Healthy Volunteers, Diabetes Mellitus, Type 1
Conditions
Keywords
dihydrotetrabenazine, beta cell mass, diabetes mellitus
Brief summary
Type 1 diabetes mellitus (T1DM) develops when there is impaired insulin production due to loss of insulin producing cells (beta cells). The amount of insulin that can be produced is imperfectly correlated with beta cell mass (BCM). The development of a reliable method to noninvasively quantify the total amount of insulin producing beta cells would be of great benefit by providing an important endpoint for the development of new treatments of diabetes. The investigators have previously identified a specific marker on islet cells called vesicular monoamine transporter 2 (VMAT2) that the investigators now propose to use in positron emission tomography (PET) scanning to determine islet beta cell mass. The PET radiopharmaceutical 18 F-fluoropropyl(FP)-dihydrotetrabenazine(DTBZ) has been used previously in human subjects without adverse effects. It has shown promise in differentiating type 1 diabetes and non-diabetes. The investigators now hypothesize that repeat PET scans will be reproducible in the same subject. Subjects with normal BCM will be recruited from among normal weight non-diabetic people with plasma insulin levels within the normal range. Subjects with predicted reduced BCM will be recruited from among patients with T1DM who have low or non-measurable insulin levels. Two PET scan measurements will be taken in each subject and the amount of VMAT2 in the pancreas will be and compared for reproducible findings. Biochemical testing will also be performed and compared to PET scans as a potential indirect marker of beta cell mass.
Detailed description
Diabetes results when the insulin secretory capacity of the beta cell population is lost or severely compromised.Plasma insulin levels have been used as a surrogate marker of beta cell mass (BCM) but insulin levels often do not correlate well. A gold standard of measurement to obtain BCM would be of great value. The aim of the proposed study is to evaluate an islet imaging technique using PET scanning to directly measure BCM and thus provide valuable information for monitoring disease progress and response to therapy in people with diabetes and in people at high risk for diabetes. Type 1 diabetes (T1DM) occurs when the beta cells are selectively destroyed by a T cell mediated autoimmune process. People at high risk for developing T1DM, such as first degree relatives of patients with T1DM, can sometimes be identified before the disease develops by measuring autoantibodies to beta cells, however this test is neither sensitive nor specific. Little is known about the natural history of BCM, turnover and cell lifetime, or the course of inflammation in diabetes. This is principally because the pancreas is a highly heterogeneous organ that is difficult to biopsy without significant complications, and BCM only comprises 1 to 2% of the total volume. Accurate assessment of BCM in human diabetes is limited to autopsy studies, which usually suffer from inadequate clinical information; thus, the development of non-invasive means of BCM measurement could be important for interventional therapies of T1DM, islet regeneration/stem cell therapy and islet transplantation.
Interventions
DRUG18 F-FP-DTBZ
The drug, no carrier added \[18 F\]-FP-DTBZ, is formulated in 5% (v/v) ethanol in 0.9% sterile saline solution to produce \[18 F\]-FP-DTBZ for injection. Subjects will receive a single i.v. administration of no more than 7.6 millicuries (mCi) of \[18 F\]-FP-DTBZ for injection immediately prior to imaging. The specific activity at time of injection will less than 1.0 mCi/microgram and thus for a 7.6 mCi dose the maximal mass dose will be less than 10 microgram.
RADIATIONPET Scanning
Individuals will be imaged continuously (i.e. dynamically) for 2 hours.
