Effects of the GLP-1 Exenatide on Satiety in Lean and Obese Women
Condition: Obesity
MeSH terms: Obesity
Study type: Interventional
Phase: Phase 1

Summary: 
      Obesity is a major health problem in the US and many Western countries, with more than half
      of the population being overweight or obese. Yet, despite intense research efforts into the
      mechanisms underlying obesity and into the development of novel pharmacologic interventions,
      bariatric surgery, including gastric bypass surgery is the only successful treatment for
      severe obesity. Mimicking one of the effects of bariatric surgery, e.g. the increased
      secretion of glucagon-like peptide 1 (GLP-1) could be an effective strategy against obesity.

      Obese individuals may be more sensitive to the rewarding aspects of food and less responsive
      to signals from the gut about actual energy needs. Using functional MRI scanning the
      investigators plan to examine the effect of Exenatide (a GLP-1 analog known to reduce caloric
      intake and produce weight loss in both obese and lean individuals) on activity within brain
      regions/networks involved in reward/motivation and in regulation of energy requirements. The
      investigators expect the peptide to change the balance between desire to eat for pleasure and
      the need to eat to maintain homeostasis.
    

Detailed description: 
      PRIMARY STUDY OBJECTIVE The proposed study aims to address two important questions regarding
      the mechanisms underlying the weight loss associated with exenatide. The investigators
      primary study objective is to determine whether Exenatide changes the resting state activity
      of the brain, and alters the connectivity between brain regions involved in homeostatic and
      hedonic brain circuits.

      SECONDARY STUDY OBJECTIVE The secondary study objective is to determine if/how these changes
      differ between lean and obese subjects

      SIGNIFICANCE Obesity is a major health problem in the US and many Western countries, with
      more than half of the population being overweight or obese. Yet, despite intense research
      efforts into the mechanisms underlying obesity and into the development of novel
      pharmacologic interventions, bariatric surgery, including gastric bypass surgery is the only
      successful treatment for severe obesity (le Roux, 2006; le Roux, 2007). Mimicking one of the
      effects of bariatric surgery, e.g. the increased secretion of glucagon-like peptide 1 (GLP-1)
      could be an effective strategy against obesity (Torekov, 2011).

      The impact of gut peptides on the brain in the regulation of ingestive behavior is an area of
      great interest, since the involved signaling mechanisms may be potential targets for the
      treatment of obesity. Both endocrine, paracrine and neurocrine (vagal) signaling pathways are
      involved in gut to brain signaling of nutrient related information (Holst, 2007). Human
      studies have demonstrated that long acting hormones like leptin and insulin act on brain
      regions such as the hypothalamus and brainstem, influencing both food intake and response
      (Ahima, 2010). More short -term gut signals relayed by hormones such as CCK and PYY have also
      been shown in humans to have an effect on subcortical regions (including the hypothalamus,
      nucleus tractus solitarius (NTS), pons, thalamus) as well as on cortical regions (middle
      temporal gyrus, insula and anterior cingulate cortex (ACC) (Ahima, 2010). Whereas CCK
      infusion in healthy human subjects was found to result in increased activity primarily in
      homeostatic brain regions (hypothalamus, brainstem), PYY infusions were associated with
      increased activity in regions of reward-circuits (orbitalfrontal cortex, insula, anterior
      cingulate cortex). To our knowledge, the central effects of GLP-1 in humans have not been
      studied. (Ahima, 2010)

      HYPOTHESIS

        1. Exenatide changes intrinsic activity in the NTS and hypothalamus, and connectivity
           between NTS and homeostatic and hedonic brain circuits

        2. These changes are seen both in lean and in obese subjects

        3. Changes in the engagement of brain circuits induced by Exenatide are correlated with
           increased ratings of satiety following a test meal

      METHODS

      The study design is a double-blind, placebo controlled, crossover study.

      Twenty healthy female subjects between the ages of 18-40 years are needed The subjects will
      be divided into two age-matched groups of obese and lean women. The ten obese females will
      have a BMI between 30-35kg/ m2 and the 10 lean females will have a BMI between 19-25kg/m2.
      All subjects will be asked to participate in the entire protocol of 3 visits. There will be a
      screening visit to determine eligibility followed by two functional MRI visits where the
      subject is given a subcutaneous injection (sc) of 10ug of Exenatide (a GLP-1 analog) at one
      visit and a an injection of saline at the other MRI visit. The choice of female participants
      is based on the greater prevalence of obesity in women and the longstanding interest of the
      center's interest in women's health. In order to control for menstrual cycle hormonal
      fluctuation all participants will be scanned during the follicular phase of the menstrual
      cycle, for this study defined as the 4th-12th day after starting menstruation.

      Screening (Visit 1):

      All potential subjects will be asked to complete an initial screening visit approximately 1.5
      hours of time. This visit will take place at the Gail and Gerald Oppenheimer Family Center
      for Neurobiology of Stress at 10833 Le Conte Ave., Los Angeles, CA 90095 Room 47-126. At the
      beginning of this visit, the subject will be given ample time to read and sign the informed
      consent. The protocol will be discussed and reviewed with a study MD or RN.

