Dopamine and Insulin Resistance

• Sponsor: Vanderbilt University (Other)
• Overall Status: Completed
• CT.gov ID: NCT00802204
• Collaborator: (none)
• Enrollment: 28
• Location: 1
• Arms: 2
• Duration (Months): 48
• Patients Per Site Per Month: 0.6

Study Details

Study Description

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

Condition or Disease	Intervention/Treatment	Phase
Obesity	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	N/A

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 28 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• 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 .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)
• Primary Purpose: Other
• Official Title: Dopamine Receptor Availability and Insulin Resistance
• Study Start Date: Dec 1, 2008
• Actual Primary Completion Date: Apr 1, 2011
• Actual Study Completion Date: Dec 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Lean controls Lean complete baseline outcome measures only	Radiation: PET scan; 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; Procedure: Oral glucose tolerance test; 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; Procedure: MRI; An MRI of the brain and abdomen will be performed prior to PET scan One time at baseline in both lean and obese; Behavioral: Psychological scales to assess attitudes and behaviors related to eating and quality of life; A series of short psychological scales will be administered during the study. Completed at baseline
Experimental: Obese Obese completing baseline and post-VLCD outcome measures	Radiation: PET scan; 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; Procedure: Oral glucose tolerance test; 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; Procedure: MRI; An MRI of the brain and abdomen will be performed prior to PET scan One time at baseline in both lean and obese; Behavioral: Psychological scales to assess attitudes and behaviors related to eating and quality of life; A series of short psychological scales will be administered during the study. Completed at baseline; Other: Caloric Restriction; Obese participants only complete a short-term (~10days) very low calorie diet

Outcome Measures

Primary Outcome Measures

1. Striatal DRD2 Receptor Binding [Baseline and after 8-10days VLCD]

   Region of interest compared to reference region to calculate binding potential

2. Insulin [Baseline to post 8-10days after VLCD]

   microU/ml

3. Glucose [Baseline to post 8-10days after VLCD]

4. Leptin [Baseline to post 8-10days after VLCD]

5. Acyl Ghrelin [Baseline to post 8-10days after VLCD]

6. Insulin Sensitivity From Oral Glucose Tolerance Test (OGTT_SI) [Baseline to post 8-10days after VLCD]

   Insulin Sensitivity from Oral Glucose Tolerance Test was estimated using the minimal model method

Secondary Outcome Measures

1. Binge Eating Score Questionnaire [Baseline]

   Increased scores indicate increased binge eating behaviors. Score 0-46

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 60 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Vanderbilt University Medical Center	Nashville	Tennessee	United States	37232

Sponsors and Collaborators

• Vanderbilt University

Investigators

• Principal Investigator: Julia P Dunn, MD, Vanderbilt University Medical Center
• Study Director: Robert M Kessler, MD, Vanderbilt University Medical Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Julia P.Dunn,MD, Physician, Vanderbilt University
• ClinicalTrials.gov Identifier: NCT00802204
• Other Study ID Numbers: IRB#080861 and 061246
• First Posted: Dec 4, 2008
• Last Update Posted: May 10, 2017
• Last Verified: Mar 1, 2017

• Keywords provided by Julia P.Dunn,MD, Physician, Vanderbilt University: Obesity; Insulin Resistance; Neuroendocrine regulation; Eating behaviors; Dopamine signaling
• Additional relevant MeSH terms: Insulin Resistance

Study Results

Participant Flow

Recruitment Details	9 lean enroll but only 8 complete. The lean complete study after baseline outcome measurements. 19 obese enroll but only 18 complete baseline outcome measurements and of these 15 completed the VLCD and post-outcome measurements

Arm/Group Title	Lean	Obese
Arm/Group Description	BMI<~25kg/m2	BMI>/=30kg/m2
Period Title: Overall Study
STARTED	9	19
COMPLETED	8	18
NOT COMPLETED	1	1

