The Inflammasome and Dysfunctional Adipose Tissue: Why Should apoB-lipoproteins be Targeted in Humans
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 发起方
- 入组人数
- 41
- 主要终点
- Fasting WAT IL-1β secretion
研究概览
简要总结
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.
详细描述
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):
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Prevention
- 盲法
- None
入排标准
- 年龄范围
- 45 Years 至 74 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Men and post-menopausal women:
- •Having a body mass index (BMI) > 20 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
排除标准
- •Subjects with elevated risk of cardiovascular disease (≥ 20% of calculated Framingham Risk Score) who require immediate medical intervention by lipid-lowering agents OR who cannot be placed on a 4 weeks wash-out period from their lipid-lowering medication at screening (i.e. upon admission to IRCM clinic).
- •Subjects with systolic blood pressure > 160 mmHg or diastolic blood pressure > 100 mmHg
- •Prior history of cardiovascular events (like stroke, transient ischemic attack, myocardial infarction, angina, heart failure...)
- •Prior history of cancer within the last 3 years
- •Thyroid disease - untreated
- •Type 1 or 2 diabetes or fasting glucose > 7.0 mmol/L
- •Claustrophobia
- •Anemia - Hb < 120 g/L
- •Creatinine > 100 μmol/L
- •Hepatic dysfunction - AST/ALT > 3 times normal limit
- •Blood coagulation problems (i.e. bleeding predisposition)
- •Autoimmune diseases
- •Chronic inflammatory diseases
- •Concomitant medications
- •Hormone replacement therapy (except thyroid hormone at a stable dose)
- •Systemic corticosteroids
- •Anti-psychotic medications - psycho-active medication
- •Anticoagulant treatment (Aspirin, NSAIDs, warfarin, coumadin..)
- •Adrenergic agonist
- •Anti-hypertensive
- •Weight-loss
- •Known substance abuse
- •Allergy to seafood or fish
- •Cancellation of the same scheduled testing visit, twice
- •Lack of time to participate in the full length of the study (18 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
结局指标
主要结局
Fasting WAT IL-1β secretion
时间窗: At 12-weeks post-intervention
Accumulation of IL-1β in WAT medium ex vivo (by AlphaLISA)
次要结局
- Insulin sensitivity and secretion(Change at 12 weeks from baseline)
- Postprandial fat metabolism(Change at 12 weeks from baseline)
- WAT function and inflammation(Change at 12 weeks from baseline)
- Systemic inflammation(Change at 12 weeks from baseline)
研究者
May Faraj, PDt, PhD
Professor
Institut de Recherches Cliniques de Montreal