Clinical trial NCT00802204: Dopamine and Insulin Resistance
Official title: Dopamine Receptor Availability and Insulin Resistance
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Obesity
Keywords: Obesity
Insulin Resistance
Neuroendocrine regulation
Eating behaviors
Dopamine signaling
Lead sponsor: Vanderbilt University Medical Center
Sponsor class: OTHER
First posted: 2008-12-04
Enrollment: 28
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention 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 .
Primary purpose: OTHER

Brief summary: 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: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Striatal DRD2 Receptor Binding
timeFrame: Baseline and after 8-10days VLCD
measure: Insulin
timeFrame: Baseline to post 8-10days after VLCD
measure: Glucose
timeFrame: Baseline to post 8-10days after VLCD
measure: Leptin
timeFrame: Baseline to post 8-10days after VLCD
measure: Acyl Ghrelin
timeFrame: Baseline to post 8-10days after VLCD
measure: Insulin Sensitivity From Oral Glucose Tolerance Test (OGTT_SI)
timeFrame: Baseline to post 8-10days after VLCD
Secondary outcomes:
measure: Binge Eating Score Questionnaire
timeFrame: Baseline
Other outcomes:
Locations:
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
Study officials:
affiliation: Vanderbilt University Medical Center
name: Julia P Dunn, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Vanderbilt University Medical Center
name: Robert M Kessler, MD
role: STUDY_DIRECTOR
References:
citation: Dunn JP, Abumrad NN, Patterson BW, Kessler RM, Tamboli RA. Brief communication: beta-cell function influences dopamine receptor availability. PLoS One. 2019 Mar 8;14(3):e0212738. doi: 10.1371/journal.pone.0212738. eCollection 2019.
citation: Dunn JP, Abumrad NN, Kessler RM, Patterson BW, Li R, Marks-Shulman P, Tamboli RA. Caloric Restriction-Induced Decreases in Dopamine Receptor Availability are Associated with Leptin Concentration. Obesity (Silver Spring). 2017 Nov;25(11):1910-1915. doi: 10.1002/oby.22023. Epub 2017 Sep 25.
citation: Garcia AE, Kasim N, Tamboli RA, Gonzalez RS, Antoun J, Eckert EA, Marks-Shulman PA, Dunn J, Wattacheril J, Wallen T, Abumrad NN, Flynn CR. Lipoprotein Profiles in Class III Obese Caucasian and African American Women with Nonalcoholic Fatty Liver Disease. PLoS One. 2015 Nov 23;10(11):e0142676. doi: 10.1371/journal.pone.0142676. eCollection 2015.
citation: Dunn JP, Kessler RM, Feurer ID, Volkow ND, Patterson BW, Ansari MS, Li R, Marks-Shulman P, Abumrad NN. Relationship of dopamine type 2 receptor binding potential with fasting neuroendocrine hormones and insulin sensitivity in human obesity. Diabetes Care. 2012 May;35(5):1105-11. doi: 10.2337/dc11-2250. Epub 2012 Mar 19.