Noninvasive longitudinal quantification of β‐cell mass with [¹¹¹In]‐labeled exendin‐4

Abstract

Currently, quantifying β‐cell mass (BCM) requires harvesting the pancreas. In this study, we investigated a potential noninvasive method to quantify BCM changes longitudinally using [Lys12(111In‐BnDTPA‐Ahx)] exendin‐4 ([111In]‐Ex4) and single‐photon emission computed tomography (SPECT). We used autoradiography and transgenic mice expressing green fluorescent protein under the control of mouse insulin 1 gene promotor to evaluate the specificity of [111In]‐Ex4 toward β cells. Using nonobese diabetic (NOD) mice, we injected [111In]‐Ex4 (3.0 MBq) intravenously and performed SPECT 30 min later, repeating this at a 2‐wk interval. After the second scan, we harvested the pancreas and calculated BCM from immunohistochemically stained pancreatic sections. Specific accumulation of [111In]‐Ex4 in β cells was confirmed by autoradiography, with a significant correlation (r = 0.94) between the fluorescent and radioactive signal intensities. The radioactive signal from the pancreas in the second SPECT scan significantly correlated (r = 0.89) with BCM calculated from the immunostained pancreatic sections. We developed a regression formula to estimate BCM from the radioactive signals from the pancreas in SPECT scans. BCM can be quantified longitudinally and noninvasively by SPECT imaging with [111In]‐Ex4. This technique successfully demonstrated longitudinal changes in BCM in NOD mice before and after onset of hyperglycemia.—Fujita, N., Fujimoto, H., Hamamatsu, K., Murakami, T., Kimura, H., Toyoda, K., Saji, H., Inagaki, N. Noninvasive longitudinal quantification of β‐cell mass with [111In]‐labeled exendin‐4. FASEB J. 33, 11836‐11844 (2019). http://www.fasebj.org

Association of glucagon‐like peptide‐1 receptor‐targeted imaging probe with in vivo glucagon‐like peptide‐1 receptor agonist glucose‐lowering effects

“…In vivo 111 In-Ex4 SPECT/CT in RCS-10 mice The pancreata of RCS-10 mice were visualized by 111 In-Ex4 SPECT/CT, as described in the previous reports 14,17,18 . Representative images of in vivo 111 In-Ex4 SPECT/CT are shown in Figure 1.…”

“…BCM has central importance in diabetes progression and responsiveness to antidiabetes treatments 19,20 . However, the influence of BCM has been little discussed, because non-invasive methods to quantify BCM were not available until the recent development of GLP1R-targeted imaging, such as the In-Ex4 probe 17,18 . In the present study, we showed that ex vivo 111 In-Ex4 pancreatic values were significantly related to the BCM of RCS-10 mice (Figure 5d), which accords with the results in other mice strains in previous reports 14,17,18 .…”

“…In addition, considering the influence of apparently reduced insulin secretory capacity in chronic hyperglycemia and glucose toxicity on conventional evaluation methods 2,3 , GLP-1R-targeted imaging might well be an option to provide more accurate prediction regardless of glycemic control status, as the significant correlations between BCM and 111 In-Ex4 SPECT values were shown even in diabetic and non-diabetic, as well as treated and non-treated subjects 17,18 . Further studies are required to elucidate the different roles in the prediction of GLP-1RA responses, and 111 In-Ex4 SPECT values and conventional evaluation methods; the former can evaluate BCM itself, whereas the latter reflects an individual's total insulin secretion capacity 17,18 .…”

“…Ex vivo pancreas analysis using the 111 In-exendin-4 probe The 111 In-exendin-4 probe, (Lys12[In-BnDTPA-Ahx])exendin-4 ( 111 In-Ex4) was synthesized, as previously reported 9 . Although the utility of 111 In-Ex4 for in vivo SPECT/computed tomography (CT) imaging was established in the previous report 14,17,18 , the pancreatic visualization of 10-week-old male RCS-10 mice was reconfirmed before the investigation in dulaglutide-treated mice. The SPECT/CT imaging was carried out using a Triumph LabPET12/SPECT4/CT (TriFoil Imaging Inc., Chatsworth, CA, USA), as previously reported 14 .…”

“…The prepared slides were analyzed using a fluorescence microscope (BZ-X710; Keyence, Osaka, Japan). BCM was calculated from histological sections according to the following formula: (insulin-positive area/whole pancreas area) 9 pancreas weight (mg), as previously reported 17,18 .…”