PANIC-ATTAC

A mouse model for inducible and reversible β-cell ablation

Zhao V. Wang, James Mu, Todd D. Schraw, Laurent Gautron, Joel K. Elmquist, Bei B. Zhang, Michael Brownlee, Philipp E. Scherer

Research output: Contribution to journalArticle

42 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)2137-2148
Number of pages12
JournalDiabetes
Volume57
Issue number8
DOIs
StatePublished - Aug 2008

Fingerprint

Caspase 8
Islets of Langerhans
Apoptosis
Pharmacology
Islets of Langerhans Transplantation
Peroxisome Proliferator-Activated Receptors
Glucagon-Like Peptide 1
Experimental Diabetes Mellitus
Hyperglycemia
Transgenic Mice
Cell Death
Research Design
Stem Cells
Animal Models
Insulin
Phenotype
Glucose
Research

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

PANIC-ATTAC : A mouse model for inducible and reversible β-cell ablation. / Wang, Zhao V.; Mu, James; Schraw, Todd D.; Gautron, Laurent; Elmquist, Joel K.; Zhang, Bei B.; Brownlee, Michael; Scherer, Philipp E.

In: Diabetes, Vol. 57, No. 8, 08.2008, p. 2137-2148.

Research output: Contribution to journalArticle

Wang, Zhao V. ; Mu, James ; Schraw, Todd D. ; Gautron, Laurent ; Elmquist, Joel K. ; Zhang, Bei B. ; Brownlee, Michael ; Scherer, Philipp E. / PANIC-ATTAC : A mouse model for inducible and reversible β-cell ablation. In: Diabetes. 2008 ; Vol. 57, No. 8. pp. 2137-2148.
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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.",
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