Recovery from diabetes in mice by β cell regeneration
Open accessAbstract
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.
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Normal β-cell growth primarily occurs by self-renewal of mature β-cells-not by replication of specialized progenitors.
“the findings of recent studies by several groups (including ours) indicate that normal β-cell growth primarily occurs by self-renewal of mature β-cells—not by replication of specialized progenitors (8–12).”
From Adaptive β-Cell Proliferation Is Severely Restricted With Advanced Age (2009) · cites this paper as [11]
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- Authors
- Nir, T., Melton, D. A., & Dor, Y.
- Affiliations
- Hebrew University of Jerusalem (IL)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Dor, Yuval
- Venue
- Journal of Clinical Investigation
- Published
- 2007-09-04
- Volume
- 117
- Issue
- 9
- Pages
- 2553-2561
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC1957545
- OpenAlex
- W2097573911
- Cited by
- 595
- References
- 56
- Citations by year
- 2026: 4 · 2025: 9 · 2024: 17 · 2023: 10 · 2022: 12 · 2021: 14 · 2020: 16 · 2019: 16 · 2018: 22 · 2017: 18 · 2016: 32 · 2015: 37 · 2014: 49 · 2013: 44 · 2012: 48
- FWCI
- 62.06
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Hebrew University of Jerusalem
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Keywords
- beta cell regeneration, type 1 diabetes, beta-cell mass, beta-cell apoptosis, diphtheria toxin, beta-cell proliferation, lineage tracing, rapamycin, tacrolimus, immunosuppressants, glucose homeostasis, islet transplantation, autoimmunity, transgenic mouse model
- MeSH terms
- Animals, Diabetes Mellitus, Immunosuppressive Agents, Mice, Transgenic, Regeneration, Cell Shape, Cell Proliferation, Insulin-Secreting Cells, Mice
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