Monounsaturated Fatty Acid Supplementation for Overweight and Obese Individuals With Prediabetes

Study Overview
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Brief Summary
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The purpose of this study is to understand and determine whether Palmitoleic acid (POA), monounsaturated omega-7 fatty acid (exists in regular diet), improves insulin sensitivity and decreases liver fat accumulation in humans. Unlike others, the study will use POA as a dietary supplement, rather than complex oils, which contain a significant amount of saturated fat palmitic acid. Palmitic acid has known harmful effects on the body. Hence, eliminating palmitic acid from supplementation of POA might increase its benefits. This trial stems from the preclinical discoveries that POA acting as a fat hormone, has beneficial effects on the liver, muscle, vessels, and fat tissue. Supporting this, higher POA levels in humans have been shown to be correlated with a reduced risk of developing type-2 diabetes and cardiovascular diseases such as heart attacks. In animals, it has been observed that POA improves sugar metabolism in a number of mechanisms related to the liver and muscle. Based on these findings, the design of this study is a double-blind placebo-controlled trial that tests the effects of POA on insulin sensitivity of overweight and obese adult individuals with pre-diabetes.

Detailed Description
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Specific aims of the study are as follows: 1) To test whether supplementation of POA, as compared to placebo, improves insulin sensitivity. 2) To test whether supplementation of POA, as compared to placebo, ameliorates hepatosteatosis and decreases whole-body fat mass, serum triglyceride, and LDL cholesterol. 3)To determine whether supplementation of POA, as compared to placebo, decreases plasma levels of fasting glucose, insulin, FABP4, glucagon, inflammatory cytokines, and hsCRP. The investigators will recruit overweight and obese individuals (BMI 25-40) with mild insulin resistance, prediabetes and/or impaired glucose tolerance. The study is powered only for the primary endpoint, insulin sensitivity. After the screening visit confirms the eligibility for the study; the investigators will perform an oral glucose tolerance test (OGTT) for stratified randomization for better homogeneity between POA and placebo groups. The investigators aim to have 40 participants complete the study which will consist of 2 main overnight visits consisting of an insulin clamp procedure and a mixed meal tolerance test the night prior. Participants will also have a liver MRI and DEXA scan at these two visits. Participants will be asked to consume a palmitoleic acid minimized diet for 10 weeks which will start two weeks before the first overnight visit. This research study will compare insulin sensitivity before and 8 weeks after taking POA vs placebo in the same individuals. After the first overnight visit participants will be given either POA or placebo capsules to take daily for 8 weeks until the second overnight visit. There will also be a short blood draw visit 4 weeks after the first overnight visit.

Official Title
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The Effect of Palmitoleic Acid (POA) Supplementation on Insulin Sensitivity and Lipogenesis in Overweight and Obese Individuals

Conditions
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PreDiabetes, Insulin Resistance, Overweight, Obesity

Intervention / Treatment
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* Dietary Supplement: Palmitoleic acid
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Overweight and obese individuals with prediabetes and/or impaired glucose tolerance Age 18 to 70 years BMI 25-40 kg/m2 HbA1c between 5.6 - 6.5, Impaired fasting plasma glucose levels (>99, ≤126 mg/dL) or OGTT blood glucose at 2 hours between 140-200 mg/dL BP <150/90 with or without medication GFR>60 ALT, AST <300 Normal thyroid function is defined as screening TSH within normal ranges, with or without medication Exclusion Criteria: Use of any medications (except thyroid hormone with normal TSH, anti-hypertensives with blood pressure <150/90 and non-steroidal rescue inhalers for asthma) Pregnancy or breastfeeding Use of over-the-counter (OTC) supplements (except vitamin D). The investigators will ensure that study participants are not using supplements containing fish oil or other lipid supplements (e.g., macadamia oil, krill oil, flaxseed, primrose oil, sea buckthorn oil) within 3 months of study participation Greater than 3 servings/day combined of cheese, whole-fat milk, kefir, or whole-fat yogurt for the last 3 months before the study. Diagnosed with any type of diabetes mellitus and/or taking glucose-lowering medications Recent weight loss (more than 7% of total body weight loss in last 3 months) Established major chronic diseases such as major cardiovascular disease (history of myocardial infarction, stroke, symptomatic heart failure, coronary artery bypass graft, Atrial fibrillation, symptomatic peripheral arterial disease), bleeding disorder or anticoagulation use, active cancer, end-stage renal disease, proteinuria (>3g/day), dementia, severe chronic obstructive pulmonary disease (needs systemic steroid therapy), significant liver disease (ALT or AST>300) History of ongoing smoking cigarettes >1 pack/day, alcohol abuse, or illicit drug abuse Treatment with any investigational drug in the one month preceding the study

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Interventional double-blinded study with participants randomized to either POA or placebo
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Palmitoleic acid<br>The treatment arm will receive Palmitoleic acid (POA) supplement as Provinal® 420 mg capsules with at least 90% pure POA Ethyl Ester (less than 1% palmitic acid). Participants will be asked to consume 2 Provinal® 420 mg capsules twice a day for 8 weeks. | Dietary Supplement: Palmitoleic acid<br>* Participants will be randomized to either POA or placebo and will be asked to take 2 capsules of the POA or placebo twice a day for 8 weeks.<br>* Other names: Provinal®;|
| Placebo Comparator: Placebo<br>The placebo is a medium chain fatty acid in triglyceride form. The placebo has no shown health effects, neither beneficial or detrimental. Participants will be asked to consume 2 placebo capsules daily twice a day for 8 weeks. | Other: Placebo<br>* Medium chain fatty acids in triglyceride form in capsules with the same shape, color, size and odor of POA capsules<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Insulin sensitivity M value change before and 8 weeks after POA vs placebo intake | Insulin sensitivity (M values) will be evaluated by hyperinsulinemic euglycemic clamp (gold standard) from the same individuals before and after taking POA vs. placebo. The investigators will compare M values before and after taking POA vs placebo intake. Hence the investigators are looking for delta changes and expect 20% statistically significant improvement with POA and no significant change with placebo. The investigators calculated sample size and powered the study for only this primary endpoint to see at least 20% difference. | 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Modified mixed meal tolerance test | The investigators will measure glucose and c-peptide response to standard mixed meal. Study participants will ingest the mixed meal and then the investigators will measure glucose and c-peptide levels from venous blood collected every 30 minutes for 2 hours. Area under the curve (AUC) for both glucose and c-peptide will be calculated and this value from same individuals before and 8 weeks after POA vs placebo intake will be compared. | 8 weeks | 
| Liver fat quantification | Liver fat percent will be evaluated by liver MRI-PDFF (proton density fat fraction). Blinded radiologist will analyze the MRI fat fraction and use standard ROI gating. The investigators will compare % fat fraction (FF) from same individuals before and 8 weeks after POA vs placebo intake | 8 weeks | 
| Total body fat mass and body composition | Body composition, which is whole-body fat vs lean mass will be evaluated by DEXA scan. Whole-body % fat mass from same individuals before and 8 weeks after POA vs placebo intake will be compared. | 8 weeks | 
| Serum; fasting glucose, insulin, LDL cholesterol, hsCRP, circulating inflammatory cytokines (TNF-a, IL-6), FABP4, glucagon | The investigoators will compare serum fasting glucose, insulin, LDL cholesterol, hsCRP, circulating inflammatory cytokines (TNF-a, IL-6), FABP4, glucagon from same individuals before and 8 weeks after POA vs placebo intake | 8 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Palmitoleic acid, Obesity, Insulin resistance, Dietary supplement, Prediabetes