110-OR: Generation of a Novel Mouse Model to Study β-Cell Proliferation

• Published in: Diabetes (New York, N.Y.) Vol. 68
• Main Authors: Tokumoto, Shinsuke, Yabe, Daisuke, Tatsuoka, Hisato, Usui, Ryota, Fauzi, Muhammad, Goto, Hisanori, Ogura, Masahito, Inagaki, Nobuya
• Format: Journal Article
• Language: English
• Published: New York American Diabetes Association 01.06.2019
• Subjects: Animal models; Beta cells; Biosensors; Cell cycle; Cell growth; Cell number; Cell proliferation; Diabetes; Diabetes mellitus; Hyperglycemia; Insulin; Mitogens; Pancreas; Phase transitions; Replication; Stochasticity
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db19-110-OR

Background and Aims: The induction of β-cell proliferation could relieve the progression of diabetes. Many factors have been claimed to be potential β-cell mitogens, but their impacts on β-cell replication have been poorly reproduced and validated due to unstandardized β-cell proliferation assay and lack of alternative methods. In this study, we aimed to generate a novel mouse model that enables more accurate quantification of β-cell proliferation by using a cell cycle monitoring biosensor (Fucci2a). imaging of the pancreas from this mouse model. Next, 3D images of optically cleared pancreas samples were obtained for the analysis of replicating β-cell number and morphometric data per islet following the mitogenic intervention of insulin receptor antagonist (S961). Moreover, in order to examine whether glucose mediates S961-induced β-cell proliferation, we compared the β-cell proliferation rate between the hyperglycemic S961 monotherapy group and the normoglycemic S961 group with coadministration of SGLT2i (S961 + SGLT2i group). vivo Materials and Methods: We established a novel mouse line in which the Fucci2a reporter is specifically expressed in β-cells (RIP-Cre; Fucci2aR). We performed real-time 3D in Results: We succeeded in real-time visualization of cell cycle progression of β-cells. A strong correlation between replicating β-cell number per islet and islet size was found in both S961 (r = 0.87, p <0.01) and vehicle groups (r = 0.77, p <0.01). While hyperglycemia induced by S961 treatment was normalized in the S961 + SGLT2i group, there was no significant difference in β-cell proliferation rate between the S961 monotherapy and S961 + SGLT2i groups. Conclusion: Here we present the first in vivo 4D images of cell cycle phase transition of β-cells. The strong correlation between islet size and its proliferative capacity suggests stochastic replication of β-cells. S961-induced β-cell replication was not mediated by glucose. Thus, this novel mouse could be a powerful tool for β-cell proliferation assessment.