Dopamine and Insulin Resistance

Study Overview
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Brief Summary
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Obese individuals have fewer striatal dopamine type 2 receptors (DRD2) than normal weight individuals. Lower DRD2 levels are associated with addiction and a decreased sense of pleasure.Obesity is also associated with insulin resistance (poor insulin action).We propose that insulin resistance and low DRD2 are associated. Using PET imaging,we aim to determine DRD2 binding potential (BP) in the brain is associated with insulin resistance and neuroendocrine hormone levels. Obese participants will be compared to lean, gender and age similar participants. We also aim to determine the effect of caloric restriction on DRD2 BP in obese subjects

Detailed Description
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In has been reported obese individuals have fewer striatal dopamine type 2 receptors (DRD2) compared to normal weight individuals congruent with diet induced obese rodent models and similar to models of addiction. Lower DRD2 levels are associated with addiction and a decreased sense of pleasure. Excessive weight gain also contributes to the onset of impaired insulin signaling (insulin resistance). In the brain insulin regulates monoamines and has trophic effects. We propose that the previous reports of low DRD2 in individuals with obesity will be associated with the degree of insulin resistance. Using PET imaging, we aim to determine DRD2 binding potential (BP) in the striatum and hypothesize these measurements will be associated with insulin resistance and potentially other neuroendocrine hormone levels. Obese participants will be compared to lean, sex and age similar participants. We also aim to determine the effect of caloric restriction on DRD2 BP in obese subjects. We hypothesize the caloric restriction will improve insulin resistance and that changes in DRD2 binding will be associated with changes in insulin signaling.

Official Title
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Dopamine Receptor Availability and Insulin Resistance

Conditions
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Obesity

Intervention / Treatment
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* Radiation: PET scan
* Procedure: Oral glucose tolerance test
* Procedure: MRI
* Behavioral: Psychological scales to assess attitudes and behaviors related to eating and quality of life
* Other: Caloric Restriction


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ages 18-60 yrs obese BMI > 30kg/m2 and Weight less than 350 lbs lean control BMI 18-25kg/m2 Exclusion Criteria: Structured exercise > equivalent to 30mins 5x week of walking times a week History of Substance Abuse, including but exclusive to alcohol, cocaine, marijuana, heroin, nicotine Current psychiatric disorder or significant h/o disorder Use or any antidepressants or antipsychotics for last 3-6months or depot antipsychotics in the last 12 months Any condition felt by PI or co-investigators to interfere with ability to complete the study Inability to abstain from alcohol, physical exercise or > 1 cup of coffee or equivalent daily for 3 days prior to imaging studies Significant co-morbidities including atherosclerotic disease, metabolic disease, liver or renal insufficiency or abnormality found on MRI Any condition which would interfere with MRI or PET studies, e.g. claustrophobia, cochlear implant, metal fragments in eyes, cardiac pacemaker, neural stimulator, tattoos with iron pigment and metallic body inclusions or other metal implanted in the body which may interfere with MRI scanning Subjects on medications determined by PI, ex. sibutramine, frequent benzodiazepines or related drugs, which could affect quality of study for last 3 months.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Lean who are age and sex similar to obese will complete baseline outcome measurements only. Obese will complete baseline outcome measurements then the VLCD intervention with post outcome measurements .
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Lean controls<br>Lean complete baseline outcome measures only | Radiation: PET scan<br>* Both lean and obese undergo a PET scan of the brain using the radioligand,fallypride [18F] at baseline. Obese subjects who complete caloric restriction will have repeat scan after diet. Completed at baseline and post-VLCD<br>Procedure: Oral glucose tolerance test<br>* Subjects will be required to drink a glucose solution; blood samples will be taken over a 5-hour time period Completed at baseline by both lean and obese and in obese post-VLCD<br>Procedure: MRI<br>* An MRI of the brain and abdomen will be performed prior to PET scan One time at baseline in both lean and obese<br>Behavioral: Psychological scales to assess attitudes and behaviors related to eating and quality of life<br>* A series of short psychological scales will be administered during the study. Completed at baseline<br>|
| Experimental: Obese<br>Obese completing baseline and post-VLCD outcome measures | Radiation: PET scan<br>* Both lean and obese undergo a PET scan of the brain using the radioligand,fallypride [18F] at baseline. Obese subjects who complete caloric restriction will have repeat scan after diet. Completed at baseline and post-VLCD<br>Procedure: Oral glucose tolerance test<br>* Subjects will be required to drink a glucose solution; blood samples will be taken over a 5-hour time period Completed at baseline by both lean and obese and in obese post-VLCD<br>Procedure: MRI<br>* An MRI of the brain and abdomen will be performed prior to PET scan One time at baseline in both lean and obese<br>Behavioral: Psychological scales to assess attitudes and behaviors related to eating and quality of life<br>* A series of short psychological scales will be administered during the study. Completed at baseline<br>Other: Caloric Restriction<br>* Obese participants only complete a short-term ( 10days) very low calorie diet<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Striatal DRD2 Receptor Binding | Region of interest compared to reference region to calculate binding potential | Baseline and after 8-10days VLCD | 
| Insulin | microU/ml | Baseline to post 8-10days after VLCD | 
| Glucose |  | Baseline to post 8-10days after VLCD | 
| Leptin |  | Baseline to post 8-10days after VLCD | 
| Acyl Ghrelin |  | Baseline to post 8-10days after VLCD | 
| Insulin Sensitivity From Oral Glucose Tolerance Test (OGTT_SI) | Insulin Sensitivity from Oral Glucose Tolerance Test was estimated using the minimal model method | Baseline to post 8-10days after VLCD | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Binge Eating Score Questionnaire | Increased scores indicate increased binge eating behaviors. Score 0-46 | Baseline | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Eating behaviors, Dopamine signaling, Obesity, Insulin Resistance, Neuroendocrine regulation