Working...
ClinicalTrials.gov
ClinicalTrials.gov Menu

Cold Induced Changes in White Adipose

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT02596776
Recruitment Status : Recruiting
First Posted : November 4, 2015
Last Update Posted : June 5, 2019
Sponsor:
Collaborator:
National Institutes of Health (NIH)
Information provided by (Responsible Party):
Philip Kern, University of Kentucky

Brief Summary:

An adaptation to a cold environment is a tendency to generate heat within our body. Some of this heat comes from our fat tissue. Although most fat tissue is "white fat", there are pockets deep within the body that are called "brown fat", which are specially adapted to burning fat and making heat. The investigator believes that our white fat, just underneath the surface of our skin, also has this property to burn fat and make heat, although not at the high level of brown fat. This study is to examine this fat-burning property of the white fat under the skin in response to seasons and to cold. Many such studies have been done in mice, but little has been done in humans.

There are a number of factors, including age, weight, and medical history, that may make a person eligible or ineligible to participate in this study. Certain medications could make a person ineligible, but if these medications can be safely altered, the individual may become eligible.


Condition or disease Intervention/treatment Phase
Obese Normal Body Weight Prediabetes Metabolic Syndrome Procedure: Fat biopsy Drug: Propranolol and fat biopsy Other: heavy water and fat biopsy Early Phase 1

  Hide Detailed Description

Detailed Description:

Metabolic syndrome is a condition involving elevated levels of fat in the blood, a tendency towards diabetes, hypertension, and too much fat around the abdomen (an increased waistline). Individuals with metabolic syndrome often have impaired glucose tolerance, which is a condition where blood sugar is normal before a person eats, but is too high after drinking a sugary drink. This is due to an abnormality in the body's sensitivity to insulin (insulin resistance), which is due in part to an inability of muscle to take up glucose. People with metabolic syndrome have inflammation in their fat tissue and this inflammation in the fat tissue may impair the ability of the white fat to burn fat and continue to promote obesity.

This study involves three arms. A propranolol with biopsy arm, a heavy water with biopsy arm, and a biopsy only arm. The goal is to understand the response of fat to cold, either acutely, or after repeated cold exposure, or in response to a change in seasons.

Individuals (subjects) accepted into the study will report to the UK Center for Clinical and Translational Science (CCTS) research unit for baseline testing and repeated procedures. Participants will then be asked to have the same procedures done approximately 6 months later.

Subjects enrolled into the study will need to come to the CCTS Unit for multiple visits. Most of these visits will be less than 1 hour, but 6 visits will involve procedures and will vary in time ranging from 4 hour to 6 hours. If a subject participates in all aspects of the study (fat biopsy from multiple depots, short term, long term, and seasons, then their total participation will be approximately 28 visits over 6-7 months. However, for most subjects, their participation will involve fewer visits, at the discretion of the principal investigator.

The first visit will involve the consent process, followed by baseline fasting blood samples and the oral glucose tolerance test. If the subject passes these screening procedures, then subsequent visits will involve the fat biopsies, DEXA, and other visits described below.

Fat biopsies (Visits 2, 14, 17 and 28). Regardless of the study arm assigned to all subjects will present to the CCTS fasting and a baseline fat biopsy will be performed on the thigh and lower abdomen. Abdominal and thigh subcutaneous adipose tissue will be removed by incision under local anesthesia. An ice pack will then be placed on the opposite thigh and lower abdomen for 30 min; 4 hr later, an adipose biopsy will be obtained from the iced area. The subject will then report to the CCTS daily for repeated 30 min ice pack procedures. However, at the discretion of the PI, participant may be able to perform the 30 min ice pack procedure at home. On day 7 and on day 14, subjects will report to the CCTS fasting and the above procedure will be repeated: an ice pack will be placed on the thigh and abdomen for 30 min, and fat biopsies will be taken from the iced area and from the non-iced area 4 hr later.

Propranolol Arm: Subjects who qualify for this subgroup will be given propranolol 10 mg three times per day. If they tolerate the medication well with no side effects, after 5 days, they will then increase the dose to 20 mg three times per day. If they tolerate the 20 mg dose well with no side effects, after another 5 days (day 10), they will then increase the dose to 40 mg three times per day and stay on this for the duration of the study.

Heavy Water Arm: Subjects who qualify for this subgroup will be given heavy water (at visit 2) every 3 hours for the next 12 hours while at the CCTS. They will then be sent home with doses of heavy water in sealed sterile vials, and will take one vial of heavy water twice per day for 5 weeks.

The following test and procedures will be performed on subjects:

Glucose tolerance test (Visits 1 and 15). This will be a standard oral glucose tolerance test using 75 g of glucose, with blood for glucose and insulin drawn at times 1, 30, 60, 90, and 120 min.

Resting metabolic rate. The investigator will measure resting metabolic rate (RMR). RMR is measured early in the morning, fasting, in a room on the CCTS.

DEXA. Body composition will be measured with DEXA.

12-Lead ECG: To examine heart rhythm and heart rate and any evidence of previous heart disease.

Urine Collection: Females who are capable of becoming pregnant will also be given a urine pregnancy test. If the test results show that they are pregnant they will not be able to participate in the study.

Unscheduled Visits: During the study if either the subject or the PI feel that that the subject should be seen for an additional visit due to an adverse event, the study staff will arrange for this visit. This visit should take no more than 30 minutes. During this visit the investigator will:

  • Review subject's current medication use, including over the counter medications and herbals.
  • Ask the subject questions about their health or any problems they may have had since their last visit.
  • If necessary, take a blood sample (about 1 tablespoon) and urine sample (about 6 teaspoons) to monitor the subject's general health.
  • If necessary, perform a ECG and measure blood pressure and pulse.
  • If necessary, ask questions about how study drug dosing at home.

