The Interaction Between Diabetes and Estradiol on Human Brain Metabolism in Postmenopausal Women (E2T2D)

• ClinicalTrials.gov Identifier: NCT03681691
• Recruitment Status: Completed
• First Posted: September 24, 2018
• Results First Posted: September 27, 2022
• Last Update Posted: September 27, 2022
• Sponsor: Wake Forest University Health Sciences
• Collaborator: National Institute on Aging (NIA)
• Information provided by (Responsible Party): Wake Forest University Health Sciences

Study Description

Brief Summary:

The primary aim of this study is to test whether type 2 diabetes interacts with estradiol on brain metabolism in vivo in humans. This will be accomplished by imaging brain metabolism using positron emission tomography before and after short-term administration of transdermal 17β-estradiol in 10 postmenopausal women with diabetes and 10 non-diabetic postmenopausal women.

Condition or disease	Intervention/treatment	Phase
Diabetes Type 2; Dementia	Drug: Estradiol patch	Phase 1

Detailed Description:

Epidemiological studies suggest there may be an interaction between type 2 diabetes and estrogen in postmenopausal women, such that diabetes may interact with estrogen levels over time to increase risk for dementia. The mechanism for this effect is now known. However, animal research suggests that it may occur through estrogen's effects on cellular metabolism of glucose and ketone bodies. The primary aim of this study is to test whether type 2 diabetes interacts with estradiol on brain metabolism in vivo in humans. This will be accomplished by imaging brain metabolism using positron emission tomography before and after short-term administration of transdermal 17β-estradiol in 10 postmenopausal women with diabetes and 10 non-diabetic postmenopausal women.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 12 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Primary Objective: The primary objective is to determine whether the effects of glucose and ketone body uptake to the brain in response to 8-week administration of transdermal 17β-estradiol differ in postmenopausal women with and without type 2 diabetes.
• Masking: None (Open Label)
• Primary Purpose: Other
• Official Title: The Interaction Between Diabetes and Estradiol on Human Brain Metabolism in Postmenopausal Women
• Actual Study Start Date: May 13, 2019
• Actual Primary Completion Date: July 19, 2021
• Actual Study Completion Date: July 19, 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: Post menopausal women with diabetes; 8-week administration of transdermal 17β-estradiol (Climara) patch in postmenopausal women with type 2 diabetes	Drug: Estradiol patch; transdermal 17β-estradiol patch; Other Name: Climara patch
Experimental: Post menopausal women without diabetes; 8-week administration of transdermal 17β-estradiol (Climara) patch in postmenopausal women without type 2 diabetes.	Drug: Estradiol patch; transdermal 17β-estradiol patch; Other Name: Climara patch

Outcome Measures

Primary Outcome Measures :

1. Fluorodeoxyglucose (FDG) Positron Emission Tomography (PET)--Whole Brain [ Time Frame: Baseline ]
   Brain metabolism will be measured using PET tracers to examine brain glucose uptake (FDG PET). PET imaging data are co-registered to T1 structural MRI data to conduct region-of-interest based analyses. Absolute global and regional uptake of FDG will be quantified.
2. FDG PET--Whole Brain [ Time Frame: Week 8 ]
   Brain metabolism will be measured using PET tracers to examine brain glucose uptake (FDG PET). PET imaging data are co-registered to T1 structural MRI data to conduct region-of-interest based analyses. Absolute global and regional uptake of FDG will be quantified.
3. Acetoacetate Uptake (AcAc) PET--Whole Brain [ Time Frame: Baseline ]
   Brain metabolism will be measured using PET tracers to examine brain ketone body (acetoacetate) uptake (AcAc). PET imaging data are co-registered to T1 structural MRI data to conduct region-of-interest based analyses. Absolute global and regional uptake of AcAc tracers will be quantified.
4. AcAc PET--Whole Brain [ Time Frame: Week 8 ]
   Brain metabolism will be measured using PET tracers to examine brain ketone body (acetoacetate) uptake (AcAc). PET imaging data are co-registered to T1 structural MRI data to conduct region-of-interest based analyses. Absolute global and regional uptake of AcAc tracers will be quantified.
5. Change in Uptake of Glucose and Ketone Bodies in Whole Brain and Alzheimer's Disease-related Regions of Interest. [ Time Frame: Baseline and 8 weeks ]
   Brain metabolism will be measured using PET tracers to examine brain glucose uptake (FDG PET) and ketone body (acetoacetate) uptake (AcAc). PET imaging data are co-registered to T1 structural MRI data to conduct region-of-interest based analyses. Absolute global and regional uptake of FDG and AcAc tracers will be quantified, as well as uptake of AcAc relative to FDG to find potential regions of compensatory ketone use

