title: Pharmacological induction of pancreatic islet cell transdifferentiation: relevance to type I diabetes.
abstract: Type I diabetes (T1D) is an autoimmune disease in which an immune response to pancreatic β-cells results in their loss over time. Although the conventional view is that this loss is due to autoimmune destruction, we present evidence of an additional phenomenon in which autoimmunity promotes islet endocrine cell transdifferentiation. The end result is a large excess of δ-cells, resulting from α- to β- to δ-cell transdifferentiation. Intermediates in the process of transdifferentiation were present in murine and human T1D. Here, we report that the peptide caerulein was sufficient in the context of severe β-cell deficiency to induce efficient induction of α- to β- to δ-cell transdifferentiation in a manner very similar to what occurred in T1D. This was demonstrated by genetic lineage tracing and time course analysis. Islet transdifferentiation proceeded in an islet autonomous manner, indicating the existence of a sensing mechanism that controls the transdifferentiation process within each islet. The finding of evidence for islet cell transdifferentiation in rodent and human T1D and its induction by a single peptide in a model of T1D has important implications for the development of β-cell regeneration therapies for diabetes.
authors: Sanford Children's Health Research Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
authors: R
authors: R
authors: Piran
authors: Sanford Children's Health Research Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
authors: S-H
authors: SH
authors: Lee
authors: Infectious and Inflammatory Disease Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
authors: C-R
authors: CR
authors: Li
authors: Animal Facility, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
authors: A
authors: A
authors: Charbono
authors: Infectious and Inflammatory Disease Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
authors: L M
authors: LM
authors: Bradley
authors: Sanford Children's Health Research Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
authors: F
authors: F
authors: Levine
mesh_terms: D000328:Adult; D000818:Animals; D054338:Cell Transdifferentiation / Q000187:drug effects*; D002478:Cells, Cultured; D002108:Ceruletide / Q000494:pharmacology*; D003922:Diabetes Mellitus, Type 1 / Q000503:physiopathology*; D005260:Female; D050416:Glucagon-Secreting Cells / Q000166:cytology* / Q000187:drug effects; D006801:Humans; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D019864:Somatostatin-Secreting Cells / Q000166:cytology* / Q000187:drug effects
chemical_list: D002108:Ceruletide