Pancreas
Islet transplantation: Islet isolation: Clinical experience
Rapamycin Impairs β-Cell Proliferation In Vivo

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Abstract

During pregnancy a high rate of β-cell proliferation occurs, making of this a useful model for the study of islet cell expansion in vivo. We used the murine pregnancy model to assess the effect of Rapamycin treatment on islet cell proliferation in vivo. Rapamycin is routinely used for the prevention of graft rejection in transplanted patients, including islet transplant recipients. As expected, pregnancy led to increased β-cell proliferation, islet yield and skewing in size distribution after isolation and pancreatic insulin content, when compared to non-pregnant females. Rapamycin treatment resulted in reduced beta cell proliferation in pregnant mice, while minimal effects of Rapamycin treatment were observed on islet function both in vivo and in vitro. Rapamycin treatment of islets resulted in reduced phosphorylation of p70s6k, a downstream effector molecule of mTOR and increased ERK1/2 phosphorylation. In conclusion, β-cell replication is reduced under Rapamycin treatment in vivo, suggesting that this mechanism may be operational and impair β-cell renewal in transplanted patients.

Section snippets

Materials and Methods

Pregnant C57BL/6 mice were treated or not with rapamycin (0.2 mg/kg per day) for 5 to 7 days starting on day 7.5 of pregnancy. Proliferation of pancreatic cell populations (endocrine and ductal cells) was evaluated by detection of BrdU incorporation by Immunohistochemistry using specific antibodies. Islets were isolated by enzymatic digestion followed by purification on density gradients, as previously described.7

Results

As previously described, increased of β-cell proliferation was observed during days 12.5 to 15.0 of pregnancy. β-Cell proliferation during the studied period of pregnancy was found to be 22.8 ± 3.1%, whereas control nonpregnant age-matched mice receiving BrdU during the same time period showed only 7.4 ± 1.3% of the β-cells underwent proliferation. Treatment of pregnant mice with rapamycin resulted in a dramatic reduction of the percentage of proliferating β-cells 11.7 ± 2.2% (P = .017). Other

Discussion

Rapamycin treatment reduces the rate of β-cell proliferation in vivo. This phenomenon may contribute to impair β-cell renewal, which, along with the metabolic side effects of chronic immunosuppression, may contribute to the progressive islet graft dysfunction observed in the transplanted patients.

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Supported by the Diabetes Research Institute Foundation (diabetesresearch.org).

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