PANIC-ATTAC: A Mouse Model for Inducible and Reversible β-Cell Ablation

Abstract

OBJECTIVE—Islet transplantations have been performed clinically, but their practical applications are limited. An extensive effort has been made toward the identification of pancreatic β-cell stem cells that 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 (pancreatic islet β-cell apoptosis through targeted activation of caspase 8) mouse.

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 animals administered streptozotocin, 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 2 months.

RESULTS—The rate of recovery can be enhanced by various pharmacological interventions with agents acting on the glucagon-like peptide 1 axis and agonists of peroxisome proliferator–activated receptor-γ. During recovery, we find an increased population of GLUT2⁺/insulin⁻ cells in the islets of PANIC-ATTAC mice, which may represent a novel pool of potential β-cell precursors.

CONCLUSIONS—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.