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.
T. Murakami: None. H. Fujimoto: None. N. Fujita: None. K. Hamamatsu: None. K. Matsumoto: None. N. Inagaki: Research Support; Self; Daiichi Sankyo Company, Limited, AstraZeneca, Ono Pharmaceutical Co., Ltd., Sanofi K.K., Mitsubishi Tanabe Pharma Corporation, Takeda Pharmaceutical Company Limited, Japan Tobacco Inc., MSD K.K., Sumitomo Dainippon Pharma Co., Ltd., Nippon Boehringer Ingelheim Co. Ltd., Novartis Pharma K.K., Kissei Pharmaceutical Co., Ltd., Novo Nordisk Pharma Ltd., Eli Lilly and Company, Sanwa Chemical Industrial Co., Ltd., Teijin Pharma Limited.