      The screening will include a medical history and physical examination. A urine test for
      pregnancy will also be done. If the pregnancy test is positive the subject will be
      immediately dropped from participation. Female subjects of child bearing potential will be
      asked to practice a medically approved birth control method during the study, including the
      oral contraceptive pill, abstinence, double barrier method (spermicide and condoms), or IUD.
      A menstrual cycle history will be obtained as part of the medical history and the first day
      of their last menses will be documented. fMRI visits will be planned during the follicular
      stage- specifically day 4-12 of their cycle. A 5 cc (1 tsp) blood draw for glucose will be
      collected. If the non- fasting blood glucose result is more than 200mg/dl the subject will be
      considered a screen fail. This value was chosen in order to exclude subjects with undiagnosed
      underlying diabetes.

      Subjects will be asked to fill out several behavioral questionnaires: the UCLA bowel symptom
      questionnaire (BSQ 5.0), the Hospital Anxiety and Depression scale (HAD), the Spielberger
      State and Trait Anxiety Inventory (STAI-Y1 and Y2) and the MRI safety screening
      questionnaire; requiring about 20 minutes to complete.

      The RN, NP or MD will review the inclusion and exclusion criteria with the subject to
      determine eligibility.

      A brief structured psychological interview (MINI+) will be done to identify any major Axis I
      psychiatric disorders in DSM-IV and ICD-10, such as anxiety, depression, substance abuse or
      phobias.

      If the subject is eligible and wishes to participate, they will be provided with instructions
      for the following study visit. As noted this visit will be scheduled during the follicular
      phase of the individual's menstrual cycle.

      Visit 2 MRI scanning visit 1:

      This visit will take approximately 2 hours of time. Subject will be asked to fast (except
      water) for eight hours prior to admission. Eligibility criteria for continuance in the study,
      including adverse events and any change in medication usage will be reviewed and recorded.
      The 1st day of last menstrual period will be noted and a urine pregnancy test will be
      performed. If positive the subject will be removed from study enrollment.

      Subjects will be escorted to the CTSI (General clinical research area) and an IV will be
      placed for the four blood draws. A baseline fasting blood glucose will be done. It needs to
      be between 65mg/dl and 126mg/dl or the visit will be cancelled. The subject will then be
      escorted to the UCLA Ahmanson-Lovelace Brain Mapping Center, 660 Charles Young Dr. South, Los
      Angeles, CA 90095-7085 and prepared for scanning. Subjects will be asked to complete a PROMIS
      questionnaire prior to scanning to evaluate the previous nights sleep quality (for RSN
      analysis) and a Fullness Questionnaire (FQ); a visual analog scale used to measure hunger and
      satiety.

      After wanding for metal safety they will be escorted into the MRI chamber. They will be given
      a synopsis of the study tests and prepared for placement in the scanner. They will be
      monitored for pulse oximetry and respiratory rate as a measure of autonomic nervous system
      and as a safety measure (after Exenatide injection) while scanning. These measures will be
      collected during all functional resting state network (RSN) scans.

      Following placement structural scans will be done After the structural scans the subject will
      undergo a 10-minute resting state (RSN) scan during which then they will be asked to lie
      still with their eyes closed but not fall asleep.

      After that RSN scan, subjects will be partially moved out of the scanner to receive either a
      subcutaneous injection of 10ug of Exenatide or a 0.5cc injection of saline (placebo) in the
      upper arm, thigh or abdomen. Randomization will be done by the UCLA research pharmacy where
      the drug is stored and dispensed. Subject and investigator will blinded to the randomization.

      Immediately following the injection the subject will be moved back into the scanner and have
      a 8.5 minute structural scanner (MP Rage: a three-dimensional, T1-weighted, gradient-echo
      sequence used for study analysis). Immediately following the MP Rage, the subject will have
      the second 10-minute RSN scan (10-minutes post drug) with the same RSN instructions. After
      the second RSN scan is completed the subjects will complete the second Fullness Questionnaire
      (FQ). This will be presented on the screen via goggles and the answers will be given to the
      scanner operator via intercom. The subject will then be partially moved out of the scanner
      for a 1 teaspoon (5cc) blood draw. This serum sample will be for glucose, insulin and
      exenatide pharmacokinetic.

      The subject will then be moved back into the scanner for the third and final 10-minute RSN
      with the same previous instructions. Immediately following this scan the subject will
      complete the third FQ and have 1 teaspoon (5cc) of blood drawn for glucose, insulin and
      Exenatide pharmacokinetic levels.

      After scanning, subjects will be taken to the CTSI and provided a full balanced standard meal
      of 1200 calories. All subjects will have 2 lunch meal choices to choose from (chicken or ham)
      and will be instructed to "eat until you are full". After the meal, the subject will complete
      the fourth FQ and a final 5cc blood draw for glucose, insulin and Exenatide PK level.
      Approximate blood sampling for the whole day will be 1-2 ounces.

      All scanning will be done in the morning, between ~9am-12pm, to account for hormonal
      fluctuation and for fasting comfort of the subject.

      Visit 3 MRI scanning Visit 2:

      Visit 3 is identical to Visit 2 except the subject will receive the opposite injection. If
      the subject was randomized to receive 10ug of Exenatide during Visit 2 then she will receive
      .5cc of saline (placebo) during Visit 3. Otherwise study procedures will be identical.
    

Intervention name(s): Exenatide; Normal saline .2cc subcutaneous injection
Intervention type(s): Drug; Drug
Intervention description(s): 10mcg sc (subcutaneous) injection once at one of the 2 MRI visits; sterile saline injection
Other intervention name(s): Byetta
Intervention MeSH terms: Exenatide
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Basic Science
Keywords: functional MRI; Structural MRI; obesity; resting state networks