Abstract
Mouse models of Streptozotocin (STZ) induced diabetes represent the most widely used preclinical diabetes research systems. We applied state of the art optical imaging schemes, spanning from single islet resolution to the whole organ, providing a first longitudinal, 3D-spatial and quantitative account of β-cell mass (BCM) dynamics and islet longevity in STZ-treated mice. We demonstrate that STZ-induced β-cell destruction predominantly affects large islets in the pancreatic core. Further, we show that hyperglycemic STZ-treated mice still harbor a large pool of remaining β-cells but display pancreas-wide downregulation of glucose transporter type 2 (GLUT2). Islet gene expression studies confirmed this downregulation and revealed impaired β-cell maturity. Reversing hyperglycemia by islet transplantation partially restored the expression of markers for islet function, but not BCM. Jointly our results indicate that STZ-induced hyperglycemia results from β-cell dysfunction rather than β-cell ablation and that hyperglycemia in itself sustains a negative feedback loop restraining islet function recovery.
Highlights
Mouse models of Streptozotocin (STZ) induced diabetes represent the most widely used preclinical diabetes research systems
Given its role in glucose metabolism, the pancreas is a key organ in the etiology of diabetes mellitus, a worldwide epidemic disease characterized by hyperglycemia
Administered as a single high dose (SHD) it generates a simple model of severe β-cell destruction and hyperglycemia, while a regimen of multiple low doses (MLD) is suggested to generate a model of induced insulitis[5,6]
Summary
We provide detailed longitudinal and whole organ 3D data, in vivo and ex vivo, on the effect of STZ on islet longevity. The markers for β-cell function Ins[1], Ins[2], Slc2a2, Glp1r, and Trpm[5] were clearly upregulated in islets from SHD-STZ + Tx as compared to non-transplanted SHD-STZ mice, alongside a major reduction in the expression of β-cell dedifferentiation markers. This suggests that hyperglycemia in itself sustains a dysfunctional endocrine pancreas function, and that pancreatic islets still have the capacity to reverse STZinduced damage, at least to some extent (see Fig. 8). Our data on the plasticity of GLUT2 expression level and on overall improvement in β-cell maturity following islet transplantation showcases the importance of glucose level normalization for a potential functional recovery of surviving β-cells in the framework of diabetes treatment
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
