Omega-3 to Reduce Diabetes Risk in Subjects With High Number of Particles That Carry "Bad Cholesterol" in the Blood
Condition: Type 2 Diabetes; Insulin Sensitivity/Resistance; Inflammatory Response; Fatty Acids, Omega-3
MeSH terms: Insulin Resistance; Hypersensitivity
Study type: Interventional

Summary: 
      In this project, investigators explored the role of the particles that carry "bad
      cholesterol" in the blood (termed LDL) that are known to promote heart disease, in the
      promotion of type 2 diabetes (T2D) in humans. In specific, they investigated how these
      particles may induce the activation of an immune pathway in human fat tissue leading to
      multiple anomalies that favors T2D. They also explored whether omega-3 fatty acids, which are
      the type of fat found in fish oils can counterbalance the negative effects of LDL in fat
      tissue, thus providing a natural way to help reduce the risk for T2D in subjects with
      elevated blood LDL.

      To do so, 41 subjects who were free of disease or medication affecting metabolism were
      enrolled at the Montreal Clinical Research Institute between 2013 and 2019 and were placed on
      an intervention with omega-3 fatty acids supplementation for 12 weeks (2.7 g/day, Triple
      Strength Omega-3 from Webbers Naturals). Investigators examined the effects of LDL and
      omega-3 on risk factors for T2D before and after the intervention in the whole body and
      specifically in fat tissue biopsies taken from the hip region. Eighty percent of the subjects
      who were enrolled into the study completed the intervention.
    

Detailed description: 
      Diabetes-attributed deaths, mostly type 2 diabetes (T2D), total more than 40,000 per year,
      out of which 80% are secondary to cardiovascular disease and stroke. Research from the
      investigators' lab and others suggests that elevated atherogenic apoB-lipoproteins, mostly
      low-density lipoproteins (LDL) may not be a mere consequence of T2D but also a cause. They
      reported that high numbers of apoB-lipoproteins (apoB) induce subcutaneous white adipose
      tissue (WAT) dysfunction and predict several risk factors for T2D in humans. However,
      mechanisms underlying LDL-induced abnormalities and nutritional approaches to target them
      remain unexplored.

      Strong evidence implicates a specific innate immunity system, the NLRP3 inflammasome/
      interleukin 1 beta (IL-1β) pathway in WAT dysfunction and associated T2D risk factors in mice
      and humans (NLRP3 for Nucleotide-binding domain and Leucine-rich repeat Receptor, containing
      a Pyrin domain 3). Preliminary evidence from the investigator's lab and their collaborator
      (Dr Maya Saleh, at McGill University) indicated that native apoB-lipoproteins activate the
      NLRP3 inflammasome leading to IL-1β secretion in murine bone marrow derived macrophages. On
      the other hand, fish-oil derived omega-3 fatty acids, eicosapentaenoic and docosahexaenoic
      acids (EPA and DHA), were reported to inhibit the NLRP3 inflammasome/ IL-1β pathway in immune
      cells.

      Thus, the central hypothesis of this trial was that apoB-lipoproteins act as metabolic
      danger-associated molecular patterns that activate the NLRP3 inflammasome in WAT leading to
      WAT dysfunction and associated risks for T2D in humans. This can be treated by EPA and DHA
      supplementation.

      The specific hypotheses examined in 2 parts of this trial, at baseline and post-intervention,
      were:

      Part A: At baseline (mechanisms):

      Primary hypothesis:

        1. Compared to subjects with low plasma apoB, subjects with high plasma apoB have higher
           WAT NLRP3 inflammasome activity indicated by higher WAT IL-1β secretion.

           Secondary hypotheses:

        2. WAT IL-1β secretion is associated with risk factors for T2D (WAT dysfunction, systemic
           inflammation, postprandial hypertriglyceridemia, insulin resistance and
           hyperinsulinemia).

        3. Ex vivo, subjects' native LDL prime and/or activate the NLRP3 inflammasome in subjects'
           own WAT.

      Part B: Post-intervention (treatment of the baseline mechanisms):

      Primary hypothesis:

        1. Compared to subjects with low plasma apoB, twelve-week supplementation with EPA and DHA
           induces a greater reduction in WAT IL-1β secretion in subjects with high plasma apoB
           eliminating baseline group-differences.

           Secondary hypotheses:

        2. Compared to subjects with low plasma apoB, twelve-week supplementation with EPA and DHA
           induces a greater reduction in risk factors for T2D in subjects with high plasma apoB.

        3. Twelve-week supplementation with EPA and DHA reduces the baseline associations of WAT
           IL-1β secretion with risk factors for T2D

        4. Ex vivo, EPA and DHA inhibit LDL-induced priming and/or activation of subjects' WAT
           NLRP3 inflammasome.

      Forty-one subjects (34% men) were enrolled in the study, of whom 33 subjects completed the
      12-week omega-3 intervention (drop out/exclusion rate = 20%). For statistical analysis,
      subjects were stratified into 2 groups based on baseline median plasma apoB per sex. The 2
      groups with high plasma apoB and low plasma apoB were characterized and compared for the
      primary and secondary outcomes at baseline and following the omega-3 intervention.
    

Intervention name(s): Omega-3 fatty acids (2.7 g/d, EPA:DHA, 2:1)
Intervention type(s): Dietary Supplement
Intervention description(s): Triple Strength Omega-3 from Webber Naturals
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Prevention
Keywords: HyperapoB; ApoB-lipoproteins; White adipose tissue; NLRP3 inflammasome; Fat metabolism; Insulin sensitivity and secretion; Systemic inflammation; Eicosapentaenoic acid (EPA); Docosahexaenoic acid (DHA)