Abstract
Islet transplantation is a novel promising strategy to cure type 1 diabetes. However, the long-term outcome is still poor, because both function and survival of the transplant decline over-time. Non-invasive imaging methods have the potential to enable monitoring of islet survival after transplantation and the effects of immunosuppressive drugs on transplantation outcome. 111In-labeled exendin-3 is a promising tracer to visualize native and transplanted islets by SPECT (Single Photon Emission Computed Tomography). In the present study, we hypothesized that islet microvasculature plays an important role determining the uptake of exendin-3 in islets when monitoring transplant survival. We observed 111In-exendin-3 accumulation in the transplant as early as three days after transplantation and an increase in the uptake up to three weeks post-transplantation. Islet-revascularization correlated with the increase in 111In-exendin-3 uptake, whereas fully re-established islet vasculature coincided with a stabilized uptake of the radiotracer in the transplant. Here, we demonstrate the importance of islet vasculature for in vivo delivery of radiotracers to transplanted islets and we demonstrate that optimal and stable uptake of exendin four weeks after transplantation opens the possibility for long-term monitoring of islet survival by SPECT imaging.
Highlights
Islets, as well as to visualize and quantify BCM in the pancreas of healthy and diabetic subjects[14,15]
We examined the influence of islet graft revascularization on the targeting characteristics of radiolabeled exendin-3, a radiotracer with great potential as imaging biomarker for non-invasive assessment of β -cell survival after transplantation
We demonstrated that an increase in vascular density, between 3 days and 3 weeks after transplantation, correlated with an increase in the accumulation of 111In-exendin-3 in the transplant
Summary
Radiolabeled exendin-3 binds to the GLP-1R on mouse islets in vitro. Incubation of 1.5 fmol of radiolabeled exendin-3 with 100 islets during 4 hours resulted in the binding of 9.1 × 10−3 fmol (Fig. 1). Quantitative analysis of 111In-exendin-3 accumulation within transplanted islets by autoradiography was 0.48 ± 0.068, 0.99 ± 0.16, 1.35 ± 1.08, 2.97 ± 0.27, 2.73 ± 0.4 and 3.45 ± 0.34 Bq/mm[2] at 3 days and 1, 2, 3, 4, 6 weeks after transplantation, respectively (Fig. 2H). To investigate whether revascularization of transplanted islets affects the uptake of radiolabeled exendin-3, VEGFR-2 and insulin expression was quantified to determine islet microvasculature and β -cells area, respectively (Fig. 4). To determine the time-point after which multiple imaging sessions result in reproducible assessment of 111In-exendin-3 uptake, each mouse was scanned twice with 7 days of interval, starting 3 days, 1, 2, 3, 4 or 5 weeks after transplantation (Fig. 7A). Quantitative analysis revealed an increase in the signal 7 days after the initial scans with stabilization being observed between 3 and 4 week-old transplants (Fig. 7B). Two transplants which were not visible 3 days or 1 week after transplantation, both became detectable at the time of the second scan
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