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PANIC–ATTAC, a mouse model for inducible and reversible β cell ablation

¹Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York
²Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
³Touchstone Diabetes Center, University of Texas Southwestern Medical Center, Dallas, Texas
⁴Department of Metabolic Disorders, Merck Research Laboratories, Rahway, New Jersey
⁵Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas
⁶Division of Hypothalamic Research, University of Texas Southwestern Medical Center, Dallas, Texas
⁷Department of Medicine and Diabetes Research Center, Albert Einstein College of Medicine, Bronx, New York

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-. 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.

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