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


METHODS
We efficiently induce beta-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 beta-cell loss are fully reversible in the PANIC-ATTAC mice, and we find significant beta-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-gamma. 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 beta-cell precursors.


CONCLUSIONS
The PANIC-ATTAC mouse may be used as an animal model of inducible and reversible beta-cell ablation and therefore has applications in many areas of diabetes research that include identification of beta-cell precursors, evaluation of glucotoxicity effects in diabetes, and examination of pharmacological interventions.
Wang
Zhao V
ZV
Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York, USA.
Mu
James
J
Schraw
Todd D
TD
Gautron
Laurent
L
Elmquist
Joel K
JK
Zhang
Bei B
BB
Brownlee
Michael
M
Scherer
Philipp E
PE
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism*; D020169:Caspases / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D000077270:Exenatide; D005951:Glucose Tolerance Test; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010455:Peptides / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016559:Tacrolimus / Q000031:analogs & derivatives / Q000494:pharmacology; D022021:Tacrolimus Binding Proteins / Q000235:genetics / Q000378:metabolism; D019076:Transgenes / Q000235:genetics; D014688:Venoms / Q000494:pharmacology
C463061:AP20187; D010455:Peptides; D014688:Venoms; D000077270:Exenatide; C505526:Casp8 protein, mouse; D053181:Caspase 8; D020169:Caspases; D022021:Tacrolimus Binding Proteins; D016559:Tacrolimus