Abstract

Objective: Islet transplantations have been performed clinically, but the practical applications are limited. An extensive effort has been made towards the identification of pancreatic β cell stem cells which has yielded many insights to date, yet targeted reconstitution of β cell mass remains elusive. Here, we present a mouse model for inducible and reversible ablation of pancreatic β cells named the PANIC-ATTAC mouse (pancreatic islet β cell - apoptosis through targeted activation of caspase 8).

Research Design and Methods: We efficiently induce β cell death through apoptosis and concomitant hyperglycemia by administration of a chemical dimerizer to the transgenic mice. In contrast to streptozotocin-treated animals, the diabetes phenotype and β cell loss are fully reversible in the PANIC-ATTAC mice and we find significant β cell recovery with normalization of glucose levels after two months.

Results: The rate of recovery can be enhanced by various pharmacological interventions with agents acting on the GLP-1 axis as well as agonists of peroxisome proliferator-activated receptor-γ. During recovery, we find an increased population of Glut2 positive, insulin negative cells in the islets of PANIC-ATTAC mice, which may represent a novel pool of potential β cell precursors.

Conclusion: The PANIC-ATTAC mouse may be used as an animal model of inducible and reversible β cell ablation and therefore has applications in many areas of diabetes research that include identification of β cell precursors, evaluation of glucotoxicity effects in diabetes and examination of pharmacological interventions.