Secondary Outcome Measures :

1. Short-Term Memory Composite Score [ Time Frame: Baseline and Week 8 ]
   A composite memory score was created by averaging z-scores for CVLT delayed recall, BVRT delayed recall, and prospective memory. A composite executive function score was created by averaging digit span forwards total correct, digit span backwards total correct, and both verbal fluency scores. Summed z-score ranging from -2 to 2 where higher score indicates better performance.
2. Executive Function Composite Score [ Time Frame: Baseline and Week 8 ]
   The California Verbal Learning Test (CVLT) is a word list recall task that can be used to test immediate and delayed verbal memory. Free recall after the short delay (immediately after learning lists) and long delay (25 minutes) are reported. Summed z-score ranging from -2 to 2 where higher score indicates better performance.
3. California Verbal Learning Task (CVLT) Long Delay Free Recall [ Time Frame: Baseline and Week 8 ]
   The CVLT is a word list recall task that can be used to test immediate and delayed verbal memory. Free recall after long delay (25 minutes). The minimum score is 0. The maximum score is 16 and a higher score represents better performance.
4. CVLT Short Delay Free Recall [ Time Frame: Baseline and Week 8 ]
   The CVLT is a word list recall task that can be used to test immediate and delayed verbal memory. Short delay free recall is immediately after learning lists. The minimum score is 0. The maximum score is 16 and a higher score represents better performance.
5. Benton Visual Retention Task (BVRT) Total Score [ Time Frame: Baseline and Week 8 ]
   The BVRT tests figural memory by testing memory for a line drawing. The minimum score is 0. The scoring used is total correct, the maximum score is 10, and a higher score represents better performance. The total score is reported.
6. Prospective Memory [ Time Frame: Baseline and Week 8 ]
   The Prospective Memory test is a test of everyday memory where participants are given instructions for 3 tasks that will occur later on during the testing session. The minimum score is 0. The maximum score is 12 points, a higher score represents better performance, and the total score is reported
7. Verbal Fluency (Letters) [ Time Frame: Baseline and Week 8 ]
   Participants were given a letter and asked to say aloud as many words as they could think of beginning with that letter. The three letters were F, A, and S, and the participant had one minute per letter to list words. The total score reported is the sum of the correct words generated for all three letters. Although there is no set maximum score, based on published data, it was anticipated that scores could range from 1 to no more than 120. A higher value reflects better performance.
8. Verbal Fluency Score (Fruits and Vegetables) [ Time Frame: Baseline and Week 8 ]
   Participants were given one minute to say aloud as many fruits as possible and one minute to list as many vegetables as possible. The total score reported is the sum of all correct fruits and vegetables listed. Although there is no set maximum score, it was anticipated that scores could range from 0 to no more than 60. A higher value reflects better performance.
9. Digit Span Forward Total Correct [ Time Frame: Baseline and Week 8 ]
   Participants listened to a sequence of two to nine numbers and were asked to repeat each sequence back to the tester in the same order the numbers were presented. The outcome measure reported here is the total number of correct responses (range of scores 0-9). Higher scores reflect better performance.
10. Digit Span Backward Total Correct [ Time Frame: Baseline and Week 8 ]
    Participants listened to a sequence of two to nine numbers and were asked to repeat each sequence back to the tester in reverse order. The outcome measure reported here is the longest span of numbers recalled (range of scores 0-9). Higher scores reflect better performance.
11. Finger Tapping Score--Dominant Hand [ Time Frame: Baseline and Week 8 ]
    The Finger Tapping test assesses fine motor speed by asking participants to tap a button as many times as possible. Seven trials were administered. The highest and lowest scores were dropped, and the reported score is the average of the remaining 5 trials. Results for the dominant hand are reported here. There is no set maximum score. However, published averages for women in this age range suggest that a value over 57 would be highly unusual. A higher value (more taps) is better performance.
12. Finger Tapping Score--Non-Dominant Hand [ Time Frame: Baseline and Week 8 ]
    The Finger Tapping test assesses fine motor speed by asking participants to tap a button as many times as possible. Seven trials were administered. The highest and lowest scores were dropped, and the reported score is the average of the remaining 5 trials. Results for the non-dominant hand are reported here. There is no set maximum score. However, published averages for women in this age range suggest that a value over 57 would be highly unusual. A higher value (more taps) is better performance.
13. Card Rotations Test Score [ Time Frame: Baseline and Week 8 ]
    The Card Rotations Test is used to assess the ability to mentally rotate figures in space. The test has two parts, each of which last 3 minutes. During each part, the participant is given a sheet of paper with 10 simple geometric figures. Next to each figure is a row of 8 similar figures. Participants are asked to mark whether each of the figures in the row is the same or different than the first figure in the row. The score reported is the number of correct responses. The minimum score is 0. The maximum possible score is 160 and a higher score reflects better performance.
14. Change in Short-term Memory and Executive Function Composite Scores. [ Time Frame: Baseline and 8 weeks ]
    A battery of cognitive tasks will be administered before and after estrogen administration. Composite z-scores will be calculated by calculating a z-score for each cognitive task and summing z-scores from -5 (low) to 5 (high) for the tasks designated as short-term memory and executive function.Higher scores denotes better outcomes.

