PancreasIslet transplantation: Islet isolation: Clinical experienceRapamycin Impairs β-Cell Proliferation In Vivo
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.
References (7)
- et al.
Islet transplantation in type 1 diabetes mellitus using cultured islets and steroid-free immunosuppression: Miami experience
Am J Transplant
(2005) - et al.
Islet transplantation: steady progress and current challenges
Curr Opin Organ Transplant
(2006) - et al.
Five-year follow-up after clinical islet transplantation
Diabetes
(2005)
Cited by (23)
Influence of mTOR in energy and metabolic homeostasis
2014, Molecular and Cellular EndocrinologyCitation Excerpt :Notably, development of glucose intolerance and diabetes are common side effects of rapamycin or its derivatives when they are used to treat cancer (i.e. renal cell carcinoma) or to induce immuno-suppression for solid organ transplantation (Kaplan et al., 2014; Soefje et al., 2011). Rapamycin has been shown to inhibit β-cell proliferation, to induce β-cell apoptosis and to cause diabetes in obese animal models by inhibiting glucose-stimulated insulin secretion (Chang et al., 2009; Fraenkel et al., 2008, Zahr et al., 2008). However, prolonged administration of rapamycin disrupts also mTORC2 in vivo, and mTORC2 disruption causes hepatic insulin resistance and increased gluconeogenesis (Lamming et al., 2012).
New-onset diabetes after renal transplantation: Diagnosis, incidence, risk factors, impact on outcomes, and novel implications
2011, Transplantation ProceedingsCitation Excerpt :Thus, SRL administration can block mTOR, theoretically reversing this insulin resistance, an effect that may be particularly significant in the presence of conditions that require an adaptive hyperinsulinemic cell response, such as pregnancy and weight gain, which produce persistent, inappropriate activation of the mTOR/S6K1 pathway.73,75 For example, SRL treatment has been shown to block β-cell proliferation induced by pregnancy in mice.76 Thus, the mTOR inhibitor SRL possibly exerts dual conflicting roles depending upon the physiologic conditions that Cruzado75 ascribed to nutrient availability.
Pancreatic and Islet Transplantation
2010, Endocrinology: Adult and Pediatric, Sixth EditionMammalian Target of Rapamycin and Diabetes: What Does the Current Evidence Tell Us?
2009, Transplantation ProceedingsCitation Excerpt :Interestingly, in this study, β cell regeneration was completely inhibited in animals treated with a SRL-TAC combination. Furthermore, in mice, SRL treatment almost completely inhibited β cell proliferation induced by pregnancy.51 Taken together, mTORC1 seems to have a dual role in β cells.
mTOR and the control of whole body metabolism
2009, Current Opinion in Cell BiologyCitation Excerpt :This effect is due to smaller pancreatic islets and a decrease in glucose-stimulated insulin synthesis and secretion, resulting in a 90% reduction in serum insulin levels [66]. In agreement with these results, rapamycin impairs the proliferation of murine β-cells in vivo [81], of isolated porcine islets [80], and of pancreatic cancer cell lines [82]. Mice deficient for S6K1 [83], or for its direct substrate S6 [84], also show reduced islet size and low serum insulin levels.
Forty Years of Publication of Transplantation Proceedings—The Fourth Decade: Globalization of the Enterprise
2011, Transplantation ProceedingsCitation Excerpt :Moore et al221 reviewed the definition of risk factors for as well as the monitoring and step-wise management of NODAT. The clinical impact of SRL on NODAT is controversial, although Zahr et al222 observed it to inhibit β-cell proliferation in an experimental model and Morel's group223 imputed the limitations of the Edmonton protocol to be because of its side effects, in addition to the reduced level of insulin synthesis caused by TRL toxicity. As patient survivals have improved, the long-term complications of bone disease and myopathy have begun to be addressed by studies of muscle energetics224 and the potential benefits of physical activity.225
Supported by the Diabetes Research Institute Foundation (diabetesresearch.org).