Baseline Characteristics

Arm/Group Title	Lean	Obese	Total
Arm/Group Description	Total of all reporting groups
Overall Participants	8	18	26
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	41 (9)	39 (8)	39 (8)
Sex: Female, Male (Count of Participants)
Female	8 100%	18 100%	26 100%
Male	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (participants) [Number]
African American Participants	1 12.5%	7 38.9%	8 30.8%
Caucasian Participants	7 87.5%	11 61.1%	18 69.2%
Region of Enrollment (participants) [Number]
United States	8 100%	18 100%	26 100%
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	60 (7)	104 (17)	91 (26)
BMI (kg/m2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m2]	23 (2)	39 (6)	33 (9)
Beck Depression Inventory II(BDI-II) (scores on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [scores on a scale]	3 (5)	7 (6)	6 (6)
OGTT_SI (Insulin Sensitivity from OGTT) ((10-4min-1/µU*mL)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [(10-4min-1/µU*mL)]	11.2 (4.1)	3.98 (2.7)	6 (5)
Insulin ((µU/ml)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [(µU/ml)]	6 (2)	18 (9)	14 (10)
Glucose (mg/dl) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mg/dl]	82 (6)	87 (9)	86 (8)
Leptin (ng/ml) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [ng/ml]	13 (5)	43 (12)	34 (18)
Acyl Ghrelin (pg/ml) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [pg/ml]	235 (104)	78 (55)	132 (106)

Outcome Measures

1. Primary Outcome

Title	Striatal DRD2 Receptor Binding
Description	Region of interest compared to reference region to calculate binding potential
Time Frame	Baseline and after 8-10days VLCD

Outcome Measure Data

Analysis Population Description

Baseline outcome measurements are compared between lean and obese. Baseline and post outcome measurements are compared for the obese who completed VLCD

Arm/Group Title	Lean Baseline	Obese Baseline	Obese Post-diet
Arm/Group Description
Measure Participants	8	18	15
caudate	28 (3)	33 (3)	32 (3)
putamen	33 (3)	38 (3)	36 (4)
ventral striatum	19 (4)	22 (3)	22 (3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Obese Baseline, Obese Post-diet
	Comments	Baseline outcome measurements are compared between lean and obese. Baseline and post outcome measurements are compared for the obese who completed VLCD
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.05
	Comments
	Method	t-test, 2 sided
	Comments	describe.....

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Obese Baseline, Obese Post-diet
	Comments	Paired t-test to compare baseline and post-diet outcome measures
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.05
	Comments
	Method	t-test, 2 sided
	Comments

2. Primary Outcome

Title	Insulin
Description	microU/ml
Time Frame	Baseline to post 8-10days after VLCD

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Lean Baseline	Obese Baseline	Obese Post-diet
Arm/Group Description
Measure Participants	8	18	15
Mean (Standard Deviation) [microU/ml]	6 (2)	19 (10)	11 (5)

3. Primary Outcome

Title	Glucose
Time Frame	Baseline to post 8-10days after VLCD

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Lean Baseline	Obese Baseline	Obese Post-diet
Arm/Group Description
Measure Participants	8	18	15
Mean (Standard Deviation) [mg/dL]	82 (6)	87 (9)	81 (7)

4. Primary Outcome

Title	Leptin
Time Frame	Baseline to post 8-10days after VLCD

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Lean Baseline	Obese Baseline	Obese Post-diet
Arm/Group Description
Measure Participants	8	18	15
Mean (Standard Deviation) [ng/ml]	13 (5)	43 (12)	34 (15)

5. Primary Outcome

Title	Acyl Ghrelin
Time Frame	Baseline to post 8-10days after VLCD

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Lean Baseline	Obese Baseline	Obese Post-diet
Arm/Group Description
Measure Participants	8	18	15
Mean (Standard Deviation) [pg/ml]	235 (104)	78 (55)	59 (36)

6. Primary Outcome

Title	Insulin Sensitivity From Oral Glucose Tolerance Test (OGTT_SI)
Description	Insulin Sensitivity from Oral Glucose Tolerance Test was estimated using the minimal model method
Time Frame	Baseline to post 8-10days after VLCD

Outcome Measure Data

Analysis Population Description

9 lean enroll but only 8 complete. A ll lean complete study after baseline outcome measurements. 19 obese enroll but only 18 complete baseline studies and of these 15 completed the VLCD

Arm/Group Title	Lean Baseline	Obese Baseline	Obese Post-diet
Arm/Group Description
Measure Participants	8	18	15
Mean (Standard Deviation) [10-4*min-1*microU-1*mL]	11 (4)	4 (3)	4 (3)

7. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Lean	Obese
Arm/Group Description
Measure Participants	8	18
Mean (Standard Deviation) [score from questionnaire]	6 (6)	12 (7)

Adverse Events

Arm/Group Title	Lean		Obese
Arm/Group Description
All Cause Mortality
	Lean		Obese
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Lean		Obese
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/9 (0%)		0/19 (0%)
Other (Not Including Serious) Adverse Events
	Lean		Obese
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/9 (0%)		0/19 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.