetes; Inflammation; Insulin Sensitivity/Resistance; Fatty Acids, Omega-3

Keywords

Proprotein Convertase Subtilisin / kexin Type 9 (PCSK9); NLRP3 inflammasome; Eicosapentaenoic acid (EPA); Docosahexaenoic acid (DHA); White adipose tissue; Fat metabolism; ApoB-lipoproteins; LDL receptors (LDLR); Cluster of differentiation 36 (CD36)

Outcome Measures

Primary Outcomes (2)

• Fasting white adipose tissue NLRP3 inflammasome activation

  White adipose tissue medium accumulation of interleukin 1 beta (IL-1β) ex vivo over 4 hours (pg/mg tissue by AlphaLISA)

  Baseline

• Fasting white adipose tissue NLRP3 inflammasome activation

  White adipose tissue medium accumulation of interleukin 1 beta (IL-1β) ex vivo over 4 hours (pg/mg tissue by AlphaLISA)

  At 24 weeks

Secondary Outcomes (22)

• Fasting plasma PCSK9 concentration

  Baseline

• Fasting plasma PCSK9 concentration

  At 24 weeks

• White adipose tissue receptors for apoB-lipoproteins

  Baseline

• White adipose tissue receptors for apoB-lipoproteins

  At 24 weeks

• White adipose tissue inflammation profile

  Baseline

Study Arms (1)

Omega-3 fatty acids

EXPERIMENTAL

3.6 g EPA:DHA / day (2:1)

Dietary Supplement: Omega-3 fatty acids

Interventions

Omega-3 fatty acids DIETARY_SUPPLEMENT

Triple Strength Omega-3 from Webber Naturals; 4 oral softgels (600 mg EPA and 300 mg DHA / softgel)

Also known as: Triple Strength Omega-3 from Webber Naturals

Omega-3 fatty acids

Eligibility Criteria

• Age: 45 Years - 74 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Men and post-menopausal women:
• Having a body mass index (BMI= 25-40 kg/m2)
• Aged between 45 and 74 years
• Having confirmed menopausal status (FSH ≥ 30 U/l)
• Non-smoker
• Sedentary (less than 2 hours of structured physical exercise (ex: sports club) per week)
• Low alcohol consumption: less than 2 alcoholic drinks/day

You may not qualify if:

• Plasma LDL cholesterol \> 3.5 mmol/L (i.e. \> 75th percentile in a Canadian population).
• Elevated risk of cardiovascular disease (≥ 20% of calculated Framingham Risk Score) who would require immediate medical intervention by lipid-lowering agents.
• Prior history of cardiovascular events (like stroke, transient ischemic attack, myocardial infarction, angina, heart failure…)
• Systolic blood pressure \> 140 mmHg or diastolic blood pressure \> 90 mmHg
• Type 1 or 2 diabetes or fasting glucose \> 7.0 mmol/L
• Prior history of cancer within the last 3 years
• Thyroid disease - untreated or unstable
• Anemia - Hb \< 120 g/L
• Renal dysfunction or plasma creatinine \> 100 µmol/L
• Hepatic dysfunction - AST/ALT \> 3 times normal limit
• Blood coagulation problems (i.e. bleeding predisposition)
• Autoimmune and chronic inflammatory disease (i.e. celiac, inflammatory bowel, Graves, multiple sclerosis, psoriasis, rheumatoid arthritis, and lupus).Known history of difficulties accessing a vein
• Claustrophobia
• Sleep apnea
• Seizures

Sponsors & Collaborators

• Institut de Recherches Cliniques de Montreal: lead
• Canadian Institutes of Health Research (CIHR): collaborator

Study Sites (1)

Montreal Clinical Research Institute

Montreal, Quebec, H2W 1R7, Canada

RECRUITING

Related Publications (12)

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

Related Links

• IRCM website for recruitment

MeSH Terms

Conditions

Diabetes Mellitus, Type 2; Inflammation; Insulin Resistance; Hypercholesterolemia, Autosomal Dominant, 3; Hyperlipoproteinemia Type II

Interventions

Fatty Acids, Omega-3

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Hyperinsulinism; Lipid Metabolism, Inborn Errors; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Hyperlipoproteinemias; Hyperlipidemias; Dyslipidemias; Lipid Metabolism Disorders

Intervention Hierarchy (Ancestors)

Dietary Fats, Unsaturated; Dietary Fats; Fats; Lipids; Fatty Acids, Unsaturated; Fatty Acids; Fish Oils; Oils

Study Officials

• May Faraj, PDt, PhD

  Montreal Clinical Research Institute/ University of Montreal

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Justine Fricher, MSc

CONTACT

514-987-5500; justine.fricher@ircm.qc.ca

Rianne Mahiout, BSc

CONTACT

514-987-5500; rianne.mahiout@ircm.qc.ca

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Masking Details: However, subjects will not know into which group they were stratified.
• Purpose: PREVENTION
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Model Details: 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.

Study Record Dates

• First Submitted: July 16, 2020
• First Posted: July 24, 2020
• Study Start: December 19, 2019
• Primary Completion (Estimated): May 31, 2027
• Study Completion (Estimated): May 31, 2027
• Last Updated: March 12, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will not share

Locations

CA (1)