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

Recovery from diabetes in mice by β cell regeneration

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 3

Cell proliferation during regeneration.

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Cell proliferation during regeneration. (A) Proliferation of differentia...
(A) Proliferation of differentiated (insulin+) β cells in 5-week-old mice treated with doxycycline between 4 and 5 weeks of age. Arrowheads denote proliferating β cells. (B) Proliferation of β cells following cell ablation and regeneration. Three days after the addition of doxycycline to the drinking water of 4-week-old mice, while fed and fasting glucose levels as well as glucose tolerance were still normal (not shown), the rate of β cell proliferation increased about 2.5-fold. The high rate of β cell proliferation was also seen after 7 days of doxycycline treatment and persisted 2 weeks after doxycycline withdrawal (i.e., 7-week-old mice, treated between weeks 4 and 5). (C) Exocrine cell proliferation during β cell ablation and regeneration. At the peak of β cell ablation (i.e., in 5-week-old mice, treated with doxycycline between weeks 4 and 5), a transient increase in exocrine cell proliferation was observed, possibly the result of an inflammatory process. Values are mean ± SD from 3 mice per time point. More than 1,000 β cells and 5,000 exocrine cells were counted per mouse. **P < 0.01.