- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01477034
Vitamin D and Adipose Tissue Inflammation
Study Overview
Status
Intervention / Treatment
Detailed Description
The objective of this project is to investigate whether vitamin D modulates chronic low-grade adipose tissue inflammation in overweight and obese, vitamin D deficient men and women.
Obesity is associated with insulin resistance and an increased risk for type 2 diabetes mellitus. Numerous studies, mostly conducted in mouse models of obesity, strongly suggest that chronic low-grade inflammation of adipose and other tissues is the major mechanism by which increased adiposity is linked to insulin resistance. Adipose tissue inflammation may therefore be a promising therapeutic target to reduce insulin resistance and the risk of type 2 diabetes mellitus in obese individuals.
Based on several lines of evidence, we hypothesize that vitamin D is an environmental factor that affects the course of the inflammatory response in most tissues of the body, including adipose tissue. In our previous studies, we found that circulating plasma concentrations of 25-hydroxy vitamin D (25-OH-D) and the primary degradation product 24,25-dihydroxy vitamin D (24,25-OH2-D) were significantly associated with adipose tissue expression of adiponectin and negatively with TNF-alpha, even when adjusted for body mass index. Because these previous studies were cross-sectional, it is critical to complete an intervention study in humans to determine whether the observed association of vitamin D levels and adipose tissue inflammation is causal. The objectives of this pilot study are therefore to collect relevant preliminary data, and to begin an exploration of the mechanisms underlying this association such as intestinal permeability.
Increased intestinal permeability may contribute to chronic low-grade inflammation and signaling through the vitamin D receptor plays an important role in the maintenance of intestinal integrity. We will assess whether normalization of vitamin D status is associated with changes in intestinal permeability.
Study Type
Enrollment (Actual)
Phase
- Not Applicable
Contacts and Locations
Study Locations
-
-
Washington
-
Seattle, Washington, United States, 98109
- Fred Hutchinson Cancer Research Center
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- Age: 18-65 years;
- BMI ≥25 kg/m2;
- Plasma 25-OH-vitamin D between 7 and 20 ng/mL
- Weight stable to within 10 pounds for 6 months prior to entering the study, and within 30 pounds of their lifetime maximum weight (excluding pregnancy);
- Ability to be admitted for ~6.5 hours on three occasions to the FHCRC Prevention Center,
- Ability to provide informed written consent;
- Willingness to take vitamin D3 capsules daily for 6 months
Exclusion Criteria:
- Chronic disease such as thyroid disease, liver disease, or kidney disease;
- Diabetes mellitus, or fasting glucose >125 mg/dL;
- Chronic inflammatory condition such as autoimmune disease or inflammatory bowel disease;
- Malabsorption syndromes (untreated celiac disease; condition after stomach or intestinal resection);
- Current or recent (within one month) chronic intake of medications likely to interfere with study endpoints [(insulin, antidiabetics, anabolic steroids, glucocorticosteroids, statins, blood thinners (warfarin, aspirin), non-steroidal anti-inflammatory drugs (if daily)];
- Current or recent (within 3 months) intake of vitamin D in excess of 600 IU/day;
- Anemia, recent history (within 3 months) of anemia; recent (within 3 months) blood donation; recent (within 3 months) participation in another study that involved blood draws; or plans to participate in other research that involves blood draws during the study period;
- Pregnancy in the last 6 months, plans to become pregnant during the study period, or current breastfeeding.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Basic Science
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Triple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: 2,000 IU/day vitamin D3 x 6 months
Subjects will take a 2,000 IU daily vitamin D3 supplement for 6 months.
|
2,000 or 4,000 IU/day vitamin D3 for 3 or 6 months.
Other Names:
|
Experimental: 4,000 IU/day vitamin D3 x 6 months
Subjects will take a 4,000 IU daily vitamin D3 supplement for 6 months.
|
2,000 or 4,000 IU/day vitamin D3 for 3 or 6 months.
Other Names:
|
Experimental: 2,000 IU/day vitamin D3 x 3 months
Subjects will take a 2,000 IU daily vitamin D3 supplement for 3 months.
|
2,000 or 4,000 IU/day vitamin D3 for 3 or 6 months.
Other Names:
|
Experimental: 4,000 IU/day vitamin D3 x 3 months
Subjects will take a 4,000 IU daily vitamin D3 supplement for 3 months.
|
2,000 or 4,000 IU/day vitamin D3 for 3 or 6 months.
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Tumor Necrosis Factor alpha expression in adipose tissue
Time Frame: Change from baseline to the 6 month visit
|
Total RNA will be extracted from whole adipose tissue.