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Columbia University
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
Yes
Inclusion criteria
* Patients with type 1 diabetes may be enrolled if they meet all of the following criteria: 1. Are males or females between 18 and 70 years of age, inclusive 2. Have a diagnosis of type 1 diabetes mellitus as defined by the American Diabetes Association (ADA) criteria or by diagnosed as per their endocrinologist; duration \>5 years; Insulin dose requirements \<0.8 units/kg/day 3. HbA1c level between 5% and 8.5% 4. Have fasting C-Peptide \< 0.1 ng/ml 5. Have a body mass index (BMI) between 18 and 32 kg/m2 6. Able to tolerate PET imaging 7. In the judgment of the physician, are capable of fasting 4 to 6 hours prior to screening and Day 1 imaging procedures 8. Give informed consent Healthy volunteers may be enrolled if they meeting all of the following criteria: 1. Are males or females between 18 and 70 years of age, inclusive 2. Have no history of type 1 or type 2 diabetes in a first degree relative 3. Fasting blood glucose less than 100 mg/dL 4. HbA1c level less than 6% 5. Normal Mixed Meal Tolerance test at screening visit 6. BMI between 18 and 32 kg/m2 7. Able to tolerate PET imaging 8. In the judgment of the physician, are capable of fasting 4 to 6 hours prior to screening and Day 1 imaging procedures, and 9. Give informed consent
Exclusion criteria
* Potential participants must not have any of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean VMAT2 Functional Binding Capacity in the β Cells to 18 F-FP-DTBZ | Up to 2 months from enrollment | The VMAT2 functional binding capacity in the body and tail of the pancreas is calculated as BPND (VMAT2 binding potential) × PET ROI (region-of-interest) Volume. BPND is unitless, and ROI unit is mL. Higher values of the VMAT functional binding capacity indicates greater β cell mass. |
Countries
United States
Participant flow
Recruitment details
Potential subjects with diabetes were recruited at the Naomi Berri Diabetes Center. The physician ascertained from the patient that he/she is willing to discuss the study with the research team before the investigators approach the patient. Non-diabetic subjects were either be referred by their physicians, by word of mouth, or by flyer.
Participants by arm
| Arm | Count |
|---|---|
| Healthy Controls Pancreatic 18 F-FP-DTBZ uptake will be measured with PET scanning in healthy controls: subjects with predicted normal BCM (healthy, normal weight, non-diabetic individuals who have stimulated insulin and c-peptide levels within the normal range).
18 F-FP-DTBZ: The drug, no carrier added \[18 F\]-FP-DTBZ, is formulated in 5% (v/v) ethanol in 0.9% sterile saline solution to produce \[18 F\]-FP-DTBZ for injection. Subjects will receive a single i.v. administration of no more than 7.6 mCi of \[18 F\]-FP-DTBZ for injection immediately prior to imaging. The specific activity at time of injection will less than 1.0 mCi/microgram and thus for a 7.6 mCi dose the maximal mass dose will be less than 10 microgram.
PET Scanning: Individuals will be imaged continuously (i.e. dynamically) for 2 hours. | 14 |
| Patients With T1D Pancreatic 18 F-FP-DTBZ uptake will be measured with PET scanning in patients with longstanding T1D: subjects with predicted reduced beta cell mass (subjects with established T1DM who have low or no measurable stimulated insulin and c-peptide levels).
18 F-FP-DTBZ: The drug, no carrier added \[18 F\]-FP-DTBZ, is formulated in 5% (v/v) ethanol in 0.9% sterile saline solution to produce \[18 F\]-FP-DTBZ for injection. Subjects will receive a single i.v. administration of no more than 7.6 mCi of \[18 F\]-FP-DTBZ for injection immediately prior to imaging. The specific activity at time of injection will less than 1.0 mCi/microgram and thus for a 7.6 mCi dose the maximal mass dose will be less than 10 microgram.
PET Scanning: Individuals will be imaged continuously (i.e. dynamically) for 2 hours. | 8 |
| Total | 22 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Healthy Controls | Patients With T1D | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 14 Participants | 8 Participants | 22 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 14 Participants | 8 Participants | 22 Participants |
| Sex: Female, Male Female | 5 Participants | 4 Participants | 9 Participants |
| Sex: Female, Male Male | 9 Participants | 4 Participants | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 14 | 0 / 8 |
| other Total, other adverse events | 0 / 14 | 0 / 8 |
| serious Total, serious adverse events | 0 / 14 | 0 / 8 |
Outcome results
Primary
Mean VMAT2 Functional Binding Capacity in the β Cells to 18 F-FP-DTBZ
The VMAT2 functional binding capacity in the body and tail of the pancreas is calculated as BPND (VMAT2 binding potential) × PET ROI (region-of-interest) Volume. BPND is unitless, and ROI unit is mL. Higher values of the VMAT functional binding capacity indicates greater β cell mass.
Time frame: Up to 2 months from enrollment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Study Controls | Mean VMAT2 Functional Binding Capacity in the β Cells to 18 F-FP-DTBZ | 103 unitless | Standard Error 12 |
| Longstanding T1D | Mean VMAT2 Functional Binding Capacity in the β Cells to 18 F-FP-DTBZ | 38 unitless | Standard Error 5 |