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 FXYD2γa 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.
Highlights
These techniques must be used in conjunction with anatomical imaging techniques such as magnetic resonance imaging (MRI) or computed tomography (CT) [38], which allows organ segmentation, an useful method to ascertain the origin of the positron emission tomography (PET) or single-photon emission computed tomography (SPECT) signal
We have shown that dipeptidyl peptidase 6 (DPP6) expressio6 nof 2is9 restricted to beta cells, with a mild expression in alpha cells and a low level of expression in neurons, siaapdgnennerosqoddnmuubelmteaerihnsniaanatcfyte-toihcdnrdboageeenbnaccytdarotcahehpimntaehaoisenaGefsgagdtuLhenigPDoedog-mnP1ivesst,Peprrtble6aslabcanetesyishoxepp[adpmt4otor7oraerDt]nrs,[krPs4rseieeP5mogrs,6nu1pafl0oeleial1srxctc]otpdp.airrvemOre2eetsefeγlssyclenii.t(nodoiFnnttXaeginYi,nsttDDhilhboeP2ionsγgPdeg)h6i-dveetisraiesfrr(faaimnianclasnudonttlyotbah-pbeti[oeogt4t-dh7e1di,lre4iydas8cig,eo]a.NnxrbprWoebesrt)leeeiac[sht4tseupa5edvma,d1tet0ioioed1nrn]estith.vonseers[lus4eomlx5pip,nea1rdol0lem1ipsm]sra.iosaoRtgn[eN4iinno5Agsf]
A recent study combined the use of two techniques, e.g., MRI and PET imaging [117] based on two different probes, namely manganese (Mn) ions (Mn ions enter beta cells via voltage-dependent calcium channels that are activated in response to glucose metabolism and are a potential surrogate for the steps leading to glucose-induced insulin release) and exendin-4 [117]
Summary
Diabetes currently affects 420 million people worldwide, and this prevalence is projected to increase to 642 million people by 2040 [1]. T2D rely on lifestyle changes (weight loss and exercise) and the use of drugs stimulating the release of endogenous insulin and/or increasing the peripheral sensitivity to this hormone, with the eventual addition of exogenous insulin [9] Both T1D and T2D are characterized by a reduced BCM [6,7,8,12,13], but the natural history of beta cell loss in these diseases, as well as the relationship between BCM and function, remains unclear. The “visualization” of beta cells is based on the high specificity and the biochemical/metabolic characteristics of the tracer molecule (chemical resolution) [37,39] that provides an estimation of the total beta cell mass These techniques must be used in conjunction with anatomical imaging techniques such as magnetic resonance imaging (MRI) or computed tomography (CT) [38], which allows organ segmentation, an useful method to ascertain the origin of the PET or SPECT signal. In light of the continuous technology improvement in the field [41], it is conceivable that MRI-based technologies for visualization of islets in humans will become widely available in the coming years
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