Effects of the GLP-1 Exenatide on Intrinsic Brain Activity in Lean and Obese Women
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 34
- 试验地点
- 1
- 主要终点
- Resting State networks in the brain
研究概览
简要总结
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.
详细描述
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
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Basic Science
- 盲法
- Triple (Participant, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 40 Years（Adult）
- 性别
- Female
- 接受健康志愿者
- 是
入选标准
- •FEMALES 18 to 40 years of age, inclusive
- •Lean control subjects with BMI's between 19 and 25kg/m
- •Obese subjects with BMI's between 30 and 35kg/m
- •Willingness to participate in this study as evidenced by a signed, written informed consent form (ICF).
- •Willingness to avoid pregnancy and practice adequate birth control (abstinence, oral contraception, intrauterine devices, implantable devices, or barrier method with spermicide) during the time of study enrollment.
- •Negative urine pregnancy tests at all visits.
- •All subjects must be premenopausal.
- •In the follicular stage of the menstrual cycle, as determined by menstrual history at Visit 2 &
- •Ambulatory outpatient (not depending exclusively on a wheelchair for mobility)
- •English is primary oral and written language.
- •Random (non fasting) Blood sugar level < 200mg/dl at screening.
- •Right-handed
- •Exclusion Criteria
- •Evidence of structural abnormality of the gastrointestinal tract or GI diseases/conditions. Exclusionary GI conditions include but are not limited to: gastrointestinal surgery (exceptions: appendectomy, benign polypectomy, cholecystectomy), pancreatitis, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), esophagitis (exception: symptom controlled reflux disease), celiac disease, gastrointestinal malignancy or obstruction, functional dyspepsia, peptic ulcer disease, lactose intolerance or any malabsorptive condition.
- •Clinical evidence of cardiovascular, respiratory, renal, hepatic, malignancy, hematologic, neurologic (including regular migraines defined as more than 1 migraine per month), psychiatric or any disease that the PI determines may interfere with safe participation in the study.
- •* Very specifically subjects with any history or symptoms of poor glucose control, osteoporosis, diabetes, thyroid, adrenal or other endocrine disorder.
- •Subjects with current psychiatric disorder, or history of such disorder in the past 5 years. This list includes but is not limited to bipolar disorder, alcohol or substance abuse/dependence, suicide attempt or behavior, or presence of anxiety or depression at the time of screening. Poorly controlled anxiety or depression will be determined as a result of MINI + interview by the clinician at screening.
- •Current history of chronic pain.
- •Use of investigational drugs, products or devices within 28 days prior to screen and through study participation.
- •Subjects with current use of any medications/drugs during the study that affect the central nervous system, gastrointestinal motility, autonomic activity or pain sensation, including but not limited to: opiates or other narcotic analgesics, THC, alpha adrenergic receptor antagonists, beta blockers, Ca+ blockers, prokinetics and sympatholytic agents, or antidepressants.
- •Subjects who have used diet aids within the last month.
- •Pregnancy, postpartum within 4 months or breast-feeding
- •Subjects who smoke more than 5 cigarettes per month.
- •Subjects with BMI of less than 20, between 26 and 29 and over
- •Subjects with metal implants, dental retainers, large tattoos (e.g. full arm or back) or claustrophobia; making MRI safety not possible.
- •Any clinically significant abnormalities from the screening medical history or physical examination.
- •Subjects who exercise excessively (more than 8 hours a week on average).
- •Postmenopausal women and/or women who have had oophorectomies.
- •Any other condition that the investigator believes would jeopardize the safety or rights of the subject or would render the subject unable to comply with the study protocol.
- •Subject taking any medications that might interfere or react badly with the GLP-1 agonist: Exenatide
- •Subjects with a non-fasting blood glucose level at > 200 dl/ml.
- •MRI visits with fasting blood sugar < 65 or 126 mg/dl
- •Left handedness
排除标准
- 未提供
研究组 & 干预措施
Exenatide
Exenatide injection 10 mcg subcutaneous
干预措施: Exenatide (Drug)
Saline
.2cc SC injection of sterile normal saline
干预措施: Normal saline .2cc subcutaneous injection (Drug)
结局指标
主要结局
Resting State networks in the brain
时间窗: one year
The proposed study aims to address two important questions regarding the mechanisms underlying the weight loss associated with exenatide. Our 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 circults.
次要结局
- Age and body size differences(one year)
研究者
Lisa Kilpatrick, PhD
Principal Investigator
University of California, Los Angeles