HUMAN ISLET ANTGEN DISCOVERY AND IMAGING

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DESCRIPTION (provided by applicant): The common pathology underlying both type 1 and type 2 diabetes (T1D and T2D) is insufficient beta-cell mass (BCM) to meet metabolic demands. An important impediment to the more rapid evaluation of interventions for both T1D and T2D is lack of suitable biomarkers of pancreatic beta cell mass. A reliable means of monitoring the mass and/or function of beta cells would enable evaluation of the progression of diabetes in real time as well as the monitoring the efficacy of pharmacologic and other interventions. This proposal addresses these needs. Recently, we identified a biomarker of beta cell mass that is quantifiable in vivo by Positron Emission Tomography (PET). PET is a tomographic imaging technique, which allows for accurate non-invasive in vivo dynamic measurements of regional radioligand uptake and clearance. These dynamic measurements of specific radiolabled compounds are sensitive in the pico- to nano-molar range and can be deconvoluted into measurements of receptor concentration. For beta cell mass estimates, we have identified VMAT2 (vesicular monoamine transporter type 2) as the biomarker and DTBZ as the transporter's ligand. VMAT2 is highly expressed in beta cells of the human pancreas relative to other cells of the endocrine and exocrine pancreas. Thus dynamic measurements of the uptake and clearance of DTBZ radioligands in the pancreas provide a measure of VMAT2 concentrations and an indirect measurement of beta cell mass. The primary aim of this renewal application is to better understand the biology and biochemistry of VMAT2 in beta cells and to provide further evidence of the clinical utility of PET scans using preclinical models of progression of T2D and therapy of T1D and T2D. In Specific Aim One we propose longitudinal studies using PET to estimate beta cell mass in a rodent models of T2D. These studies are designed to understand how estimates of BCM made PET scans with [18F]-FP-DTBZ perform under metabolic perturbations of beta cell mass and function. In Specific Aim Two, using insights developed in Aim one, we will analyze PET imaging of beta cells in the context of beta cell regeneration. In Specific Aim Three, we will study the tissue distribution of VMAT2 in a unique area of the human pancreas, the posterior lobe of the head, where VMAT2 expression may extend to cells expressing pancreatic polypeptide. In this Aim we will quantitate the co-expression of VMAT2 and pancreatic polypeptide to determine how far astray VMAT2 falls from being the "perfect" beta cell biomarker. Overall, the proposed studies in Aims one, two and three constitute the next logical next steps in our ongoing clinical evaluation of the use of VMAT2 as biomarker of BCM in human health and disease. PUBLIC HEALTH RELEVANCE: The rising world-wide incidence of diabetes, combined with the lack of suitable endpoints of the body's measurable and true capacity to produce insulin, constitute a serious restriction facing health care professionals and the pharmaceutical industry. Recently, we identified a biomarker of beta cell mass that is quantifiable in vivo by PET. This application proposes a series of studies aimed at validating the utility of this technique in monitoring diabetic disease progression in a non-invasive real time manner. The ability to noninvasively measure the mass of insulin producing beta cells will be of critical value towards characterizing new drugs and refining the diagnosis and treatment of this devastating disease.