Sirolimus Is Associated With Reduced Islet Engraftment and Impaired β-Cell Function

Abstract

Successful islet transplantation depends on the infusion of sufficiently large quantities of islets, but only a fraction of transplanted islets can survive and become engrafted, and yet the underlying mechanism remains unclear. In this study, we examined the effect of sirolimus, a key component of the immunosuppressive regimen in clinical islet transplantation, on islet engraftment and function. To distinguish the effect of sirolimus on immune rejection from its effect on islet engraftment, we used a syngeneic model. Diabetic mice were transplanted with 250 islets under the renal capsule, followed by treatment with sirolimus or vehicle for 14 days. Thirty days posttransplantation, islet grafts were retrieved for the determination of insulin content and vascular density. Compared with mocktreated controls, diabetic recipient mice receiving sirolimus exhibited impaired blood glucose profiles and reduced glucose-stimulated insulin secretion, correlating with reduced intragraft insulin content and decreased vascular density. Islets exposed to sirolimus for 24 h in culture displayed significantly diminished glucose-stimulated insulin release, coinciding with decreased pancreas duodenum homeobox-1 and GLUT2 expression in cultured islets. Furthermore, sirolimus-treated diabetic recipient mice, as opposed to mock-treated controls, were associated with dyslipidemia. These data suggest that sirolimus, administered in the early posttransplantation phase, is a confounding factor for reduced islet engraftment and impaired ␤-cell function in transplants. Diabetes 55:2429 -2436, 2006 T he Edmonton protocol for islet transplantation depends on the infusion of ϳ10,000 IE (islet equivalents)/kg body wt, requiring multiple cadaver pancreata per diabetic recipient (1-4). Despite the implantation of such a large quantity of islets, Ͻ30% of transplanted islets can survive the procedure and gain stable engraftment, and yet the mechanism underlying the loss of a vast majority of islet mass in the early posttransplantation phase remains elusive (4,5). Unlike whole-organ transplantation, by which grafts are implanted as vascularized tissue, islets are transplanted as single islets or islet clusters that are considered avascular following collagenase digestion and isolation. Although residual endothelial cells in isolated islets may contribute to islet revascularization (6,7), adequate intraislet blood flow requires the formation of a functional microvascular network that links engrafted islets to surrounding tissues. These data suggest that microvascular perfusion to newly transplanted islets does not resume immediately after transplantation and can take up to 2 weeks before the reestablishment of a functional microvasculature in islet grafts (8,9). This delay in islet revascularization can potentially deprive islets of oxygen and nutrients, resulting in islet cell death, particularly within the core of engrafted islets. There is mounting evidence that impaired islet revascularization is an independent factor that limits the success rate...

A low-risk ZnT-8 allele (W325) for post-transplantation diabetes mellitus is protective against cyclosporin A-induced impairment of insulin secretion

“…16 In contrast, rapamycin inhibits the mammalian target of rapamycin without affecting calcineurin activity as well as inhibiting GSIS in b-cells. 26,31 Although the therapeutic ranges of tacrolimus and rapamycin are comparable, the potency of rapamycin in inhibiting insulin secretion seemed to be much lower than that of tacrolimus in this study. This may partly explain why rapamycin has less diabetogenic activity.…”

“…We compared two immunosuppressive drugs: rapamycin, which suppresses insulin secretion but not calcineurin activity, 26 and tacrolimus, which inhibits both. 16 Cells expressing ZnT-8 R325 that were treated with 5-500 nM tacrolimus (Figure 6a) and 0.02-2 mM rapamycin (Figure 6b) showed a similar pattern of suppression of insulin secretion.…”

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).…”

mTORC1 signaling and regulation of pancreatic β-cell mass

“…Rapamycin treatment has been shown to have mixed effects on insulin secretion, depending on the experimental conditions. [56][57][58][59] The role of mTORC1 in β-cell proliferation using rapamycin has been explored in multiple studies, which have resulted in five important observations. (1) Rapamycin treatment blocks β-cell expansion, cell size and proliferation induced by an activation of AKT in β cells.…”