Investigation of the preservation effect of canagliflozin on pancreatic beta cell mass using SPECT/CT imaging with 111In-labeled exendin-4

Abstract

Radiolabeled exendin derivatives are promising for non-invasive quantification of pancreatic beta cell mass (BCM); longitudinal observation of BCM for evaluation of therapeutic effects has not been achieved. The aim of this study is to demonstrate the usefulness of our developing method using [Lys12(111In-BnDTPA-Ahx)]exendin-4 to detect longitudinal changes in BCM. We performed a longitudinal study with obese type 2 diabetes model (db/db) mice administered canagliflozin, which is reported to preserve BCM. Six-week-old mice were assigned to a canagliflozin-administered group or a control group. Blood glucose levels of the canagliflozin group were significantly lower than those of the control group. Plasma insulin levels, insulin secretion during OGTT and insulin content in the pancreas were preserved in the canagliflozin group in comparison with those in the control group. According to SPECT/CT imaging analysis using [Lys12(111In-BnDTPA-Ahx)]exendin-4, pancreatic uptake was significantly decreased in the control group, whereas there was no significant change in the canagliflozin group. After nine weeks, both pancreatic uptake and BCM of the canagliflozin group were significantly higher than those of the control group, and a correlation between them was observed. In conclusion, our imaging method confirmed the BCM-preservation effect of canagliflozin, and demonstrated its potential for longitudinal evaluation of BCM.

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

“…In db/db mice, longitudinal in vivo SPECT observations revealed a spontaneous reduction in pancreatic probe uptake (35, 103) and that diet-restriction attenuated the reduction in BCM loss (35). In vivo SPECT observations also observed that canagliflozin (a sodium glucose transporter-2 inhibitor) and DS-8500a (a G protein-coupled receptor 119 agonist) attenuated the progression of BCM loss in db/db mice (34,103). Although chronic hyperglycemia might affect probe uptake via changes in GLP-1R expression levels on the b-cell membrane surface (110), the pancreatic uptake of [Lys 12 ( 111 In-BnDTPA-Ahx)]exendin-4 in SPECT images could replicate the BCM relationship among these model mice with different glycemic states (35,102,103).…”

“…In vivo SPECT observations also observed that canagliflozin (a sodium glucose transporter-2 inhibitor) and DS-8500a (a G protein-coupled receptor 119 agonist) attenuated the progression of BCM loss in db/db mice (34,103). Although chronic hyperglycemia might affect probe uptake via changes in GLP-1R expression levels on the b-cell membrane surface (110), the pancreatic uptake of [Lys 12 ( 111 In-BnDTPA-Ahx)]exendin-4 in SPECT images could replicate the BCM relationship among these model mice with different glycemic states (35,102,103). Moreover, the pancreatic uptake of [Lys 12 ( 111 In-BnDTPA-Ahx)]exendin-4 maintained a linear correlation with histological BCM, even among diabetic and non-diabetic RCS-10 mice (11).…”

“…Although SPECT appears to present drawbacks in in vivo quantification analysis due to the decay and diffusion of its low-energy gamma rays, recent studies have demonstrated that SPECT could yield sufficient quantitative information, especially in rodents (12,13,101,102). 111 In-labeled exendin-3 derivatives have been reported as useful for quantifying rat BCM with ex vivo SPECT scans of resected pancreata (12,103). In Brown Norway rats with and without alloxan treatment, 111 In-[Lys 40 ]exendin-3 demonstrated a good correlation between pancreatic uptake (determined by the quantitative analysis of SPECT scans) and BCM (determined by the histological analysis of immunohistological staining with insulin antibodies) (r = 0.83) (12).…”

First-in-Human Evaluation of Positron Emission Tomography/Computed Tomography With [18F]FB(ePEG12)12-Exendin-4: A Phase 1 Clinical Study Targeting GLP-1 Receptor Expression Cells in Pancreas

“…In order to solve this issue, pancreatic b-cell-specific imaging using nuclear medicine techniques has been developed in recent years (7)(8)(9)(10)(11). In particular, radioisotope-labeled probes using exendin peptidesincluding glucagon-like peptide-1 receptor (GLP-1R) agonist and antagonist-have been promising for positron emission tomography (PET) and single-photon emission computed tomography (SPECT) imaging (12)(13)(14), which enabled mouse pancreas imaging, its image analysis for BCM quantification (15,16), and investigation of the protective effect of pancreatic b cells on anti-diabetic treatment (17,18). In addition, these probes were shown to be useful for the detection of insulinoma (13).…”

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

“…Exendin-4 can also be used to monitor endogenous BCM evolution in mice after drug intervention. Thus, after nine weeks of canagliflozin treatment (a sodium-glucose transporter-2 inhibitor), an increase in BCM and accumulation of [Lys 12 ( 111 In-Bn-diethylenetriaminepenta-acetic acid(DTPA)-Ahx)]exendin-4 was observed in mice [ 59 ]. The same probe was also used to assess the protective effect of DS-8500a (a novel G protein-coupled receptor-119 agonist) on BCM in db / db mice, a model of severe insulin resistance and diabetes [ 60 ].…”