Recovery from diabetes in mice by β cell regeneration
Tomer Nir, Douglas A. Melton, Yuval Dor
Tomer Nir, Douglas A. Melton, Yuval Dor
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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 5

SirTac inhibits β cell regeneration.

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SirTac inhibits β cell regeneration. (A) Treatment with SirTac for 14 da...
(A) Treatment with SirTac for 14 days immediately after doxycycline withdrawal caused an approximately 80% decrease in β cell proliferation in both wild-type and diabetic mice. Mice were treated with doxycycline from birth to 1 month of age, and sacrificed 2 weeks later. (B) Accumulation of β cells during SirTac treatment, as assessed by administering BrdU to the drinking water between doxycycline withdrawal and sacrifice, concomitant with SirTac administration as in A. Values are mean ± SD (n = 3–6). More than 500 β cells were counted per mouse. *P < 0.05. (C) Representative images of new β cell accumulation in transgenic mice recovering from diabetes in the absence or presence of SirTac. Arrowheads denote BrdU+Insulin+ cells. (D) Islet morphology at 1 and 3.5 months of age with or without SirTac treatment for months 1–3.5. Note the persistent ablated islet phenotype following SirTac treatment, in contrast to the spontaneous recovery of islet morphology in its absence. Slides were stained for insulin (brown) and hematoxylin (blue). Original magnification, ×350. (E) Abrogation of β cell regeneration in SirTac-treated transgenic mice. Doxycycline was administered from birth to 1 month, after which mice were sacrificed (n = 13) or allowed to recover for 2.5 months in the absence (n = 4) or presence (n = 6) of SirTac. (F) Blood glucose levels of mice treated as in D and E. n = 5 (SirTac-treated wild-type); 4 (untreated transgenic); 9 (SirTac-treated transgenic).