The impact of the mTOR inhibitor sirolimus on the proliferation and function of pancreatic islets and ductal cells

Abstract

Aims/hypothesis The Edmonton Protocol for islet transplantation has provided hope for type 1 diabetic patients. However, this protocol requires lifelong immunosuppression, specifically sirolimus, a cellular antiproliferate. The effect of sirolimus on human pancreatic ductal cells (HDCs) is not known. This may be important since HDCs are believed to be islet precursors. Since neonatal porcine islets (NPIs), which contain many ductal precursor cells, could be a potential clinical source of islets, we also tested the effects of sirolimus on this tissue. Methods HDCs (n=4), NPIs (n=9) and human islets (n=5) were cultured with and without sirolimus (20 ng/ml) for 6 days. Results HDCs and NPIs cultured with sirolimus showed a 50 and 28% decrease, respectively, in cell number relative to control (p<0.05). Control cultures expanded 1.65-and 2.44-fold relative to time 0. Decreases in cell number of sirolimus-treated HDCs were not due to apoptosis as measured by TUNEL staining. No functional effects on human islets or NPIs were observed following static incubation with high glucose. Treatment of syngeneically transplanted and naïve BALC/c mice with sirolimus resulted in altered OGTT profiles with prolonged elevation of hyperglycaemia and weight gain. There was no difference in graft and organ insulin content between treatment groups. Conclusions/interpretation Our results indicate that sirolimus decreases ductal cell numbers in culture and alters glucose-stimulated insulin secretion in vivo. The administration of sirolimus to islet transplant recipients is likely to impair graft function as a result of decreasing ductal neogenesis and induction of insulin resistance.

Vascular endothelial growth factor as a survival factor for human islets: effect of immunosuppressive drugs

“…Thus, rapamycin exposure could have a major adverse effect on the function and survival of transplanted islets. Additionally, a recent study highlighted a deleterious effect of rapamycin on islet ductal cell proliferation [49]. The authors speculate that this inhibition of ductal neogenesis could be a contributor to the failure of islet grafts in the long term, as has been recently reported [50].…”

Embryonic pig pancreatic tissue for the treatment of diabetes in a nonhuman primate model

“…Preliminary results in the mouse model, evaluating potential substitutes for Evorolimus with co-stimulatory blockade agents other than anti-CD40L have shown encouraging results (35). Such substitutes could be of particular importance considering the skin lesions found in animal #3 (see SI for details) and other reported adverse effects of Rapamycin on islet function (19)(20)(21).…”

Sirolimus Is Associated with New-Onset Diabetes in Kidney Transplant Recipients

“…Other mechanisms that have been proposed for the induction of hyperglycemia by sirolimus include ectopic triglyceride deposition with sirolimus leading to insulin resistance, 23,24 impairment of insulinmediated suppression of hepatic glucose production, 22 or a direct toxic effect on pancreatic ␤ cells. 25,26 When interpreting the results of this study, readers should consider the inherent limitations of retrospective analyses of administrative data sets including nonrandom assignment of patients to different immunosuppressive medication protocols. Although we adjusted for multiple factors known to be associated with NOD, the associations identified may be confounded by other factors not included in our analysis.…”

“…20,21 There are a number of possible mechanisms by which sirolimus may cause NOD, including impaired insulin-mediated suppression of hepatic glucose production, 22 insulin resistance from ectopic triglyceride deposition, 23,24 or direct ␤ cell toxicity. 25,26 Although multicenter trials using sirolimus failed to demonstrate an association between sirolimus and NOD, [27][28][29] patients in the comparator groups in these studies received corticosteroids and CNI; therefore, an independent association between sirolimus and NOD may not have been evident despite the relatively large number of participants in these trials. We therefore performed this analysis using patients captured in the United States Renal Data System (USRDS) to determine whether there is an association between sirolimus and NOD.…”