After completing the above procedure, the subject will be asked to come back for the same set of procedures the following season (i.e. winter, if original procedure was summer, or vice versa).

Therefore, if the subject completes all the procedures in both seasons, a total of 16 biopsies will be performed. Following initial studies, the investigator may refine the protocol and take fewer biopsies. For example, if early experiments determine that abdominal fat is not responsive to seasons, the investigator may discontinue this procedure. The investigator may determine that the baseline fat biopsy (prior to icing) is unnecessary.


Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 90 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: Cold Induced Changes in Human Subcutaneous White Adipose
Study Start Date : March 2016
Estimated Primary Completion Date : December 2019
Estimated Study Completion Date : December 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Biopsy
Drug Information available for: Propranolol

Arm Intervention/treatment
Active Comparator: Fat biopsy
From each abdominal and thigh biopsy, between 0.5 - 3 g of tissue is obtained (often less from the thigh), which is used for immunohistochemistry and frozen for subsequent RNA or protein isolation.
Procedure: Fat biopsy
up to 16 biopsy samples will be taken from each subject

Experimental: Propranolol and Fat Biopsy
From each abdominal and thigh biopsy, tissue will be examined for gene expression, with a focus on genes believed to be involved in adipose beiging (PGC1α, UCP1, TMEM26, IL4, Metrnl, CPA3, Siglec 8, tyrosine hydroxylase, others), and with immunohistochemistry, with a focus on beige adipocytes, macrophages, eosinophils and mast cells.
Procedure: Fat biopsy
up to 16 biopsy samples will be taken from each subject

Drug: Propranolol and fat biopsy
subset of subjects will receive propranolol and have fat biopsy performed

Active Comparator: Heavy Water and Fat Biopsy
The investigator will measure in vivo adipose lipolysis and triglyceride (TG) turnover in response to cold to physiologically demonstrate the impact of cold exposure on tissue function. The subjects will then be given 50 mL sterile containers of 70% 2H2O and consume two 50 mL vials per day during the remainder of the 5-week labeling period. Plasma and urine will be collected weekly so that body 2H2O can be measured.
Procedure: Fat biopsy
up to 16 biopsy samples will be taken from each subject

Other: heavy water and fat biopsy
subset of subjects will be given heavy water and have fat biopsy performed




Primary Outcome Measures :
  1. WAT changes during repeated exposure to cold temperatures [ Time Frame: 28 Weeks (Summer and Winter Seasons) ]
    Adipose biopsies will be performed

  2. WAT changes following Propranolol dosing [ Time Frame: 17 days in the summer season ]
    Subjects will be prescribed propranolol and adipose biopsies will be obtained.

  3. In vivo measurement of adipose lipolysis and triglyceride (TG) turnover [ Time Frame: 5 weeks per season (summer and winter) ]
    The heavy water will be given to and adipose biopsies will be obtained.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   35 Years to 60 Years   (Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • the lean subjects body mass index (BMI) < 27
  • subjects with obesity/MetS (BMI 27-45 with IGT, IFG, or 3 features of MetS)
  • Insulin resistance Fasting blood sugar >126, or 2 hr glu >200, but with A1C<7.5 (i.e. we will include subjects with T2DM on no meds and with good glycemic control)
  • adequate platelet count (>100,000)
  • hematocrit of >32
  • stable weight

Exclusion Criteria:

  • obese subjects (BMI > 45)
  • anti-inflammatory drugs, β-blockers, any diabetes drugs or drugs known to affect adipose tissue
  • an unstable medical condition
  • coronary artery disease
  • congestive heart failure
  • heart block or a history of or any contraindication to a β-blocker.
  • asthma
  • previous stroke
  • use of anticoagulants or aspirin
  • pregnant or breastfeeding
  • lifestyles involving absent or extreme temperature exposure (eg. homebound or institutionalized subjects, outdoor workers).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02596776


Contacts
Layout table for location contacts
Contact: Philip Kern, MD (859) 323-4933 ext 81394 pake222@uky.edu

Locations
Layout table for location information
United States, Kentucky
University of Kentucky Medical Center Center for Clinical and Translational Science Recruiting
Lexington, Kentucky, United States, 40536
Contact: Brianna Harfmann, PhD    859-218-1362    harfmanndb@uky.edu   
Sponsors and Collaborators
Philip Kern
National Institutes of Health (NIH)
Investigators
Layout table for investigator information
Principal Investigator: Philip Kern, MD University of Kentucky

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Layout table for additonal information
Responsible Party: Philip Kern, Principal Investigator, University of Kentucky
ClinicalTrials.gov Identifier: NCT02596776     History of Changes
Other Study ID Numbers: 15-0663
First Posted: November 4, 2015    Key Record Dates
Last Update Posted: June 5, 2019
Last Verified: June 2019

Additional relevant MeSH terms:
Layout table for MeSH terms
Metabolic Syndrome
Prediabetic State
Body Weight
Insulin Resistance
Hyperinsulinism
Glucose Metabolism Disorders
Metabolic Diseases
Signs and Symptoms
Diabetes Mellitus
Endocrine System Diseases
Deuterium Oxide
Propranolol
Adrenergic beta-Antagonists
Adrenergic Antagonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Anti-Arrhythmia Agents
Antihypertensive Agents
Vasodilator Agents
Antineoplastic Agents
Radiation-Protective Agents
Protective Agents