Type 2 Diabetes Clinical Trial
Official title:
The Inflammasome and Dysfunctional Adipose Tissue: Why Should apoB-lipoproteins be Targeted in Humans
Verified date | October 2023 |
Source | Institut de Recherches Cliniques de Montreal |
Contact | n/a |
Is FDA regulated | No |
Health authority | |
Study type | Interventional |
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.
Status | Completed |
Enrollment | 41 |
Est. completion date | February 24, 2020 |
Est. primary completion date | January 22, 2020 |
Accepts healthy volunteers | Accepts Healthy Volunteers |
Gender | All |
Age group | 45 Years to 74 Years |
Eligibility | Inclusion Criteria: 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 Exclusion Criteria: - 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 |
Country | Name | City | State |
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n/a |
Lead Sponsor | Collaborator |
---|---|
May Faraj, PDt, PhD | Canadian Institutes of Health Research (CIHR) |
Bissonnette S, Lamantia V, Cyr Y, Ouimet B, Devaux M, Rabasa-Lhoret R, Chrétien M, Saleh M, Faraj M. Native low-density lipoproteins are priming signals of adiposetissue NLRP3 inflammasome/interleukin-1ß pathway in humans. 2023. Research Square.
Bissonnette S, Saint-Pierre N, Lamantia V, Cyr Y, Wassef H, Faraj M. Plasma IL-1Ra: linking hyperapoB to risk factors for type 2 diabetes independent of obesity in humans. Nutr Diabetes. 2015 Sep 28;5(9):e180. doi: 10.1038/nutd.2015.30. — View 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. — View Citation
Lamantia V, Bissonnette S, Provost V, Devaux M, Cyr Y, Daneault C, Rosiers CD, Faraj M. The Association of Polyunsaturated Fatty Acid delta-5-Desaturase Activity with Risk Factors for Type 2 Diabetes Is Dependent on Plasma ApoB-Lipoproteins in Overweight and Obese Adults. J Nutr. 2019 Jan 1;149(1):57-67. doi: 10.1093/jn/nxy238. — View 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. — View Citation
Lamantia V, Sniderman A, Faraj M. Nutritional management of hyperapoB. Nutr Res Rev. 2016 Dec;29(2):202-233. doi: 10.1017/S0954422416000147. Epub 2016 Nov 8. — View 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. — View Citation
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Other | Plasma and red blood cells phospholipid fatty acid profile to assess compliance | by gas chromatography mass spectrometry | Baseline | |
Other | Plasma and red blood cells phospholipid fatty acid profile to assess compliance | by gas chromatography mass spectrometry | Change at 12 weeks from baseline | |
Other | Subject phenotyping | Fasting plasma metabolites (e.g. lipids, apoB) by COBAS INTEGRA, body composition (lean and fat mass in kg) by dual energy x-ray absorptiometry, total energy (kcal/day) and macronutrient intake (g/d) by 3-day dietary records and total energy (kcal/day) and macronutrient oxidation (g/d) by indirect calorimetry | Baseline | |
Other | Subject phenotyping | Fasting plasma metabolites (e.g. lipids, apoB) by COBAS INTEGRA, body composition (lean and fat mass in kg) by dual energy x-ray absorptiometry, total energy (kcal/day) and macronutrient intake (g/d) by 3-day dietary records and total energy (kcal/day) and macronutrient oxidation (g/d) by indirect calorimetry | Change at 12 weeks from baseline | |
Other | Post-hoc analysis of WAT receptors for apoB-lipoproteins and fatty acids | WAT surface-expression of LDLR and CD36 in WAT slides | Baseline | |
Primary | Fasting WAT IL-1ß secretion | Accumulation of IL-1ß in WAT medium ex vivo (by AlphaLISA) | Baseline | |
Primary | Fasting WAT IL-1ß secretion | Accumulation of IL-1ß in WAT medium ex vivo (by AlphaLISA) | At 12-weeks post-intervention | |
Secondary | WAT function and inflammation | Protein and gene expression of a panel of markers related to WAT function (e.g. ADIPOQ, PPARG, HMGCR, SREBP1C and 2) and inflammation (e.g. MCP1, ADGRE1, IL1B, NLRP3, IL10) by immunohistochemistry (relative to a total protein) and RT-qPCR (relative to HPRT). | Baseline | |
Secondary | WAT function and inflammation | Protein and gene expression of a panel of markers related to WAT function (e.g. ADIPOQ, PPARG, HMGCR, SREBP1C and 2) and inflammation (e.g. MCP1, ADGRE1, IL1B, NLRP3, IL10) by immunohistochemistry (relative to a total protein) and RT-qPCR (relative to HPRT). | Change at 12 weeks from baseline | |
Secondary | Postprandial fat metabolism | Area under the 6 hour time curve of plasma triglycerides after a high-fat meal (66% fat) | Baseline | |
Secondary | Postprandial fat metabolism | Area under the 6 hour time curve of plasma triglycerides after a high-fat meal (66% fat) | Change at 12 weeks from baseline | |
Secondary | Systemic inflammation | Fasting plasma inflammatory parameters including IL-1Ra | Baseline | |
Secondary | Systemic inflammation | Fasting plasma inflammatory parameters including IL-1Ra | Change at 12 weeks from baseline | |
Secondary | Insulin sensitivity and secretion | Glucose-induced insulin secretion and insulin sensitivity by Botnia clamps | Baseline | |
Secondary | Insulin sensitivity and secretion | Glucose-induced insulin secretion and insulin sensitivity by Botnia clamps | Change at 12 weeks from baseline |
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