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 gluca- gon-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 pharmaco- logical interventions. © 2008 by the American Diabetes Association.