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

March 21, 2023 updated by: May Faraj, PDt, PhD, Institut de Recherches Cliniques de Montreal

White Adipose Tissue LDL Receptors and Omega-3 as Modulators of the Risk for Type 2 Diabetes in Subjects With Normal Plasma LDL Cholesterol

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

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.

Study Type

Interventional

Enrollment (Anticipated)

48

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • Canada
    • Quebec
      • Montréal, Quebec, Canada, H2W 1R7
        • Recruiting
        • Montreal Clinical Research Institute
        • Contact:
        • Contact:
        • Principal Investigator:
          • May Faraj, PDt, PhD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

45 years to 74 years (Adult, Older Adult)

Accepts Healthy Volunteers

Yes

Genders Eligible for Study

All

Description

Inclusion Criteria:

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

Exclusion Criteria:

  • 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
  • Concomitant medications: Hormone replacement therapy (except thyroid hormone at a stable dose), systemic corticosteroids, anti-psychotic medications and psycho-active medication, anticoagulant or anti-aggregates treatment (Aspirin, NSAIDs, warfarin, coumadin..), adrenergic agonist, anti-hypertensive drugs, weight-loss medication, lipid lowering medication
  • Known substance abuse
  • Already taking more than 250 mg of omega-3 supplements (EPA/DHA) per day
  • Allergy to seafood or fish
  • Allergy to Xylocaine
  • Unable to eat the components of the high fat meal (croissant, cheese, bacon, brownies)
  • None compliance to the study requirements (i.e. not being fasting) or cancellation of the same scheduled testing visit more than once.
  • Lack of time to participate in the full length of the study (33 weeks)
  • Have exceeded the annual total allowed radiation dose (like X-ray scans and/or tomography in the previous year or in the year to come) according to the physician's judgement.
  • All other medical or psychological conditions deemed inappropriate according to the physician

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Prevention
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Omega-3 fatty acids
3.6 g EPA:DHA / day (2:1)
Dietary supplement: Omega-3 fatty acids
Tripple Strength Omega-3 from Webber Naturals; 4 oral softgels (600 mg EPA and 300 mg DHA / softgel)
Other Names:
  • Tripple Strength Omega-3 from Webber Naturals

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Fasting white adipose tissue NLRP3 inflammasome activation
Time Frame: Baseline
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
Time Frame: At 24 weeks
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 Outcome Measures

Outcome Measure
Measure Description
Time Frame
Fasting plasma PCSK9 concentration
Time Frame: Baseline
Plasma PCSK9 (g/L by ElISA kit)
Baseline
Fasting plasma PCSK9 concentration
Time Frame: At 24 weeks
Plasma PCSK9 (g/L by ElISA kit)
At 24 weeks
White adipose tissue receptors for apoB-lipoproteins
Time Frame: Baseline
Fasting and 4 hour-postprandial change in white adipose tissue surface-expression LDLR and CD36 (% of control by immunohistochemistry in white adipose tissue slides)
Baseline
White adipose tissue receptors for apoB-lipoproteins
Time Frame: At 24 weeks
Fasting and 4 hour-postprandial change in white adipose tissue surface-expression LDLR and CD36 (% of control by immunohistochemistry in white adipose tissue slides)
At 24 weeks
White adipose tissue inflammation profile
Time Frame: Baseline
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)
Baseline
White adipose tissue inflammation profile
Time Frame: At 24 weeks
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)
At 24 weeks
White adipose tissue function ex vivo
Time Frame: Baseline
Fasting and 4 hour postprandial change in situ lipoprotein lipase activity (nmol 3H-triglyceride/mg tissue)
Baseline
White adipose tissue function ex vivo
Time Frame: At 24 weeks
Fasting and 4 hour postprandial change in situ lipoprotein lipase activity (nmol 3H-triglyceride/mg tissue)
At 24 weeks
Postprandial fat metabolism
Time Frame: Baseline
Area under the 6 hour time curve of plasma triglycerides (mmol/hour) after a high-fat meal (66% fat)
Baseline
Postprandial fat metabolism
Time Frame: At 24 week
Area under the 6 hour time curve of plasma triglycerides (mmol/hour) after a high-fat meal (66% fat)
At 24 week
Systemic inflammation
Time Frame: Baseline
Fasting and 4 hour postprandial change in plasma inflammatory parameters including IL-1Ra and IL-1β (pg/mL by AlphaLISA)
Baseline
Systemic inflammation
Time Frame: At 24 weeks
Fasting and 4 hour postprandial change in plasma inflammatory parameters including IL-1Ra and IL-1β (pg/mLby AlphaLISA)
At 24 weeks
Disposition index
Time Frame: Baseline
Calculated as glucose-induced insulin secretion (uU/mL/min) multiplied by insulin sensitivity (glucose infusion rate mg/kg/min) measured by Botnia clamp
Baseline
Disposition index
Time Frame: At 24 weeks
Calculated as glucose-induced insulin secretion (uU/mL/min) multiplied by insulin sensitivity (glucose infusion rate mg/kg/min) measured by Botnia clamp
At 24 weeks
Fatty acid profile in red blood cell phospholipid fraction
Time Frame: Baseline
(As μmol/L by gas chromatography mass spectrometry)
Baseline
Fatty acid profile in red blood cell phospholipid fraction
Time Frame: At 24 weeks
(As μmol/L by gas chromatography mass spectrometry)
At 24 weeks
Body composition
Time Frame: Baseline
Fat and lean body mass (as kg by dual energy x-ray absorptiometry)
Baseline
Body composition
Time Frame: At 24 weeks
Fat and lean body mass (as kg by dual energy x-ray absorptiometry)
At 24 weeks
Resting energy expenditure
Time Frame: Baseline
(As kcal/hour by indirect calorimetry)
Baseline
Resting energy expenditure
Time Frame: At 24 weeks
(As kcal/day by indirect calorimetry)
At 24 weeks
Energy intake
Time Frame: Baseline
(Average of 3 day energy intake as kcal/day collected by 3-day dietary records)
Baseline
Energy intake
Time Frame: At 24 weeks
(Average of 3 day energy intake as kcal/day collected by 3-day dietary records)
At 24 weeks
Physical activity
Time Frame: Baseline
(using Godin Leisure Time Exercise Questionnaire)
Baseline
Physical activity
Time Frame: At 24 weeks
(using Godin Leisure Time Exercise Questionnaire)
At 24 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Institut de Recherches Cliniques de Montreal

Collaborators

Canadian Institutes of Health Research (CIHR)

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

December 19, 2019

Primary Completion (Anticipated)

March 31, 2024

Study Completion (Anticipated)

October 31, 2025

Study Registration Dates

First Submitted

July 16, 2020

First Submitted That Met QC Criteria

July 21, 2020

First Posted (Actual)

July 24, 2020

Study Record Updates

Last Update Posted (Actual)

March 23, 2023

Last Update Submitted That Met QC Criteria

March 21, 2023

Last Verified

March 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2020-1035
  • NUT407816 (Other Grant/Funding Number: Canadian Institutes of Health Research (CIHR))

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

IPD Plan 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.

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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