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PMID: 17786244 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Recovery from diabetes in mice by beta cell regeneration.

The Journal of clinical investigation ·Vol. 117 ·No. 9 ·2007-09-00 ·Pages 2553-61

Nir T, Melton DA, Dor Y

Abstract

The mechanisms that regulate pancreatic beta cell mass are poorly understood. While autoimmune and pharmacological destruction of insulin-producing beta cells is often irreversible, adult beta cell mass does fluctuate in response to physiological cues including pregnancy and insulin resistance. This plasticity points to the possibility of harnessing the regenerative capacity of the beta cell to treat diabetes. We developed a transgenic mouse model to study the dynamics of beta cell regeneration from a diabetic state. Following doxycycline administration, transgenic mice expressed diphtheria toxin in beta cells, resulting in apoptosis of 70%-80% of beta cells, destruction of islet architecture, and diabetes. Withdrawal of doxycycline resulted in a spontaneous normalization of blood glucose levels and islet architecture and a significant regeneration of beta cell mass with no apparent toxicity of transient hyperglycemia. Lineage tracing analysis indicated that enhanced proliferation of surviving beta cells played the major role in regeneration. Surprisingly, treatment with Sirolimus and Tacrolimus, immunosuppressants used in the Edmonton protocol for human islet transplantation, inhibited beta cell regeneration and prevented the normalization of glucose homeostasis. These results suggest that regenerative therapy for type 1 diabetes may be achieved if autoimmunity is halted using regeneration-compatible drugs.

MeSH Terms
Animals Cell Proliferation Cell Shape Diabetes Mellitus/pathology Immunosuppressive Agents/pharmacology Insulin-Secreting Cells/drug effects,pathology Mice Mice, Transgenic Regeneration/drug effects
Chemicals
Immunosuppressive Agents
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Nir Tomer
Department of Cellular Biochemistry and Human Genetics, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Melton Douglas A
Dor Yuval
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Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
0021-9738
DOI
10.1172/JCI32959
Published
2007-09-00
Pages
2553-61
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC1957545
Subset
IM
Corrections
CommentIn
PMID: 17786232
External Links
PubMed source DOI: 10.1172/JCI32959 PMC Full Text View journal details
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