Noninvasive Longitudinal Evaluation of GPR-119 Agonist Effects on ß-Cell Mass Using GLP-1 Receptor-Targeting SPECT/CT

Aims:Type 2 diabetes mellitus (T2DM) is known as a progressive disease with loss of pancreatic β-cell mass (BCM) and functions. However, longitudinal changes of BCM remain veiled since non-invasive techniques for observation of BCM in vivo have not been established. We developed [Lys¹²(¹¹¹In-BnDTPA-Ahx)]exendin-4 (¹¹¹In-Ex4) targeting a glucagon-like peptide 1 (GLP-1) receptor, which enabled to quantify BCM non-invasively. DS8500a, a G protein-coupled receptor 119 (GPR119) agonist, is under investigation for the treatment of T2DM. Some GPR119 agonists showed the possible stimulation of β-cell replication, which suggested some preferable effects of GPR119 agonists on BCM. Therefore, we investigated this GPR119 agonist effect on BCM in diabetic mice using our ¹¹¹In-Ex4 SPECT/CT technique.

Method: Five-week-old male db/db mice with dietary restriction were assigned to the following two groups: mice fed with normal chaw (group C) and those with DS8500a-mixed chaw (group DS). We performed ¹¹¹In-Ex4 SPECT/CT every four weeks until 13 weeks old and evaluated the RI accumulations in the pancreas. Ex-vivo pancreatic RI intensities, together with pathological and immunohistochemical analysis of BCM were also examined.

Results: As for ¹¹¹In-Ex4 SPECT/CT, pancreatic RI intensities in group DS were significantly higher than those of group C, at the age of 9 and 13 weeks old. Moreover, ex-vivo pancreatic RI intensities in group DS were significantly higher than those of group C. Pathological BCM analysis revealed significantly larger BCM in group DS than in group C.

Conclusion: ¹¹¹In-Ex4 SPECT/CT as wells as ex-vivo pancreatic analysis showed preserved BCM in mice with DS8500a. This result was corroborated by the conventional pathological method. Taken together, ¹¹¹In-Ex4 SPECT/CT showed DS8500a, a GPR119 agonist, could attenuate the progression of BCM loss in diabetic mice.