Brown Fat Activation Study
Condition: Obese; Metabolic Syndrome
MeSH terms: Metabolic Syndrome
Study type: Interventional
Phase: Early Phase 1

Summary: 
      This is an open lable, pilot study in which the investigator will research the effect of two
      FDA approved drugs, Mirabegron and Pioglitazone on fat tissue.

      Pioglitazone is drug approved by the FDA for the treatment of diabetes and Mirabegron is a
      drug that is approved by the FDA for the treatment of overactive bladder. These drugs are not
      approved by the FDA for the purposes being studied in this research. Therefore, the way in
      which the investigator intends to use them in this study are considered investigational.
    

Detailed description: 
      The purpose of this study is to determine whether the amount and activity of brown adipose
      tissue (BAT) and beige adipose can be increased with the use of Mirabegron or Pioglitazone,
      alone or in combination.

      The research procedures will be conducted at the University of Kentucky (UK) Medical Center
      at the Center for Clinical Translational Sciences research unit (CCTS). Study participants
      will need to come to the CCTS Unit for approximately 9 visits, as outlined below. Most of
      these visits will be less than 1 hour, but 3 visit will involve procedures and will vary in
      time ranging from 4 hour to 8 hours. Thus, a participant's total participation will be
      approximately 9 visits over the next 12 weeks.

      After passing the screening phase, participants will be randomized (like the flipping of
      coin) at Visit 4 to one of three treatment groups and the participant will stay in their
      assigned treatment group during their entire participation in the study. The three groups
      are:

        -  Group M: Mirabegron 50 mg/day

        -  Group P: Pioglitazone 30 mg/day

        -  Group MP: combination Mirabegron 50 mg/day and Pioglitazone 30 mg/day

      Fasting requirements: Nothing to eat after 9 pm the night before a specific test or
      procedure.

      Glucose tolerance test and fasting lab tests: This will be a standard oral glucose tolerance
      test using 75 g of glucose, with blood for glucose and insulin drawn at times 0, 30, 60, 90,
      and 120 min. This test will determine if the participants have impaired glucose tolerance,
      diabetes, or are normal. This fasting blood sample will be used to conduct routine blood
      tests that are a normal part of a physical exam, such as cholesterol, liver enzymes and
      electrolytes.

      Based on the blood tests, the oral glucose tolerance test (OGTT), and other measurements, the
      investigator will determine whether a participant has impaired glucose tolerance or a normal
      glucose level, and whether they fit the other criteria of the study.

      Body Mass Index and DXA Scan: The investigator will record the participant's weight, height,
      waist and hip measurements. Measurement of total body fat will be performed to determine the
      participant's percent body fat using dual energy X-ray absorptiometry (DXA). DXA uses very
      low levels of X-ray to measure the amount of fat, muscle, and bone in different body areas.
      Participants will be asked to lie on a table while wearing light clothing or a gown.

      Positron Emission Tomography (PET) Scan: A PET scan is a type of imaging test. It uses a
      radioactive substance called a tracer to look for high areas of metabolic activity in the
      body. A PET scan is a standard test performed for certain conditions, and in this instance it
      is being used to see a participant's brown fat. 18F-2-fluoro-2-deoxy-D-glucose
      fluorodeoxyglucose (FDG) is an FDA-approved drug that is injected into the body before a PET
      scan, and used as a "tracer" to help light up the areas the doctors need to see. The
      investigators is not studying the effectiveness of this drug in this study.

      To see the brown fat, the investigator will first need to make a participant cold. To do
      this, a participant will change into loose fitting light clothing, and then place around
      their midsection, a special jacket, and cold water will circulate through this jacket for 1
      hr.

      The jacket is then removed, and the participants are injected through a vein (IV) with the
      FDG tracer. The IV needle is most often inserted on the inside of the elbow. The tracer
      travels through the blood and collects in organs and tissues. This helps the radiologist see
      certain areas more clearly.

      Participants will lie on a narrow table that slides into a large tunnel-shaped scanner. The
      PET detects signals from the tracer. A computer changes the signals into 3D pictures. The
      images are displayed on a monitor for the radiologist to read.

      Fat biopsies: After an overnight fast, the biopsy procedures will be performed as follows: A
      fat sample (called a fat biopsy) will be removed by the investigator from the lower abdomen
      and from the thigh. The skin at the biopsy sites will be anesthetized using the local
      anesthetic, lidocaine, then a 1 incision will be made on the abdomen and a ½ inch incision on
      thigh, through the skin, and a small amount of fat tissue will be removed. The incisions will
      then be closed using stitches. Participants will have a total of 4 fat biopsies: Two prior to
      receiving study drug (at any time between visits 2-4) and two while taking the study drug (at
      any time between visits 6-9).

      Muscle biopsy. At the time of the thigh adipose biopsy, a muscle biopsy is performed through
      the same skin incision. Participants will have a total of 2 muscle biopsies: 1 prior to
      receiving study drug (at any time between visits 2-4) and one while taking the study drug (at
      any time between visits 6-9).

      Euglycemic clamp: Insulin sensitivity will be measured using a clamp. Participants will come
      to the CCTS after fasting overnight. Two intravenous plastic tubes will be inserted into
      veins in their arm. Participants will then be given a constant injection of glucose along
      with a constant injection of insulin. The glucose and insulin are balanced such that the
      participant's blood glucose stays constant between about 90-100 mg/dl. Blood will then be
      drawn from the intravenous line frequently (about every 5-10 minutes) for measurement of
      blood glucose and insulin. These blood measurements will continue for 4 hours; the total
      amount of blood that will be withdrawn will be about 100 cc (about 6 tablespoons), which is
      about one quarter as much as would be taken if the participant were to donate blood.

      Urine Collection: Females who are capable of getting pregnant, will also be asked to give a
      sample of urine to test for pregnancy. If the test results positive for pregnancy,
      participants will not be able to participate in the study.
    

Intervention name(s): Mirabegron; Pioglitazone; Mirabegron and Pioglitazone
Intervention type(s): Drug; Drug; Drug
Intervention description(s): Mirabegron 50 mg/day; Pioglitazone 30 mg/day; Mirabegron 50 mg/day and Pioglitazone 30 mg/day
Other intervention name(s): MYRBETRIQ; ACTOS; MYRBETRIQ and ACTOS
Intervention MeSH terms: Pioglitazone; Mirabegron
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Basic Science