? We hypothesize that non-invasive PET quantitation of vesicular monoamine transporters type 2 using the PET radioligand [11C] DTBZ will provide clinically meaningful estimates of beta cell mass (BCM) in prospective studies of individuals with type 1 diabetes mellitus (T1DM). This hypothesis is based on preclinical studies in rodent models of diabetes where we have demonstrated that PET based quantitation of [11C] DTBZ activity in the pancreas region of interest (pROI) is a valid surrogate marker of beta cell mass. In this application the following series of studies are proposed to determine the feasibility of using [11 C] DTBZ and PET to quantify beta cell mass in clinical research and practice.
Specific Aim 1 will test the hypothesis that there is significant difference in [11C] DTBZ radioligand uptake within the pancreata of normal individuals and patients with long standing type 1 diabetes mellitus (T1DM). We propose a cross-sectional study to determine whether there are measurable differences in BCM, as defined by PET scan using [11C] DTBZ, between euglycemic healthy controls and T1DM patients with biochemically documented inability to secrete c-peptide.
In Specific Aim 2, we will determine the clinical operating characteristics of PET scans with [11C] DTBZ. In these studies we will perform test-retest experiments in healthy volunteers to better understand the inter- and intra- assay variability of beta cell mass determinations by PET. We expect that the current PET imaging techniques and quantitation will be sufficiently precise to allow detection of the anticipated differences in BCM that accompany disease progression.
In Specific Aim 3, we propose to serially measure BCM by PET in individuals with new onset T1DM. We hypothesize that longitudinal measurement of [11C] DTBZ activity in the pROI will reveal 1) declining BCM, and 2) that the loss of BCM will correlate with standard laboratory measures of T1DM progression. The study population will be imaged by PET with [11C] DTBZ within 100 days of T1DM diagnosis and at two additional time points yearly for a total of 3 years.. Quantitation of radioligand uptake in the pROI will be performed by standard techniques including compartmental modeling. If successful, these studies will provide a foundation for further development of a new tool for 1) studying the natural history of diabetes (both type 1 and type 2), 2) evaluating pharmaceutical and cell-based treatments of diabetes, and 3) making clinical diagnoses related to incipient disease. ? ? ?
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