Beta Cell Imaging—From Pre-Clinical Validation to First in Man Testing

Abstract

There are presently no reliable ways to quantify human pancreatic beta cell mass (BCM) in vivo, which prevents an accurate understanding of the progressive beta cell loss in diabetes or following islet transplantation. Furthermore, the lack of beta cell imaging hampers the evaluation of the impact of new drugs aiming to prevent beta cell loss or to restore BCM in diabetes. We presently discuss the potential value of BCM determination as a cornerstone for individualized therapies in diabetes, describe the presently available probes for human BCM evaluation, and discuss our approach for the discovery of novel beta cell biomarkers, based on the determination of specific splice variants present in human beta cells. This has already led to the identification of DPP6 and FXYD2ga as two promising targets for human BCM imaging, and is followed by a discussion of potential safety issues, the role for radiochemistry in the improvement of BCM imaging, and concludes with an overview of the different steps from pre-clinical validation to a first-in-man trial for novel tracers.

Non-invasive Beta-cell Imaging: Visualization, Quantification, and Beyond

“…However, conventional markers such as plasma and urine C-peptide levels do not provide direct information regarding BCM and do not discriminate changes in BCM from those of individual b-cell function. Therefore, the exact relationship between BCM and b-cell function in the onset and progression of diabetes remains unclear (17)(18)(19). Direct information regarding BCM itself provides a novel parameter for understanding the pathophysiology of diabetes and evaluating the efficacy of new and existing antidiabetic therapy.…”

“…Another major obstacle is the spatial resolution of clinical imaging modalities, given that the islets of Langerhans are approximately 40-300 mm in diameter. In vivo b-cell visualization and quantification require imaging modalities with sufficiently high spatial resolution to image individual islets, and no widely available clinical modality [including computed tomography (CT) and magnetic resonance imaging (MRI)] has satisfied this requirement (17). Therefore, instead of resolving single islets, the strategy has been to measure total pancreas signals from tracer molecules highly specific to b cells and provide an estimated BCM.…”

“…In this context, nuclear medicine imaging techniques such as SPECT and PET have attracted attention (20,37) due to their ability to detect their radioisotope-labeled probes at picomolar ranges, despite their limited spatial resolutions (38). The high specificity to b cells of high-sensitivity imaging modalities combined with radioisotopelabeled probes outweighs the shortcomings of their spatial resolution (17,39). Accordingly, SPECT and PET have been investigated for the application to in vivo b-cell-specific imaging.…”

“…( 11C)HTP PET also demonstrated its potential utility for the longitudinal observation of islet mass in type 1 diabetes mellitus and islet transplantation (49,51). However, conflicting reports have suggested that HTP is accumulated in other pancreatic endocrine and exocrine cells and have encountered difficulties in distinguishing BCM between healthy participants and patients with diabetes due to the large overlap (17,61,62).…”

From Pancreatic β-Cell Gene Networks to Novel Therapies for Type 1 Diabetes

“…In the case of T1D, siRNA-mediated STAT2 blockade could be achieved by targeting the siRNA to proteins specifically expressed at the b-cell surface, as has recently been done with another cargo with use of a GLP1 analog coupled to an ASO (59). Targeting moieties for b-cell delivery of therapeutic siRNA can be readily developed from the ligands validated in human pancreatic imaging studies such as exendin 4, nanobodies against dipeptidyl peptidase like 6 (DPP6), and others (60).…”