TNF alpha mRNA will be quantified using PCR, and normalized using a normalization factor based on three housekeeping genes.
We will compute the change in adipose tissue TNF alpha mRNA level between baseline and the 6 month visit.
|
Change from baseline to the 6 month visit
|
Tumor Necrosis Factor alpha expression in adipose tissue
Time Frame: Change from baseline to the 3 month visit
|
Total RNA will be extracted from whole adipose tissue.
TNF alpha mRNA will be quantified using PCR, and normalized using a normalization factor based on three housekeeping genes.
We will compute the change in adipose tissue TNF alpha mRNA level between baseline and the 3 month visit.
|
Change from baseline to the 3 month visit
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Plasma concentrations of 24,25-dihydroxy vitamin D [24,25(OH)2D]
Time Frame: Change from baseline to the 6 month visit
|
The concentration of 24,25(OH)2D will be measured in fasting plasma using high performance liquid chromatography-tandem mass spectometry (LC/MS/MS).
|
Change from baseline to the 6 month visit
|
Adipose tissue concentration of 25-hydroxy vitamin D [25(OH)D]
Time Frame: Change from baseline to the 6 month visit
|
Adipose tissue 25(OH)D will be measured using high performance liquid chromatography-tandem mass spectometry (LC/MS/MS.)
|
Change from baseline to the 6 month visit
|
CD16+ macrophages in adipose tissue
Time Frame: Change from baseline to the 6 month visit
|
The number or CD16+ macrophages in adipose tissue, normalized to the total number of CD14+CD206+ macrophages or the total number of CD45+ cells, will be measured using multi-parameter flow cytometry.
|
Change from baseline to the 6 month visit
|
CD8+ T cells in adipose tissue
Time Frame: Change from baseline to the 6 month visit
|
The number of CD8+ T cells in adipose tissue, normalized to the total number of CD3+ cells, will be measured using multi-parameter flow cytometry.
|
Change from baseline to the 6 month visit
|
Plasma concentration of 25-hydroxy vitamin D [25(OH)D]
Time Frame: Change from baseline to the 6 month visit
|
Plasma 25(OH)D will be measured by high performance liquid chromatography-tandem mass spectometry (LC/MS/MS).
|
Change from baseline to the 6 month visit
|
Adipose tissue concentration of cholecalciferol (vitamin D3)
Time Frame: Change from baseline to the 6 month visit
|
Adipose tissue concentrations of cholecalciferol will be measured by high performance liquid chromatography-tandem mass spectometry (LC/MS/MS)
|
Change from baseline to the 6 month visit
|
CD11c+ macrophages in adipose tissue
Time Frame: Change from baseline to the 6 month visit
|
The number of CD11c+ macrophages in adipose tissue, normalized to the total number of CD45+ cells, will be measured by multi-parameter flow cytometry.
|
Change from baseline to the 6 month visit
|
CD4+CD25+ T cells in adipose tissue
Time Frame: Change from baseline to the 6 month visit
|
The number of CD4+CD25+ T cells in adipose tissue, normalized to the total number of CD4+ T cells, will be measured by multi-parameter flow cytometry.
|
Change from baseline to the 6 month visit
|
Intestinal permeability, as assessed by the 5-hour urinary lactulose/mannitol test
Time Frame: Change from baseline to 6 month clinic visit.
|
Intestinal permeability will be assessed at each clinic visit by administering 2g of mannitol and 5 g of lactulose to the oral glucose tolerance test beverage followed by collection of urine for 5 hours afterwards.
Recovery of mannitol and lactulose in urine will be measured by gas chromatography, and will be indicative of the degree of intestinal permeability.
|
Change from baseline to 6 month clinic visit.
|
Fasting plasma zonulin concentrations
Time Frame: Change from baseline to 6 month clinic visit
|
Zonulin concentrations will be measured by enzyme-linked immunosorbent assay in fasting plasma collected at all clinic visits.
Plasma zonulin is a marker of intestinal permeability.
|
Change from baseline to 6 month clinic visit
|
Fasting plasma lipopolysaccharide binding protein (LBP)
Time Frame: Change from baseline to 6 month clinic visit
|
Lipopolysaccharide binding protein (LBP) will be measured by enzyme-linked immunosorbent assay in fasting plasma collected at all clinic visits.