Other Outcome Measures:

1. Regional Ratio of Ketone/Glucose Uptake [ Time Frame: Baseline and Week 8 ]
2. Number of White Matter Hypertensities [ Time Frame: Baseline and Week 8 ]
   Attained from a T2-weighted FLAIR image, an indicator of small-vessel disease correlated with diabetes status and hypertension
3. Number of Microbleeds [ Time Frame: Baseline and Week 8 ]
   Attained from a susceptibility-weighted image

Eligibility Criteria

• Ages Eligible for Study: 60 Years to 80 Years (Adult, Older Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: Yes

Criteria

Inclusion Criteria:

1. Willing to provide written informed consent
2. Stated willingness to comply with all study procedures and availability for the duration of the study
3. Female, postmenopausal, aged 60-80
4. Normal results on recommended healthcare screenings (e.g., mammogram, pap smear, colonoscopy)
5. BMI 20-35 kg/m2
6. No evidence of dementia or mild cognitive impairment (MoCA score >25)
7. Able to access reliable transportation to study and intervention visits

Exclusion Criteria:

1. Use of hormone replacement therapy within the past 3 months
2. History of renal, heart, liver, or neurological disease; head injury with loss of consciousness in the past 5 years; chronic pain, anxiety or depression
3. Presence of medical conditions that might contraindicate estrogen use (e.g., unexplained vaginal bleeding, history of reproductive tissue cancer, thrombosis)
4. Currently taking insulin, metformin, or any other drug or medication judged by the study physician to affect safety or research outcomes of interest
5. Involved in another research study
6. Contraindications for MRI or PET scanning
7. Current smoker

Contacts and Locations

Locations

United States, North Carolina

Wake Forest University Health Sciences

Winston-Salem, North Carolina, United States, 27157

Sponsors and Collaborators

Wake Forest University Health Sciences

National Institute on Aging (NIA)

Investigators

• Principal Investigator: Christina Hugenschmidt, PhD; Wake Forest Health Sciences

  Study Documents (Full-Text)

Documents provided by Wake Forest University Health Sciences:

Study Protocol and Statistical Analysis Plan  [PDF] March 16, 2021

Informed Consent Form  [PDF] April 19, 2021

More Information

• Responsible Party: Wake Forest University Health Sciences
• ClinicalTrials.gov Identifier: NCT03681691
• Other Study ID Numbers: IRB00049740; R21AG054955 ( U.S. NIH Grant/Contract )
• First Posted: September 24, 2018
• Results First Posted: September 27, 2022
• Last Update Posted: September 27, 2022
• Last Verified: July 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided
• Plan Description: Undecided at the present time.

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Keywords provided by Wake Forest University Health Sciences:

women's health; estradiol; postmenopausal

Additional relevant MeSH terms:

Diabetes Mellitus; Diabetes Mellitus, Type 2; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Estradiol; Estrogens; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs