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.
Highlights
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
We established an analytical method for single photon emission computed tomography (SPECT) imaging of living mice to quantify pancreatic uptake of [111In]Ex49, and reported that pancreatic uptake is correlated with BCM as calculated by the product of the pancreatic weight and the area ratio of tissue immunostained with anti-insulin antibody to whole pancreas[10]
In order to enable longitudinal observation, we established an analytical method using SPECT imaging of living mice to quantify pancreatic uptake of [111In]Ex49; we reported a correlation between pancreatic uptake and BCM and a longitudinal decrease in BCM in NOD mice, an animal model of type 1 diabetes[10]
Summary
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. 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. Impaired insulin secretion is an important pathophysiological factor in the development of type 2 diabetes This may implicate dysfunction of individual beta cells and a decrease of beta cell mass (BCM). Administration of sodium glucose transporter-2 inhibitors (SGLT2i) to obese type 2 diabetes model mice such as db/db mice was shown to preserve BCM11,12 In these studies, longitudinal changes of BCM in the same individual could not be discerned because the mice were sacrificed at the respective time points for evaluation of BCM using the harvested pancreata. To demonstrate that our SPECT/CT imaging of pancreatic beta cells with [111In]Ex4 is useful for longitudinal observation of BCM, we performed a longitudinal study on BCM of db/db mice administered canagliflozin
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