A clinically viable means to measure pancreatic beta-cell mass (BCM) is essential for evaluating the physiological basis of therapeutic approaches to restore deficient insulin secretory capacity. Major advances in imaging BCM have been made by taking advantage of receptor-specific imaging probes that have been successfully used for neuroimaging. Neurons and ?-cells are functionally similar in being able to respond to cell-specific extracellular stimuli with the secretion of the contents of intracellular vesicles. Hence, Positron Emission Tomography (PET) imaging ligands that were originally developed to specifically bind to neurons may prove useful for imaging BCM. The Yale PET Center has been at the forefront of imaging both brain receptors and BCM and proposes to evaluate its extensive library of human neuroimaging agents as in vivo probes to quantitatively determine BCM. To maximize the value of these studies, pancreatic imaging in humans will be obtained together with validation studies in healthy and type 1 and 2 diabetes mellitus pancreas. Imaging probes that show suitable in vivo specific uptake in pancreas and appropriate imaging properties in humans, and can distinguish between healthy and diabetic pancreas in vitro will then be tested in a limited clinical PET-imaging trial to assess whether there is a measurable decrease in radiotracer binding in the pancreas of T1DM patients.
In Specific Aim 1, we will evaluate whether the approved radiotracers currently in use at the Yale PET center for human neuroimaging can be used for imaging BCM in healthy individuals. We plan to either piggyback onto ongoing imaging studies to evaluate the suitability for pancreas imaging of at least 10 radioligands currently in use for neuroimaging.
In Specific Aim 2, we will validate ?-cell specificity of the radioligands in vitro in healthy, T1DM, and T2DM human pancreas tissue obtained from the network for Pancreatic Organ Donors with Diabetes (nPOD), and in human islets. Those radioligands that may be useful for measuring insulin secreting beta-cells will have higher specific binding to healthy human islets and to pancreas from healthy donors compared to pancreas from patients with T1DM or T2DM.
In Specific Aim 3, we will perform a clinical evaluation in healthy and T1DM volunteers of those agents that meet the criteria of 1) promising pancreas imaging characteristics determined in Aim 1 and 2) favorable ?-cell specificity as determined in Aim 2. A limited clinical evaluation is necessary to establish whether the radioligand can quantitatively measure changes in BCM that are physiologically relevant to diabetes progression.
A clinically viable means to measure pancreatic beta-cell mass (BCM) is essential for evaluating the physiological basis of therapeutic approaches to restore deficient insulin secretory capacity. This proposal will identify whether imaging agents already in use for human neuroimaging would also be useful for measuring BCM. These tracers may provide unique insight into the biochemical mechanisms that contribute to beta-cell compensation in the face of insulin resistance, and the mechanisms that contribute to beta-cell failure and loss.