Central Effects of Endogenous Glucagon Like Peptide-1 (GLP-1) and the GLP-1 Analog Liraglutide on Brain Satiety and Reward Circuits and Feeding Behavior in Diabetes
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 发起方
- 入组人数
- 50
- 试验地点
- 1
- 主要终点
- food-stimuli related neuronal activity in reward and satiety circuits as represented by BOLD fMRI signal change from baseline (%)
研究概览
简要总结
The aim of this study is to investigate if endogenous Glucagon Like Peptide -1 (GLP-1) has an effect on brain satiety and reward systems and if there are alterations in obese patients with type 2 diabetes (T2DM). Secondly, the aim is to investigate whether treatment with a GLP-1 analog, liraglutide, restores these signals in obese patients with type 2 diabetes. Finally, also the endogenous GLP-1 effects will be investigated in obese individuals before and after gastric bypass surgery on brain satiety and reward systems.
详细描述
First aim will be addressed in a cross-sectional randomized study. 20 healthy, lean and 20 obese individuals with type 2 diabetes (T2DM) will be exposed to food cues and with concomitant infusion of glucagon Like peptide-1 (GLP-1) receptor antagonist or saline, to assess the involvement of endogenous GLP-1, secreted in response to a meal. Measurements activation of CNS circuits involved in satiety and reward will be performed using blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI).
The second aim will be addressed in cross-over randomized-controlled trial (RCT) in the T2DM patients only. Patients will be randomly assigned liraglutide vs insulin glargine treatment, during a treatment period of 12 weeks each with a 12-week washout period in between. The investigators will perform the same fMRI protocol.
The third aim will be addressed in a study with obese individuals who are scheduled for a gastric bypass surgery. The same protocol as for the first aim will be performed and this will be before and after the surgery in the same individuals.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •For the healthy, lean individuals:
- •Age 18-65 years
- •Women: post menopausal (excluding possible menstruation cycle effects)
- •Body-mass index (BMI) of <25 kg/m2,
- •Stable bodyweight (<5% reported change during the previous 3 months).
- •Normal fasting and 2h post load glucose as ascertained during a 75-g oral glucose tolerance test (OGTT) (34)
- •Right handed
- •For the obese T2DM individuals:
- •Age 18-65 years
- •Women: post menopausal (excluding possible menstruation cycle effects)
- •BMI 25-40 kg/m2
- •Stable bodyweight (<5% reported change during the previous 3 months).
- •Diagnosed with T2DM > 3 months prior to screening
- •HbA1C 6.5-8.5%
- •Treatment with metformin at a stable dose for at least 3 months.
- •Right handed
- •For the obese individuals scheduled for gastric bypass surgery:
- •Age 18-65 years
- •Women: preferably post menopausal (excluding possible menstruation cycle effects)
- •Body-mass index (BMI) of >30 kg/m2,
- •Stable bodyweight (<5% reported change during the previous 1 months).
- •Normal or impaired fasting and 2h post load glucose as ascertained during a 75-g oral glucose tolerance test (OGTT) (defined as glucose fasting < 7.1 mmol/l and after OGTT t=120min < 11.0 mmol/l) (39)
- •Right handed
排除标准
- •GLP-1 based therapies, thiazolidinediones, sulphonylurea or insulin within 3 months before screening
- •Weight-lowering agents within 3 months before screening.
- •Congestive heart failure (NYHA II-IV)
- •Chronic renal failure (glomerular filtration rate < 60 mL/min/1.73m2 per Modification of Diet in Renal Disease (MDRD))
- •Liver disease
- •History of gastrointestinal disorders (including gastropareses, pancreatitis and cholelithiasis)
- •Neurological illness
- •Malignancy
- •Other type of bariatric surgery (Redo-GBP, sleeve, distal GBP, adj banding, Scopinaro)
- •History of major heart disease
- •History of major renal disease
- •Pregnancy or breast feeding
- •Implantable devices
- •Substance abuse
- •Addiction
- •Contra-indication for MRI, such as claustrophobia or pacemaker
- •Any psychiatric illness; including eating disorders and depression
- •Chronic use of centrally acting agents or glucocorticoids within 2 weeks immediately prior to screening.
- •Use of cytostatic or immune modulatory agents
- •History or known allergy for acetaminophen.
- •History of allergy for insulin analog
- •History of allergy for liraglutide
- •Participation in other studies
- •Individuals who have received treatment within the last 30 days with a drug that has not received regulatory approval for any indication at the time of study entry
- •Individuals who are investigator site personnel, directly affiliated with the study, or are immediate family
研究组 & 干预措施
Liraglutide
12 week treatment with liraglutide in fixed dosage
干预措施: Liraglutide treatment 12 weeks (Drug)
Insulin glargine
12 week treatment, once daily, with insulin glargine. Dosage based on fasting blood glucose measurements
干预措施: insulin glargine treatment (Drug)
before start of treatment period
before start of the treatment period, one day with tests will be performed. During this test a GLP-1 receptor antagonist will be administered In the group with obesity and planned gastric bypass surgery, the GLP-1 receptor agonist will be administered during 1 test before and 1 test after the surgery
干预措施: GLP-1 receptor antagonist (Drug)
结局指标
主要结局
food-stimuli related neuronal activity in reward and satiety circuits as represented by BOLD fMRI signal change from baseline (%)
时间窗: approximately 3 years
* differences between obese T2DM patients and healthy lean subjects food-stimuli related neuronal activity in reward and satiety circuits as represented by BOLD fMRI signal change from baseline (%) * the involvement of endogenous GLP-1 food-stimuli related neuronal activity in reward and satiety circuits as represented by BOLD fMRI signal change from baseline (%) * Effects of treatment with the GLP-1 analog liraglutide in obese patients with type 2 diabetes in food-stimuli related neuronal activity in reward and satiety circuits as represented by BOLD fMRI signal change from baseline (%) * - To investigate the involvement of the increased meal-related endogenous GLP-1 levels after gastric bypass surgery in these food-stimuli related CNS satiety and reward responses and to investigate whether pharmacological blocking of endogenous GLP-1 receptor activation, using a GLP-1 antagonist, differentially affects these responses before and after gastric bypass surgery in obese individuals.
次要结局
- GLP-1 analog treatment related changes in obese patients with type 2 diabetes in microvascular function and vasomotion(approximately 3 years)
- GLP-1 analog treatment related changes in obese patients with type 2 diabetes in cardiovascular autonomic nervous balance(approximately 3 years)
- Alterations in resting state brain activity networks in obese patients with type 2 diabetes compared to lean, healthy individuals and the involvement of endogenous GLP-1(approximately 3 years)
- Alterations in brain arterial blood flow in obese patients with type 2 diabetes compared to lean, healthy individuals and the involvement of endogenous GLP-1(approximately 3 years)
- GLP-1 analog treatment related changes in obese patients with type 2 diabetes in self-reported hunger, satiety, fullness(approximately 3 years)
- GLP-1 analog treatment related changes in obese patients with type 2 diabetes in concomitant changes in metabolic and humoral markers(approximately 3 years)
- GLP-1 analog treatment related changes in obese patients with type 2 diabetes in basal metabolic rate and post-prandial energy expenditure(approximately 3 years)
- GLP-1 analog treatment related changes in obese patients with type 2 diabetes in resting state brain activity networks.(approximately 3 years)
- GLP-1 analog treatment related changes in obese patients with type 2 diabetes in brain arterial blood flow.(approximately 3 years)
研究者
RG IJzerman
MD, PhD
Amsterdam UMC, location VUmc