LBP is an acute phase protein secreted by the liver in response to endotoxin (lipopolysaccharide) exposure.
|
Change from baseline to 6 month clinic visit
|
Plasma concentrations of 24,25-dihydroxy vitamin D [24,25(OH)2D]
Time Frame: Change from baseline to the 3 month visit
|
The concentration of 24,25(OH)2D will be measured in fasting plasma using high performance liquid chromatography-tandem mass spectometry (LC/MS/MS).
|
Change from baseline to the 3 month visit
|
Adipose tissue concentration of 25-hydroxy vitamin D [25(OH)D]
Time Frame: Change from baseline to the 3 month visit
|
Adipose tissue 25(OH)D will be measured using high performance liquid chromatography-tandem mass spectometry (LC/MS/MS.)
|
Change from baseline to the 3 month visit
|
CD16+ macrophages in adipose tissue
Time Frame: Change from baseline to the 3 month visit
|
The number or CD16+ macrophages in adipose tissue, normalized to the total number of CD14+CD206+ macrophages or the total number of CD45+ cells, will be measured using multi-parameter flow cytometry.
|
Change from baseline to the 3 month visit
|
CD8+ T cells in adipose tissue
Time Frame: Change from baseline to the 3 month visit
|
The number of CD8+ T cells in adipose tissue, normalized to the total number of CD3+ cells, will be measured using multi-parameter flow cytometry.
|
Change from baseline to the 3 month visit
|
Plasma concentration of 25-hydroxy vitamin D [25(OH)D]
Time Frame: Change from baseline to the 3 month visit
|
Plasma 25(OH)D will be measured by high performance liquid chromatography-tandem mass spectometry (LC/MS/MS).
|
Change from baseline to the 3 month visit
|
Adipose tissue concentration of cholecalciferol (vitamin D3)
Time Frame: Change from baseline to the 3 month visit
|
Adipose tissue concentrations of cholecalciferol will be measured by high performance liquid chromatography-tandem mass spectometry (LC/MS/MS)
|
Change from baseline to the 3 month visit
|
CD11c+ macrophages in adipose tissue
Time Frame: Change from baseline to the 3 month visit
|
The number of CD11c+ macrophages in adipose tissue, normalized to the total number of CD45+ cells, will be measured by multi-parameter flow cytometry.
|
Change from baseline to the 3 month visit
|
CD4+CD25+ T cells in adipose tissue
Time Frame: Change from baseline to the 3 month visit
|
The number of CD4+CD25+ T cells in adipose tissue, normalized to the total number of CD4+ T cells, will be measured by multi-parameter flow cytometry.
|
Change from baseline to the 3 month visit
|
Intestinal permeability, as assessed by the 5-hour urinary lactulose/mannitol test
Time Frame: Change from baseline to 3 month clinic visit.
|
Intestinal permeability will be assessed at each clinic visit by administering 2g of mannitol and 5 g of lactulose to the oral glucose tolerance test beverage followed by collection of urine for 5 hours afterwards.
Recovery of mannitol and lactulose in urine will be measured by gas chromatography, and will be indicative of the degree of intestinal permeability.
|
Change from baseline to 3 month clinic visit.
|
Fasting plasma zonulin concentrations
Time Frame: Change from baseline to 3 month clinic visit
|
Zonulin concentrations will be measured by enzyme-linked immunosorbent assay in fasting plasma collected at all clinic visits.
Plasma zonulin is a marker of intestinal permeability.
|
Change from baseline to 3 month clinic visit
|
Fasting plasma lipopolysaccharide binding protein (LBP)
Time Frame: Change from baseline to 3 month clinic visit
|
Lipopolysaccharide binding protein (LBP) will be measured by enzyme-linked immunosorbent assay in fasting plasma collected at all clinic visits.
LBP is an acute phase protein secreted by the liver in response to endotoxin (lipopolysaccharide) exposure.
|
Change from baseline to 3 month clinic visit
|
Collaborators and Investigators
Sponsor
Collaborators
Investigators
- Principal Investigator: Mario Kratz, Ph.D., Fred Hutchinson Cancer Center
Publications and helpful links
Study record dates
Study Major Dates
Study Start
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Estimate)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Pathologic Processes
- Glucose Metabolism Disorders
- Metabolic Diseases
- Endocrine System Diseases
- Nutrition Disorders
- Avitaminosis
- Deficiency Diseases
- Malnutrition
- Diabetes Mellitus
- Diabetes Mellitus, Type 2
- Inflammation
- Vitamin D Deficiency
- Physiological Effects of Drugs
- Micronutrients
- Bone Density Conservation Agents
- Calcium-Regulating Hormones and Agents
- Vitamin D
- Cholecalciferol
- Vitamins
- Ergocalciferols
Other Study ID Numbers
- UW NORC P&F KRATZ
- 7598 (Other Identifier: FHCRC)
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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