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Recovery from diabetes in mice by β cell regeneration
Tomer Nir, … , Douglas A. Melton, Yuval Dor
Tomer Nir, … , Douglas A. Melton, Yuval Dor
Published September 4, 2007
Citation Information: J Clin Invest. 2007;117(9):2553-2561. https://doi.org/10.1172/JCI32959.
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Research Article Article has an altmetric score of 8

Recovery from diabetes in mice by β cell regeneration

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Abstract

The mechanisms that regulate pancreatic β cell mass are poorly understood. While autoimmune and pharmacological destruction of insulin-producing β cells is often irreversible, adult β 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 β cell to treat diabetes. We developed a transgenic mouse model to study the dynamics of β cell regeneration from a diabetic state. Following doxycycline administration, transgenic mice expressed diphtheria toxin in β cells, resulting in apoptosis of 70%–80% of β 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 β cell mass with no apparent toxicity of transient hyperglycemia. Lineage tracing analysis indicated that enhanced proliferation of surviving β cells played the major role in regeneration. Surprisingly, treatment with Sirolimus and Tacrolimus, immunosuppressants used in the Edmonton protocol for human islet transplantation, inhibited β 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.

Authors

Tomer Nir, Douglas A. Melton, Yuval Dor

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Figure 1

A transgenic mouse system for specific and conditional ablation of pancreatic β cells.

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A transgenic mouse system for specific and conditional ablation of pancr...
(A) Application of doxycycline (Dox) to the drinking water of Insulin-rtTA;TET-DTA mice induces the expression of DTA specifically in β cells, causing apoptotic β cell death. (B) Normal islet morphology in a 4-week-old double-transgenic mouse untreated with doxycycline. (C) Normal blood glucose levels (measured during the day) in 3-week-old mice in the absence of doxycycline. Untreated transgenic mice at 1.5 years had blood glucose levels indistinguishable from those of age-matched wild-type mice (not shown). (D) In the absence of doxycycline, 4-week-old double-transgenic mice had normal fasting blood glucose levels and glucose tolerance. Values are mean ± SD (n = 5–7). Single-transgenic TET-DTA littermates are referred to as wild-type. (E) β Cell specificity of ablation. Four-week-old mice were treated with doxycycline for 48 hours, then sacrificed and assessed for apoptotic cell death. Extensive β cell apoptosis was detected by TUNEL staining in double-transgenic mice. No apoptosis was seen in non-β cells in islets or in the exocrine pancreas. Doxycycline-treated single-transgenic littermates showed no sign of apoptosis. (F) Quantification of β cell apoptosis detected 48 hours after the administration of doxycycline to 4-week-old mice. Values are mean ± SD from 5-week-old mice exposed to doxycycline for 48 hours before sacrifice (n = 3 per group). For each mouse, about 2,000 β cells were counted. Scale bars: 100 μm.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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